Type 2 Diabetes Mellitus (T2DM) is a serious problem in the world. 5-Hydroxytryptamine  plays an important role in obesity, glucose control and insulin resistance. The polymorphism of the serotonin transporter gene linked promoter region (5-HTTLPR) might influence 5-HTT expression and serotonin uptake. The polymorphism results in two alleles of L (Long) and S (Short). The aim of the present study was to evaluate the association between 5-HTTLPR genotypes in type 2 diabetes mellitus (T2DM), obesity as well as serum biochemical profiles in Iranian population from 2012 until 2015.180 patients with T2DM and 180 controls were selected and the frequency of S and L alleles was determined by PCR. Then, the relationship between genotypes, body mass index (BMI) and serum biochemical variables was investigated.The frequency of S and L alleles in experimental and control groups was the same . However, the mean triglyceride, cholesterol, LDL-C, systolic and diastolic blood pressure levels in the diabetic subjects with LL genotype were significantly higher than LS and SS genotypes (p<0.001) in this population.The L allele of 5-HTTLPR was related to the increased serum lipids and blood pressure in the diabetic patients. However, there was no relationship between the polymorphism of 5-HTTLPR L/S and T2DM in Iranian population. Serotonin (5-hydroxytryptamine or 5-HT) synthesis occurs in the periphery within the gut neurons and enterochromaffin cells and centrally within the neurons of the raphe in the brain stem The serotonin transporter  is one of the important parts of serotonergic body system which is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain 5-HTT gene is located on chromosome 17 at 17q11.2-17q11.12 5-HTT gene expression. The transcription level of S allele is 2 to 3 times lower than L allele. Therefore, the cells carrying S allele have a lower number of 5-HTT as well as lower efficacy for re-absorption of serotonin The human Elimination of 5-HTC2 receptor gene in experimental mice led to insulin resistance and T2DM e.g., active smoking, quality of sleep, and diet).Our study suffered from some limitations, such as a relatively small sample size and a lack of data on the lifestyle habits of patients .A total of 180 patients with T2DM and 180 non-diabetic healthy control subjects  were randomly recruited from Iranian general population. Iranian patients with T2DM were recruited from Diabetes and Metabolic Disorders Specialty Clinic (Tehran) who came from all over Iran and were referred to that clinic from 2012 to 2015. The diagnosis of T2DM was based on the guidelines of WHO The members of the control group were randomly selected from sex and age matched healthy individuals who had no symptoms of T2DM who were referred to the blood transfusion organizations from approximately all over Iran. Written informed consent was obtained from the all the subjects. In addition, the study was approved by the Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran.ml blood sample was obtained from each subject after an overnight fasting. The serum samples were isolated and some of biochemical parameters such as serum cholesterol, Triglyceride (TG), Fasting Blood Glucose (FBG) and glycosylated hemoglobin (HbA1C) were assessed by auto analyzer . BMI was calculated as the ratio of weight to the square of the height (kg/m2) 17. The blood pressure measurement was determined while the subjects were in the sitting position. Blood pressure was taken by using a periodically calibrated mercury sphygmomanometer.A five et alµl containing 100 ng DNA, 2.0 mM MgCl2, 0.2 mM dNTPs, 0.4 mM of each primer, and 2 unit Taq DNA polymerase . The forward and reverse primers were:Forward: 5′ GGCGTTGCCGCTCTGAATGC3′Reverse: 5′ GAGGGACT GAGCTGGAC AACCAC3′Genomic DNA was extracted from white blood cells for each patient and healthy individual by using Qia Amp DNA Mini Kit . Then, the polymorphic promoter region was proliferated by polymerase chain reaction (PCR) as previously described by Nazem °C for 5 min and then the genome was amplified for 35 cycles. Each amplification cycle was performed at 94°C for 45 s, 60oC for 45 s, and 72°C for 45 s. The final extension was performed at 72°C for 5 min.The PCR was done with initial denaturation at 94bp fragment, those with LL genotype had a 528 bp fragment, and the individuals with (LS) genotype had two 484 bp and 528 bp bonds . Individuals with SS genotype had a 484 bp bonds .Statistical analysis of the data was accomplished using SPSS software version 11.5 . A p-value of less than 0.05 was considered statistically significant (p≤0.05). Descriptive data were presented as mean±standard deviation (Mean±SD) and the qualitative variables were shown based on percentage. Chi-square test was used to measure the deviation from Hardy-Weinberg equilibrium and compare the two groups regarding the frequency of the alleles and genotypes. Moreover, the OR (Odds ratio) and its 95% confidence interval were calculated using logistic regression analysis. Finally, student t-test was used to compare the quantitative variables between the control and the patient groups, while one way ANOVA was used to compare the quantitative variables between different genotypes.1C levels in the diabetic patients was significantly (p<0.001) higher than the control group. HDL cholesterol was significantly (p< 0.001) lower in diabetic than control group. Genotype frequencies were in Hardy-Weinberg equilibrium in both groups. The frequency of LL, LS, and SS genotypes was respectively 46.7, 40, and 13.3% in the diabetic patients and 42.2, 44.4, and 13.3% in the normal subjects  and those without S (LL)  and also between the patients carrying L allele (LS+LL) and those without L (SS) . Moreover, no significant differences were observed between the male and female subjects regarding the frequency of genes and alleles.1C, were not significantly different between the diabetic patients of different genotypes. The results of BMI showed that individuals who are not carriers for the long allele (SS) are known to be at risk for higher levels of obesity (p=0.029)  were significantly higher than subjects without L allele (SS) (p<0.001). Also, Systolic Blood Pressure (SBP) was significantly higher in patients with L (LL+LS) allele compared to subjects without L allele (SS) (p=0.013). However, the mean levels of other profiles, including FBG and HbAp=0.029) .Some studies were carried out in order to find the relationship between polymorphism of 5-HTTLPR and T2DM in different populations et al showed that in Greek population, S allele is a risk factor for T2DM which was independent of age and sex et al indicated that there was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in the Mexican population et al recently showed that there was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in Pakistani population et al confirms the difference in the alleles' frequency in various populations Iordanidou On the other hand, in Pakistani population, although the frequency of S allele (61%) was different in comparison with the results of our study (33.3%), there was no relationship between T2DM and 5-HTTLPR polymorphism et al reported the frequency of S allele (52.2%) in Kurdish population from western Iran Recently, Mohammadi et al in 2010 reported that the S allele related to serum TG increased in the diabetic patients but not cholesterol in population in south of Iran et al found that cholesterol levels were significantly greater in the LS heterozygotes than either LL or SS homozygotes in patients with heart disease. They mentioned that there was a significant association between LS heterozygosity and heart disease, angina, and heart attacks 28. So, it seems that the patients with T2DM carrying the L allele could be at high risk of heart disease.Nazam et al among adolescent and adult men from Argentina Also, a direct association was observed between the presence of S allele and the increase in BMI in diabetic patients. These results are in agreement with the reports of Sookoian This study completed and confirmed the previous work which was performed among the population in the south of Iran There were several limitations in this study. The first limitation is that most of the present population was selected from Iranians who were referred to Tehran for treatment and maybe new condition affected their serum profiles. Second, other genetic and environmental factors were ignored in the present study. On the other hand, maybe the number of subjects was not large enough in the current study and the lack of any association between 5-HTTLPR polymorphism and T2DM can be attributed to limited number of subjects.


Renal function decline is associated with progressive type 2 diabetes mellitus, which causes mineral and bone disorders. In the present study, we defined the ratio of urinary phosphate excretion (mg/day) to serum fibroblast growth factor 23 as the nephron index. We examined changes in the nephron index in type 2 diabetes patients with early stage chronic kidney disease (stages 1–3), enrolling 15 patients and retrospectively analysing the follow-up data. After follow-up at 5.4 years, we observed no significant changes in the estimated glomerular filtration rate; the nephron index, however, was significantly reduced between the baseline and the follow-up. We propose that the nephron index may be potentially useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic chronic kidney disease patients. Several biomarkers relevant to bone and mineral metabolism in chronic kidney disease (CKD)—for which type 2 diabetes mellitus (T2DM) is an important risk—are associated with cardiovascular complications. Among them, serum levels of fibroblast growth factor 23 (FGF23) have been identified, from as early as stage 2 CKD, as one of the earliest biomarkers that start increasing, and correlate with cardiac hypertrophy, heart failure, and all-cause mortality , 2.Following phosphate intake, the bone secretes the peptide hormone FGF23, which acts on the kidney to induce urinary phosphate excretion, thereby maintaining the phosphate balance. However, for several hours after oral phosphate administration, T2DM patients reportedly showed higher serum phosphate and lower serum FGF23 levels than nondiabetes patients, even when there was no difference in their renal function [FGF23 exerts phosphaturic activity through its ability to suppress phosphate resorption in the renal proximal tubule. FGF23 is thus thought to correlate with phosphate excretion per nephron. Namely,on index , 5.In a recent cross-sectional study, we reported the nephron index to be decreased in T2DM patients with stages 1–3 CKD and associated with macrovascular complications . In the 2. Because 3 patients had incomplete urine collection records, we did not consider them for this study, and finally we analysed the present data for 15 patients . Daily phosphate intake had been managed between 600 and 700 mg/day by a nutritionist. We used fasting blood samples to measure 24 h urinary phosphate excretion (mg/day) and other mineral and metabolic parameters. We collected the clinical parameters based on medical records and laboratory data. Intact FGF23 had been measured using an enzyme-linked immunosorbent assay (ELISA)  in our previous study [2) = 194 × serum creatinine (mg/dL)−1.094× age−0.287× 0.739 . Baseline and follow-up eGFR was calculated by blood test for each hospitalization. We compared the data relating to the two dates using a paired t test. Data are expressed as the mean ± standard deviation or median with interquartile range. We considered a p value < 0.05 to be statistically significant. We performed all analyses using EZR , a graphical user interface for R  and a modified version of the R Commander (ver. 1.6-3), with additional frequently used biostatistical functions [We enrolled 18 patients with T2DM who had been admitted twice to Jichi Medical University Saitama Medical Center for diabetes control between October 2006 and January 2017 depending on the 2-week diabetes education program. The 24-hour urine collections were performed 10 days after the hospitalization. All the patients had an estimated glomerular filtration rate (eGFR) greater than 45 mL/min/1.73 mThis study was approved by the Ethics Committee at Jichi Medical University Saitama Medical Center (No. S17-007) and performed in compliance with the Declaration of Helsinki.2 and 75 ± 25 mL/min/1.73 m2, p = 0.082). However, we found a significant reduction in the nephron index from 13.7 ± 6.5 to 9.1 ± 4.6 (p = 0.001) and a significant elevation in the serum FGF23 from 43.3 ± 18.2 to 55.0 ± 20.8 ng/mL (p = 0.022). We did not find any change in fractional excretion of phosphate (FEP) (%) after the follow-up  ( p = 0.1999). The eGFR decline slope was −1.11 ± 2.64 mL/min/1.73 m2/year. During the follow-up, there were no cardiovascular events.The average age and follow-up period were 64 ± 8 and 5.4 ± 2.9 years, respectively . We obse= 0.211)  and in sIn this retrospective observational study, we detected the decline in renal function during the ~5-year follow-up period using the nephron index, but not the eGFR. We propose that the nephron index may potentially be useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic CKD patients.Up × V)/Pp) to creatinine clearance ( = (Ucr × V)/Pcr). Up is urinary phosphate concentration, V is urine volume (24 h), Pp is serum phosphate concentration, Ucr is urinary creatinine concentration, Pcr is serum creatinine concentration, and Ccr is creatinine clearance.Because the hormone FGF23 increases phosphate excretion per nephron, it is thought to correlate with FEP, which is defined as the ratio of phosphate clearance ( = (nephron  index × FGF23 for Up × V in (α-klotho, a coreceptor for FGF23, is reduced in the kidney, leading to FGF23 hyporesponsiveness, namely, FGF23 resistance in kidney [Higher serum FGF23 levels are, in fact, associated with higher FEP. However, in early to moderate CKD, some patients have a lower FEP than others with the same serum FGF23 level, suggesting the variability among individuals in renal sensitivity to FGF23. Those considered resistant to FGF23 because they exhibit low FEP relative to high FGF23 are associated with poor clinical outcomes . In the F23Ccr×Pp∴FEPFGF23Up×V=neph × V in (FEP=nephrThere were some limitations of the present study. The first limitation of our study is its small number and retrospective observational nature. Large-size, prospective studies are necessary to verify whether the nephron index is a useful predictor of the decline of CKD. Second, we could not examine the pathological analysis by using human kidney specimen. Pathological examination is necessary to validate whether nephron index reflects exact nephron numbers. Finally, we enrolled only uncontrolled type 2 diabetic patients who had undergone a second admission for diabetes control. In that sense, the participants of this study were highly selected, and the follow-up period was limited. Moreover, it will be necessary to compare the present results of nephron index with those in other renal diseases, such as glomerular diseases.In summary, the nephron index—defined as the ratio of urinary phosphate excretion to serum FGF23—holds promise as an indicator for clinical outcomes among CKD patients with similar renal function and as a noninvasive estimation of the residual nephron number. We might estimate residual nephron number by using nephron index and nephron index could be an early intervention target for CKD patients with type 2 diabetes. Further prospective and interventional studies using the nephron index are essential to establish its usefulness in the management of CKD patients.


Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) often develop hypertension in childhood or early adulthood. Although this could result in left ventricular hypertrophy (LVH), a major risk factor for cardiovascular morbidity and mortality, prior studies of LVH in ADPKD have yielded conflicting results. We estimated the prevalence of LVH using consensus echocardiography criteria and examined the independent association of ADPKD severity with LV mass in a contemporary cohort of ADPKD patients.2 were enrolled in a single-center study. Left Ventricular Mass (LVM) was quantified using 2D echocardiography, and LVH was defined using gender-specific cut-points of LVM and LVM indexed to body surface area (LVMI) from consensus guidelines. Total Kidney Volume (TKV) was quantified using Magnetic Resonance Imaging, and GFR was estimated from serum creatinine using the CKD-Epi equation. Multiple linear regression was used to estimate the association of TKV and eGFR with LVM and LVMI, adjusting for potential confounders.Adults with ADPKD and eGFR> 15 ml/min/1.73mp = 0.8) between those with and without HTN, and was similar (21.4%) after excluding those (N = 21) with known cardiac disease. Greater TKV and lower eGFR were directly correlated with greater LVMI . In multiple linear regression models accounting for potential confounders including blood pressure, greater TKV was positively associated with LVM (p = 0.04).Among 126 participants (78% with hypertension), median age was 46 years, median eGFR 63 ml/min/1.73 m2, and median [IQR] systolic blood pressure was 125 [116–133] mmHg. Prevalence of LVH was 21.4% as defined by LVMI and was not significantly different (In a contemporary cohort of ADPKD patients with well-controlled blood pressure, the prevalence of LVH is high, and ADPKD severity as reflected by TKV is independently associated with greater LV mass. These results may suggest a relationship between ADPKD pathophysiology and increased LV mass. Hypertension is a highly prevalent and often early manifestation of autosomal dominant polycystic kidney disease (ADPKD), and a major risk factor for cardiovascular morbidity and mortality , 2. TherIncreased left ventricular mass (LVM) and the development of left ventricular hypertrophy (LVH) are consequences of long-standing hypertension and strong predictors for risk of cardiovascular morbidity and mortality in the general population . Prior sIn this observational study, we examined the prevalence of LVH among a cohort of adults with ADPKD using echocardiography, defining LVH with contemporary guidelines and normative data. We also investigated the relationship of ADPKD severity with greater LVM, accounting for other risk factors that determine LVM. We hypothesized that LVH remains highly prevalent in ADPKD and correlates with greater ADPKD severity as quantified by kidney volume and renal filtration function.2 were excluded. Patients were not excluded based on prior or current cardiovascular disease. The study protocol was approved by the University of Maryland, Baltimore Institutional Review Board.Adults 18 years and older with ADPKD were enrolled into an observational cohort study at the Baltimore Polycystic Kidney Disease Center at the University of Maryland School of Medicine from June 2013 to March 2017. Patients with ADPKD as defined by Pei-Ravine criteria were included  eccentric. Among those with HTN, LVH defined by abnormal LVMI was present in 22 (22.4%) individuals, as compared to 5 (17.9%) among the minority of study participants without hypertension (p = 0.8). In a sensitivity analysis using allometric height to index LV mass, prevalence of LVH was 14.3% (N = 18).As shown in Table p = 0.8 and 1.0, respectively).After excluding the 21 participants (16.7% of cohort) with known overt cardiac disease, estimates of LVH prevalence  remained very similar to the results from all participants . In multivariate analyses accounting for demographic and anthropometric characteristics , greater TKV was significantly associated with higher LVM .In unadjusted analyses, greater TKV and lower eGFR were both significantly associated with greater LVM and LVMI  or after additional adjustment for SBP, hypertension and cardiac disease (p = 0.6). In this model, higher SBP was significantly associated with greater LVM (p = 0.02). We also regressed both TKV and eGFR on LVM (Table p = 0.7). Similar results were found when additionally adjusting for cardiac disease, SBP and hypertension , this relationship was attenuated after additional adjustments for SBP, cardiac disease and hypertension (p = 0.13).Since eGFR is derived from an equation as a function of age, race, and gender (factors which may relate independently to LVM), we further evaluated the association of serum creatinine (rather than eGFR) with LVM. Results showed that while serum creatinine was significantly correlated with LVM when accounting for demographic factors and body size (p = .04). This association remained significant when additionally considering eGFR  rather than unindexed LVM, without further adjustment for body size as covariates. As shown in Tables Among 126 adults with ADPKD, we found that left ventricular hypertrophy as assessed by 2D echocardiography was present among roughly 20% of patients, and this prevalence was not significantly different between subjects with and without hypertension. We further observed a linear association of greater total kidney volume with greater left ventricular mass, even after accounting for blood pressure, body size, and other risk factors. This observational study provides a contemporary analysis of the relationship between left ventricular mass and ADPKD. Our results confirm some previous findings and provide several key new insights.2 in men and 88 g/m2 in women in the present study, versus 125 g/m2 in men and 110 g/m2 in women in Chapman et al).Comparison of LVH prevalence across different studies is challenging because of differences in imaging techniques and LVH definitions, as well as variability in the characteristics of study participants. An early study from Chapman et al. reported a 41% prevalence of LVH using transthoracic echocardiography, with a prevalence of 48% among those subjects with hypertension . The preImproved blood pressure control may account for at least a part of the difference between our data and those presented in Chapman et al. Mean systolic and diastolic blood pressure in our participants were about 10 mmHg and 12 mmHg lower, respectively, compared with the cohort studied by Chapman et al. Alternatively, different definitions of LVH could explain the lower prevalence. We utilized a consensus definition which defined the upper limit of LVM based on gender-stratified normative values; in contrast, the prior study utilized a local healthy control population, among whom 16% was reported to have LVH.2; however, mean blood pressure in the HALT cohort was similar to that observed in the present study. Whether patient factors, differences in imaging modality, or the selection of the normative reference data explain the marked differences in LVH prevalence compared to our study and that of Chapman et al. is uncertain.In contrast, a more recent analysis of data from the HALT clinical trial, utilizing cardiac MRI , reporteThe prevalence of LVH in our ADPKD population is substantial when using gender-stratified LVM thresholds recommended by the ASE; however, there is debate regarding the appropriateness of indexing or stratifying LVH definitions based on age and race. Current clinical practice as consistent with ASE guidelines do not utilize age and race stratifications. In the present study, we found no independent associations of older age with greater LVM, supporting the use of age-independent LVH definitions for our primary analysis.There is likewise ongoing debate about the most appropriate methods for indexing LV mass for body size. Although prior studies of LVH in ADPKD used BSA to index LVM - and guidelines from the ASE likewise recommend BSA indexing – this may lead to an over-estimation of LVH in obese individuals. As expected, the prevalence of LVH was lower (14.3% vs. 21.4%) when LVMI was defined by indexing to allometric height rather than BSA. However, caution should be used when interpreting this LVH prevalence, considering the less robust normative data available for LVMI indexed to allometric height.We subclassified a majority of LVH cases (63%) as eccentric. We are not aware of prior reports on the relative LV geometry observed in LVH cases in ADPKD. We have previously reported a similar frequency (71%) of eccentric pattern of LVH among older community-dwelling adults with and without hypertension . Prior sWe found significant associations of greater total kidney volume with greater left ventricular mass even after accounting for differences in age, gender, and body size. Furthermore, these associations were not explained by higher blood pressure, the presence of diagnosed/treated hypertension, nor known cardiac disease. Prior studies also reported significant unadjusted associations of kidney volume with greater LVM by echocardiography or Cardiac MRI, but these associations were not observed after accounting for other patient characteristics including renal function, blood pressure, age, and gender . Total K2 in neither unadjusted nor adjusted analyses. However, the study by Chapman et al., [p = .05) associations of higher serum creatinine with greater LVMI, although the magnitude of this association was not reported. As serum creatinine concentrations and even estimating equations for GFR are insensitive for detecting differences in true GFR when GFR > 60 ml/min/1.73m2, the relationship of eGFR and serum creatinine with LVM may only be apparent among ADPKD patients with more advanced renal functional impairment. Furthermore, detectable decline in eGFR may be a later manifestation of ADPKD, observable only after substantial nephromegaly has occurred.In contrast, although lower eGFR was modestly associated with greater LVM in unadjusted analyses, no associations were observed after accounting for demographic factors and body size. Likewise, Perrone et al.  found no et al.,  conducte2, when using cystatin C-based eGFR equations, among 2400 younger adults without ADPKD. These results suggest a possible association of mild kidney disease with greater LVMI among those without ADPKD. The use of a less sensitive creatinine-based estimating equation and the smaller sample size in our study may have precluded detecting more modest associations [Of note, Bansal et al. recently reported modestly greater LVMI associated with eGFR 60–75 ml/min/1.73mciations .rds of participants were on current treatment with RAAS inhibitors.Our findings of a notably greater prevalence of LVH in ADPKD patients, and significant independent associations of TKV with greater LV mass, support the hypothesis of a relationship between ADPKD and progressive hypertrophy of the left ventricle. Several mechanisms have been proposed to account for this relationship. The relationship between ADPKD and higher blood pressure has been extensively documented in both adults and children –23, and It is also important to note that the association between TKV and LVM, though significant, is only modest to moderate in magnitude. Thus, while ADPKD severity alone can impact LVM independent of blood pressure and other factors, and as such suggest a biological relationship of ADPKD severity with LVM in adult ADPKD patients, the clinical implications of this association may be modest. Furthermore, while LVH is potentially reversible with proper BP control, LVH may still remain as a complication of past uncontrolled hypertension (not assessed in this study). Therefore, we do not suggest that TKV can be considered as a reliable predictor for the presence or absence of LVH, nor that the relationship between ADPKD and LVH is completely independent of blood pressure.This was a single-center study, although conducted within a tertiary subspecialty PKD center with a large geographic referral base in the Mid-Atlantic US. Results may not be generalizable to other regions. The study cohort was largely Caucasian, with insufficient number of ethnic/racial minorities to examine LVH prevalence and correlations separately in these subgroups. This study had only a moderate sample size, which makes analyses vulnerable to imprecisions in LVH estimates and leads to limited power to detect smaller associations of patient factors with LVM. Echocardiography is the most widely used method in clinical practice for the detection and quantification of LVH, but this imaging modality has substantially greater measurement error than cardiac MRI. Blood pressure measurements were acquired in a single office setting as opposed to 24 h measurements and may not reflect overall blood pressure control. Past history and duration of uncontrolled hypertension, which may lead to increased LVM, were not assessed. We attempted to minimize measurement variability between subjects by utilizing a central echocardiography laboratory and standardized technique for all participants. To the extent that measurement error would be expected to occur at random with regards to PKD severity, such random error would be expected to lead to a bias towards the null hypothesis of no association between TKV and LVM/LVMI.In this observational cohort study, we found that adult ADPKD patients have a higher prevalence of LVH as evaluated by echocardiography compared to the normal healthy population, and that ADPKD disease severity as measured by TKV is significantly correlated with increased LVM after accounting for well-known covariates such as gender, race, age, body size, blood pressure, cardiac disease, and history of hypertension. Further investigations are needed to more clearly validate these associations and elucidate underlying mechanisms.


There has been limited data discussing the relationship between apparent treatment-resistant hypertension (ATRH) and cardiovascular disease risk in patients receiving maintenance hemodialysis. We analyzed data for 2999 hypertensive patients on maintenance hemodialysis. ATRH was defined as uncontrolled blood pressure despite the use of three or more classes of antihypertensive medications, or four or more classes of antihypertensive medications regardless of blood pressure level. We examined the relationships between ATRH and cardiovascular events using a Cox proportional hazards model. The proportion of participants with ATRH was 18.0% (539/2999). During follow-up , 931 patients experienced cardiovascular events including coronary heart disease (n = 424), hemorrhagic stroke (n = 158), ischemic stroke (n = 344), and peripheral arterial disease (n = 242). Compared with the non-ATRH group, the ATRH group showed a significant increased risk of developing cardiovascular disease , coronary heart disease , ischemic stroke , and peripheral arterial disease  even after adjusting for potential confounders. This study demonstrated that ATRH was significantly associated with increased cardiovascular risk in hemodialysis patients. Lowering blood pressure is associated with reduced risk of cardiovascular disease in patients with chronic kidney disease, including the dialysis population4. A meta-analysis reported that hypertensive dialysis patients are more likely to derive benefit from blood pressure lowering therapy5. Despite the use of multiple classes of antihypertensive drugs, dialysis patients often suffer refractory hypertension likely because of population-specific treatment resistance factors including expanded extracellular fluid volume, activation of the renin-angiotensin and sympathetic nervous systems, and imbalances between vasodilators and vasoconstrictors such as nitric oxide and endothelin9.Hypertension is one of the most important risk factors for cardiovascular disease, and it remains an important contributor to the global health burden10. Accumulating epidemiological evidence shows that the prevalence of ATRH in patients with hypertension is approximately 3–30%11, and that ATRH is a powerful risk factor for cardiovascular disease in the general population14. The relationship between ATRH and cardiovascular disease has also been investigated in patients with chronic kidney disease. However, most studies were conducted in predialysis patients16. Therefore, there is not enough evidence to clarify the influence of ATRH on cardiovascular disease incidence in hemodialysis patients at this time. Considering the high prevalence of refractory hypertension in hemodialysis patients, it is important to clarify the precise relationship between ATRH and cardiovascular disease risk in this population. In this study, we analyzed data from the Q-cohort study, which is a longitudinal observational cohort of maintenance hemodialysis patients. The purpose of our study was to examine the association between ATRH and cardiovascular disease incidence among hemodialysis patients.A recent scientific statement from the American Heart Association defined apparent treatment-resistant hypertension (ATRH) as uncontrolled blood pressure with concurrent use of three antihypertensive medication classes, or four or more antihypertensive medication classes regardless of blood pressure level17. For our study, we recruited 3598 outpatients aged 18 years or older undergoing hemodialysis in 39 dialysis facilities between 31 December 2006 and 31 December 2007. Participants were followed prospectively until 31 December 2016. Exclusion criteria to determine the final analysis population are shown in the flow diagram in Fig. The details of the design of the Q-cohort study are described elsewhere10. Serum concentrations of albumin, calcium, phosphorus, and C-reactive protein were determined using standard methods17. The corrected serum calcium concentration was calculated depending on the serum albumin concentration based on Payne’s formula: corrected calcium (mg/dL) = observed total calcium (mg/dL) + .The main exposure was the presence of ATRH at baseline, and potential confounders were age; sex; dialysis vintage; presence of diabetes mellitus; history of cardiovascular disease; predialysis systolic blood pressure; predialysis diastolic blood pressure; serum albumin, corrected calcium, phosphorus, cholesterol, and C-reactive protein levels; Kt/V, normalized protein catabolic rate (nPCR); body mass index (BMI); use of antihypertensive agents; and dosage of erythropoiesis-stimulating agents (ESA) (per 1000 U/week increment). The ESA dosage for darbepoetin alfa administration was calculated by multiplying the dosage (µg) of darbepoetin alfa by 200. These data were collected by reviewing medical records. Blood samples were collected before starting dialysis. Controlled blood pressure was defined as SBP <140 mmHg and DBP <90 mmHg. ATRH was defined as uncontrolled blood pressure with concurrent use of three antihypertensive medication classes, or four or more antihypertensive medication classes regardless of blood pressure levelThe primary outcome was cardiovascular disease (CVD) incidence, which was defined as the development of coronary heart disease (CHD), stroke, myocardial infarction, subarachnoid hemorrhage, and/or peripheral arterial disease (PAD). CHD was defined as myocardial infarction, hospitalization for unstable angina, and/or coronary intervention (coronary artery bypass surgery or angioplasty). Stroke was defined as a persistent symptomatic neurological deficit diagnosed using brain imaging. PAD was defined as critical limb ischemia requiring amputation or revascularization. The secondary endpoint was a composite of cardiovascular death, non-fatal CHD and non-fatal stroke . Participants’ health status was checked annually by local physicians at each dialysis facility. When the patient moved to another dialysis facility where a collaborator of this study was not present, we conducted follow-up surveys by mail or telephone. The events were determined on the basis of patients’ medical records.18. Furthermore, we also tested the functional form of continuous covariates in the fitted Cox models using Martingale residual analysis19. All models were adjusted for potential risk factors for cardiovascular outcomes including age; sex; dialysis vintage; presence of diabetes mellitus; history of cardiovascular disease; serum levels of albumin, corrected Ca, phosphorus, total cholesterol, and log-transformed C-reactive protein; Kt/V; nPCR; BMI; and ESA dosage. Statistical analyses were conducted using the SAS software package  and the STATA software package . A two-tailed P-value < 0.05 was considered statistically significant.Group differences in continuous variables were determined using the t-test; categorical variables were compared using the chi-square test. The incidence rates and 95% confidence intervals (95% CI) for mortality and cardiovascular events were calculated using the person-year method. Poisson models were fitted to estimate incident rate ratios (IRR) and 95% CI for each event. Multivariate-adjusted hazard ratios (HR) with 95% CI for each risk factor for developing cardiovascular events were calculated using a Cox proportional hazards model. The proportional hazards assumption was assessed graphically by examining plots of log and tested using analysis of Schoenfeld residualsFrom a total of 3598 enrolled dialysis patients, 2999 participants (83.4%) were included in these analyses, and participants’ baseline characteristics are shown in Table The median follow-up period was 106.6 months , during which 1484 (49.5%) patients died from all-cause including 546 (18.2%) fatal cardiovascular events and 931 (31.0%) patients experienced cardiovascular events and 424 (14.1%) patients developed CHD. One thousand one hundred and eighty-three participants (39.5%) experienced MACE. The event-free survival rate of each outcome was lower among patients with ATRH compared with those without ATRH  trial26. Also, a history of cardiovascular disease is presumed to be associated with increased atherosclerotic burden. ESA dosage was also found to be a powerful determinant of ATRH. ESA has a direct blood pressure-elevating effect regardless of its erythropoietic effect and blood rheology effect27. Plausible mechanisms include increased adrenergic sensitivity and changes in hemodynamics via elevated vascular endothelin-1 level and vasoactive hormone activation28. Also, lower BMI may reflect a patient’s poor nutritional status. With these considerations, it is reasonable to assume that malnutrition and ESA hyporesponsiveness might be closely related to the pathophysiology of ATRH in hemodialysis patients.Our results also identified the risk factors associated with ATRH in hemodialysis patients. An independent association between younger age, shorter dialysis period, and ATRH may be explained by the adverse effects of insufficient educational guidance on lifestyle habits including salt restrictionAll-cause and cardiovascular mortality did not show a significant association with ATRH despite the increased incidence of cardiovascular events in patients with ATRH. We speculate that this may reflect a reduction in the risk of death after the onset of the event due to the effect of secondary prevention, including strengthening drug interventions and lifestyle modifications. Since secondary prevention after the onset of the cardiovascular events may reduce the risk of subsequent cardiovascular mortality, the relevance between ATRH at baseline and 10-year mortality may probably be weaken over time, which might bias the results toward the null hypothesis. Unfortunately we do not have any information after the event on changes in clinical parameters such as blood pressure, lipids or therapeutic interventions. We believe that the significance of ATRH for secondary prevention of CVD should be addressed in our future researches.29. Second, medication nonadherence may also have increased cardiovascular risk in the ATRH group. The estimated prevalence of “pseudo-resistant hypertension”, which is elevated blood pressure secondary to white-coat hypertension, inaccurate blood pressure measurement, or medication nonadherence, is presumed to be as high as approximately 33% of resistant hypertension cases11. Finally, unmeasured residual confounders may explain part of the association between ATRH and cardiovascular disease. Excessive circulating aldosterone following activation of the renin angiotensin and sympathetic nervous systems, fluid retention, sleep apnea, and arterial stiffness and remodeling may contribute to the pathophysiology of ATRH31, and these conditions may be independently related to increased cardiovascular disease risk.We found a significant association between ATRH and the incidence of cardiovascular disease, CHD, ischemic stroke, and PAD in our hemodialysis patients. We hypothesize that multifactorial mechanisms contribute to the increased cardiovascular disease risk among these patients. First, a possible longer period of exposure to elevated blood pressure in the ATRH group may have resulted in more severe arteriosclerosis than in non-ATRH patients secondary to accumulated blood pressure burdenThis study has several limitations. First, the single-time blood pressure measurement could have resulted in misclassification of participants into different blood pressure categories. Second, we did not exclude pseudo-resistant hypertension in our patient selection. This exclusion is required to determine the true ATRH prevalence and its influence on cardiovascular outcomes, and can be addressed by electronic pill bottle monitoring, pill counts or therapeutic drug monitoring, standardized blood pressure measurements, and 24-h ambulatory blood pressure monitoring. Third, we could not examine the influence of ATRH on the development of myocardial infarction due to the lack of information on a detailed list of CHD. Finally, we could not obtain data for potential secondary causes of treatment-resistant hypertension including renovascular hypertension, thyroid disease, primary aldosteronism, and sleep apnea syndrome. Despite these limitations, we believe that our findings provide useful insights that highlight the influence of ATRH on cardiovascular outcomes in maintenance hemodialysis patients.In conclusion, our study revealed that ATRH was significantly associated with increased risks of cardiovascular disease, CHD, ischemic stroke, and PAD in hemodialysis patients. Further studies are needed to determine whether interventions to ATRH regulatory factors improve cardiovascular prognosis in maintenance hemodialysis patients.


Previous studies have found suboptimal control of symptom burden to be widespread among patients with asthma and chronic obstructive pulmonary disease (COPD). The Phase IV SPRINT study was conducted in 10 countries in Europe to assess asthma disease control and COPD symptom burden in patients treated with a fixed-dose combination (FDC) of inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs). SPRINT included 1101 patients with asthma and 560 with COPD; all were receiving treatment with an FDC of ICS/LABA, delivered via various inhalers. Data were obtained over a 3-month period, during a single routine physician’s office visit. Asthma control was defined as Asthma Control Test (ACT) score >19. COPD symptom burden was assessed by COPD Assessment Test (CAT), with a CAT score <10 defining low COPD symptom burden. Among patients using any ICS/LABA FDC, 62% of patients with asthma had achieved disease control (ACT score >19) and 16% of patients with COPD had low symptom burden (CAT score <10). The convenience of having both substances in a single inhaler may help improve treatment adherence and is often cost saving, compared with using two separate inhalers.13 In April 2014, marketing authorisation was granted for DuoResp® Spiromax®, a budesonide/formoterol combination treatment alternative to the existing Symbicort Turbuhaler, which contains the same active substances but uses a different dry powder inhaler (DPI) mechanism with fewer preparation manoeuvres.14Combined inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) treatments play a central role in the management of persistent asthma (Step 3 and above)The present real-world observational study was conducted to obtain a cross-sectional overview of asthma disease control and COPD symptom burden among patients receiving treatment with an FDC of ICS and LABA administered twice daily using a DPI. Additional aims of the study were to evaluate patient adherence in a real-world clinical practice population and to collect information on the patients’ background and their healthcare utilisation, in order to assess the relationship between these factors and disease burden. Another purpose of the study was to analyse clinical data among patients using the FDC budesonide/formoterol DuoResp Spiromax inhaler. The data on DuoResp Spiromax adherence, satisfaction, and ease of use will be reported separately.A total of 1138 patients with asthma were enrolled in the study. Enrolment by country is presented in Supplementary Table A total of 596 patients with COPD were enrolled in the study. Enrolment by country is presented in Supplementary Table 1) % predicted was 81.7% (23.1) in the asthma cohort and 58.3% (23.6) in the COPD group.Patient demographics are presented in Table In the overall asthma population, 684 patients 62.4%) had an Asthma Control Test (ACT) score >19 and were considered to have achieved disease control at the time of the assessment, after ≥3 months of FDC inhaler use  questionnaire. A greater proportion of patients in the COPD group had high adherence compared with patients in the asthma group . Table Table Healthcare resource utilisation in the 3 months preceding the study was determined. In the total cohort, asthma- or COPD-related visits to a physician  and emergency department  and hospitalisations lasting >1 day  were rare events.15 and the 2014 REcognise Asthma and LInk to Symptoms and Experience (REALISE) study conducted across Europe (20%).16The results of this observational study of patients receiving inhaled maintenance treatment with ICS/LABA FDC showed that almost two-thirds of asthma patients met the threshold for asthma control (ACT score >19). The rate of asthma control in the SPRINT study (62.4%) was higher than the pan-European rate reported in the International Cross-Sectional and Longitudinal Assessment on Asthma Control (LIAISON) studies conducted in 2012–2013 (43.5%)16 This underestimation of disease control probably has a significant impact on asthma outcomes. A report by the Royal College of Physicians in the UK estimated that >65% of asthma deaths were associated with potentially preventable factors, including trigger avoidance, medication adherence, and regular medical follow-up.17Research has shown that asthma patients’ perceptions of disease control are often at odds with more objective measures of disease control. For example, >80% of patients in the REALISE study considered their asthma to be controlled, and more than two-thirds did not consider their condition as serious, whereas in fact only one patient in five met the criteria for controlled asthma.18 However, all patients classified had mild-to-moderate COPD. Most patients in the SPRINT cohort were elderly (median age 70 years). As symptoms become more difficult to manage as COPD progresses, the low rate of achievement of the pre-defined CAT score threshold in the SPRINT study COPD cohort is not unexpected. Taken together, these results suggest that a CAT threshold of 10 is probably too low to define low COPD symptom burden.19 In view of the lack of reversibility that is typical of COPD, the threshold might need to be adapted to the baseline severity of the disease.Comparatively few patients in the SPRINT study (15.5%) met the pre-defined criterion for low COPD symptom burden (CAT score <10). A recently reported multicentre, observational study in Europe classified 21% of COPD patients as ‘controlled’, using the same CAT score criteria.20 whereas the mean EQ VAS in our COPD cohort was 62.8. Asthma appeared to have less effect on overall health status; the mean EQ VAS in our asthma cohort was 74.3, which is within the average range for a 55-year-old person living in these European countries (72.0–81.7).20Significant negative effects of COPD on health-related quality of life are reflected in the health status scores reported among SPRINT study participants. For example, the mean EQ-5D-3L for a 70-year-old person (mean age of the COPD cohort) living in the European countries that were included in the SPRINT study is between 69.0 and 81.5,15 Consistent with previous reports of relatively inferior adherence among younger vs older patients using inhaled medications,21 SPRINT study participants with COPD were more likely than those with asthma to be adherent, with more than half having an MMAS-8 score indicative of high adherence. The rates of adherence and asthma control among participants in the SPRINT study were consistent with other recent reports of real-world studies in both asthma and COPD cohorts.22 As expected, adherence was markedly lower than is typically seen in clinical trials.The findings of the SPRINT study indicate that suboptimal adherence to inhaled treatment regimens is widespread among patients with asthma and COPD. In particular, only 34.4% of patients with asthma had an MMAS-8 score indicative of high adherence, and >30% had a score indicative of low adherence. Poor adherence leading to poor outcomes in patients with asthma was also seen in the LIAISON study, which used the 4-item Morisky Medication Adherence Scale (MMAS-4) and found that patients with uncontrolled asthma were more likely to have MMAS-4 scores indicative of low adherence than those with controlled asthma.24Relationships between disease control and other variables were explored for asthma patients using multiple regression. Although no model could be found that could explain most of the variance in the data, analysis findings suggested that male sex and higher education may be positively associated, and body mass index (BMI) negatively associated, with disease control. These observations are consistent with previous findings.27 However, even in adherent patients, other factors may influence outcomes. For example, inhaler technique is an important determinant of outcome, as it influences the dose of drug delivered to the lungs at each inhalation.6 Demographic factors may also influence disease control. For example, the LIAISON study found that females, those aged 40–64 years, and patients who were overweight or obese were less likely to achieve asthma control compared with males, other age groups, and those of normal weight, respectively.15 Other studies have confirmed the interaction between obesity and disease control in asthma. Scott et al. showed that, among asthma patients who are adherent to therapy, those who are obese (BMI >30 mg/m2) have difficulty achieving asthma control.28 Thirty percent of patients in the SPRINT cohort had a BMI >30 kg/m2, and the proportion of obese patients was similar in the asthma (30.6%) and COPD (30.1%) cohorts. This is slightly higher than the proportion of obese patients reported in the LIAISON study of European asthma patients (26.1%).15Previous research has linked adherence with clinical symptoms and outcomes.30 Owing to the stringent selection criteria that are typically applied, randomised clinical trial cohorts are poorly representative of the broader COPD population, most of whom are treated in primary care.32 Comorbidities, which may be a reason to exclude patients from randomised clinical trials,32 were present in 83.5% of COPD patients in the SPRINT study. This is higher than the prevalence of significant comorbidity reported in a Norwegian study of COPD patients seen in primary care or hospital outpatient clinics (60.7%)32 but lower than the prevalence reported in US COPD patients (96.4%), according to the National Health and Nutrition Examination Survey, 1999–2008.30 Furthermore, the mean age of COPD patients in the SPRINT study, 69.5 years, was markedly higher than is typical for large randomised COPD studies, for which Kruis and colleagues reported a mean age of 63.7 years.31COPD patient demographics showed that participants receiving an ICS/LABA FDC in this study covered the range of COPD subtypes encountered in routine clinical practice .33 However, the SPRINT study also has some limitations. As an observational study, it is subject to confounders and potential bias. For example, assessments by patients were subject to recall bias and reporting bias (e.g. with regard to adherence). Wherever possible, attempts were made to minimise recall bias by using patient records to assess preceding medical visits. In addition, this study was not designed to assess the comparative effectiveness of different ICS/LABA FDC inhalers, and the findings likely describe a class effect rather than the effect of any specific type of inhaler.Strengths of the SPRINT study include the pan-European context, involving 10 countries from across Europe, and the generalisability to the population of patients seen in everyday clinical practice. The study included all patients with asthma or COPD receiving twice-daily ICS/LABA FDC and did not exclude anyone on demographic or clinical grounds. Another strength is the inclusion of patient-reported outcome measures that are widely used and validated in COPD and asthma populations.The results of this observational clinical study showed that the majority (62%) of asthma patients using ICS/LABA FDC inhalers meet the threshold for asthma control in real-world clinical practice and that the burden of symptoms for COPD in real-world clinical practice is high. Adult patients with asthma and COPD have a high rate of comorbidities, but adherence to ICS/LABA therapy in real-world asthma and COPD patients is low.In conclusion, this large, observational study in adult patients with asthma and COPD across 10 countries in Europe found that more than half of asthma patients using any ICS/LABA FDC inhaler met the threshold for asthma disease control. The pre-defined threshold for low symptom burden was met by few patients with COPD; however, this is probably to be expected in a chronic disease with an overall more advanced patient population than for asthma. Suboptimal adherence was widespread, particularly among asthma patients. Both patient populations had a high rate of comorbidities, and many of the patients would have been ineligible to participate in recent randomised controlled trials of asthma and COPD medications. The findings of the SPRINT study highlight the need for more attention by European physicians on patient-reported symptoms and adherence in the asthma and COPD patients they see in clinical practice.This was a Phase IV, multi-country, observational, prospective study in patients with asthma or COPD who were on a stable dose of ICS/LABA FDC administered by DPI twice daily. The study was performed between May 2015 and April 2017 at 140 centres in Croatia (15 sites), Denmark (7), Ireland (7), Italy (25), The Netherlands (7), Norway (4), Portugal (10), Spain (39), Sweden (2), and the UK (24). Prior to study initiation, Independent Ethics Committee approval was obtained from all relevant national or regional bodies.Data were collected for the whole population of patients receiving any ICS/LABA treatment in a routine setting . Participating physicians did not perform any additional medical procedures, other than those that were part of routine practice. All treatment decisions were at the sole discretion of participating physicians.Patients were eligible to participate if they had a diagnosis of persistent asthma or COPD in accordance with the GINA or GOLD reports, respectively, and were receiving treatment with a stable dose of an ICS/LABA FDC, administered twice daily by DPI for 3 months prior to enrolment. Dose stability was defined as no change in dose by >50% in the past 3 months. Patients with asthma were eligible to participate if they were aged ≥18 years, and those with COPD could participate if they were aged ≥40 years and/or a current or ex-smoker with a smoking history of >10 pack-years. In addition, all participants had to agree to participate in the study and to disclose any medical events to the treating physician and to be willing and able to provide written informed consent and complete the questionnaires. The only exclusion criterion was that patients could not currently be, or plan to be, enrolled in an interventional study.34 The burden of COPD symptoms was evaluated using CAT.35 Patients rated their own adherence to therapy using the MMAS-8 questionnaire.38 Patients also rated their general health status using the EQ-5D-3L questionnaire.39 The two-part questionnaire is comprised of the EQ-5D descriptive system and the EQ VAS, which measure 5 dimensions  on a 3-point scale and self-rated health on a VAS, respectively.Demographic and clinical characteristics  were collected from the patient’s medical records by the investigational centres. During the study visit, the patient’s respiratory disease burden was evaluated by a series of paper questionnaires, completed by patients in their local language. Asthma disease control was assessed using the ACT questionnaire.The primary endpoint was the percentage of patients whose respiratory disease was well controlled, which was defined as having an ACT score >19 in patients with asthma and low symptom burden (defined as CAT score <10) in patients with COPD. Secondary endpoints were self-reported adherence based on the MMAS-8 score, health status defined by the EQ-5D-3L, and recent healthcare resource utilisation in terms of physician visits, emergency room visits, and hospitalisations lasting >1 day for asthma or COPD.A target sample size of approximately 792 patients with asthma and 648 patients with COPD was planned. Based on the calculated sample size, the half-width of the 95% confidence interval for the proportion of patients with asthma with controlled disease is 0.035 for all patients treated with ICS/LABA. Similarly, based on this sample size, the half-width of the 95% confidence interval for the proportion of patients with COPD with low symptom burden (considered controlled disease) is 0.032 for all patients treated with ICS/LABA. Statistical analysis was based on the Safety Set, which included all patients enrolled in the study in accordance with the inclusion criteria.All data  were summarised descriptively using number and percentage for categorical variables and mean (SD) or median and 25th and 75th percentiles, as appropriate, for continuous variables.t test. Hypotheses for t test were assessed using Kolmogorov–Smirnov test with Lilliefors correction  and Levene test (homoscedasticity). If homoscedasticity failed, Welch t test was considered instead; if normality failed, Wilcoxon test was considered, whether homoscedasticity failed or not. Pearson correlation was considered to assess the relationship between two continuous variables. If normality failed, Spearman and Kendall correlation were obtained instead. Unless otherwise stated, p values were two sided. For both the chi-square test and Fisher’s exact test, Phi was obtained as a measure of the effect size for 2 × 2 tables and Cramer’s V for tables with more than 2 rows. For the t test and Wilcoxon test, Cohen’s d and Cliff’s delta were provided, respectively, as a measure of the effect size.Test parameters for hypothesis testing are summarised in Supplementary Table In an exploratory analysis, multiple regression models were constructed to analyse the relationship between the dependent variable “disease control” variable (based on ACT or CAT scores) and several independent variables .At the end of the study, all data were pooled, and global analysis performed . No imputation was made for missing data.The study protocol was approved by the Hospital Universitario de Canarias, Spain; Lakemedelsverket and the National Ethics Committee, Sweden; 25 local Ethics Committees in Italy; The Foundation for the Code for Pharmaceutical Advertising, Netherlands; 10 local Ethics Committees in Portugal; one National Ethics Committee in the UK; one National Ethics Committee in Ireland; and one National Ethics Committee in Croatia.Further information on research design is available in the Supplementary MaterialReporting Summary


Neurological injuries remain the leading cause of death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Adequate blood pressure is of paramount importance to optimize cerebral perfusion and to minimize secondary brain injury. Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic variations after successful resuscitation are needed to assist a more individualized post-resuscitation care. Currently, no technique is available for bedside evaluation of global cerebral energy state, and until now blood pressure targets have been based on limited clinical evidence. Recent experimental and clinical studies indicate that it might be possible to evaluate cerebral oxidative metabolism from measuring the lactate-to-pyruvate (LP) ratio of the draining venous blood. In this study, jugular bulb microdialysis and immediate bedside biochemical analysis are introduced as new diagnostic tools to evaluate the effect of higher mean arterial blood pressure on global cerebral metabolism and the degree of cellular damage after OHCA.This is a single-center, randomized, double-blinded, superiority trial. Sixty unconscious patients with sustained return of spontaneous circulation after OHCA will be randomly assigned in a one-to-one fashion to low (63 mm Hg) or high (77 mm Hg) mean arterial blood pressure target. The primary end-point will be a difference in mean LP ratio within 48 h between blood pressure groups. Secondary end-points are (1) association between LP ratio and all-cause intensive care unit (ICU) mortality and (2) association between LP ratio and survival to hospital discharge with poor neurological function.Markers measuring cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic changes after successful resuscitation are urgently needed to enable a more personalized post-resuscitation care and prognostication. Jugular bulb microdialysis may provide a reliable global estimate of cerebral metabolic state and can be implemented as an entirely new and less invasive diagnostic tool for ICU patients after OHCA and has implications for early prognosis and treatment.NCT03095742). Registered March 30, 2017.ClinicalTrials.gov  contains supplementary material, which is available to authorized users. In comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA), anoxic brain injuries remain the leading cause of death . The oveReduced cerebral blood flow (CBF), which is mainly dependent upon mean arterial blood pressure (MAP), can result in brain ischemia and enhance secondary brain injury after cardiac arrest. Arterial hypotension may exacerbate brain injury following cardiac arrest because of ongoing cerebral hypoperfusion. Cerebral autoregulation is frequently impaired after cardiac arrest , 13, andWhen considering blood pressure goals, clinicians should balance the metabolic needs of an ischemic brain with the potential for overstressing a decompensated heart. Post-cardiac arrest myocardial dysfunction, caused by coronary infarction and ischemia–reperfusion injury, is common after CA and resuscitation. Excessive vasopressor use may cause increased afterload and augmented oxygen consumption of the heart, thereby aggravating the myocardial damage . High-doRandomized control trials addressing specific MAP targets in post-resuscitation care have not yet been performed. This study addresses strategies for neuroprotection and will randomly assign a total of 60 unconscious resuscitated patients after OHCA in a double-blinded one-to-one fashion to low (mean 63 mm Hg) or high (mean 77 mm Hg) MAP target.Secondary brain injury processes throughout the post-resuscitation period remain complex and involve numerous pathophysiological pathways that result from secondary ischemia and reperfusion injury. These include cerebral edema, inflammation, unbalanced CBF, and mitochondrial dysfunction . MarkersMicrodialysis (MD) allows biochemical variables of the extracellular interstitial fluid to be monitored continuously and provides data on substrate supply and metabolism at the cellular level in the brain . CerebraClinical MD monitors the supply of glucose and its metabolism via glycolysis to pyruvate, which under oxidative conditions enter the tricarboxylic acid cycle. During hypoxic conditions or if mitochondrial function is compromised, pyruvate is metabolized to lactate. Therefore, the LP ratio is used as a marker of aerobic versus “anaerobic” metabolism not requiring oxygen . High LPThe LP ratio obtained from MD of cerebral venous blood may be a sensitive indicator of impending cerebral damage and secondary neurological deterioration and might play a critical role in detecting the early responses of post-resuscitation care. The use of global cerebral MD may potentially aid clinicians in providing individualized and tailored brain resuscitation strategies that prevent secondary brain injury and lead to improved survival and neurological outcomes after cardiac arrest.Our group recently reported how it is technically simple and feasible to place an MD catheter in the jugular bulb and monitor biochemical variables related to global cerebral energy metabolism at the bedside during cardiac surgery . In the This study is a double-blinded, randomized, superiority clinical trial assessing the effect of different blood pressure levels on global cerebral metabolism in addition to TTM in adult comatose patients resuscitated from OHCA. Patients are enrolled at one Danish university hospital with a population background of about 1.3 million citizens for highly specialized cardiac care. The SPIRIT  2013 Checklist, together with the Statement, facilitated with drafting of the trial protocol  investigate whether the LP ratio obtained by MD of the cerebral venous outflow reflects a derangement of global cerebral energy state after OHCA, (b) investigate the effect of higher MAP on global cerebral metabolism and LP ratio in comatose patients resuscitated from OHCA, and (c) investigate the correlation between LP ratio and neurological outcome . The null hypothesis is that a higher MAP will not reduce LP ratio within 48 h compared with lower MAP.Comatose patients after OHCA admitted to the hospital with sustained return of spontaneous circulation (ROSC) are eligible for screening. Acute computed tomography (CT) scan or acute coronary angiogram performed before ICU admission is also included in this phase. The inclusion window is 220 min from ROSC to screening. Patients eligible for the trial must comply with all inclusion criteria according to Table Enrollment of patients will be performed by the attending physician who is not involved in data collection or assessment. Randomization of blood pressure target was performed by a computerized algorithm using STATA  in varying block sizes of 4, 8, and 12 patients. Baseline characteristics are obtained.OHCA patients are randomly allocated to either low- or high-blood pressure target during ICU stay: Allocation of patients resuscitated from OHCA to low- or high-blood pressure target during ICU stay):. The  first invasive blood pressure using the trial blood pressure module is marking the start of the intervention, most often coinciding with initiation of TTM. Interventions are considered emergency procedures, and study blood pressure measurement using the study blood pressure modules (HP/Philips M1006B Invasive Pressure module) is commenced as soon as possible after sustained ROSC, screening, and randomization. Study target blood pressure will be blinded. In half of the modules, the calibration factor will be adjusted in order to show the blood pressure measurements about 10% lower than the patients’ actual blood pressure at 100 mm Hg, and in half of the patients, the blood pressure measurements will be shown to be about 10% higher at 100 mm Hg. Targeting an MAP of 70 mm Hg during treatment in both groups will mean a blinded comparison of 63 and 77 mm Hg, both of which are within the usually acceptable ranges of blood pressure. A prospective, randomized, controlled clinical study has validated this method for double-blinded comparison of MAP targets in the ICU setting . The intMAP is increased by administration of (a) volume resuscitation until CVP is at least 10 mm Hg and distensibility index of the inferior vena cava is less than 12%, unless pulmonary edema is clinically apparent, and (b) norepinephrine (μg/kg per min solution) is administered in increments of 0.02 μg/kg per min until a dose of 0.2 μg/kg per min is reached. A higher dose will be used at the discretion of the attending physician; (c) dopamine (μg/kg per min solution) will be used in addition to norepinephrine at a maximal dose of 10 μg/kg per min.2), central venous, and pulmonary pressures were measured continuously by PAC  linked to the correct monitor . These data, together with information on blood temperature, oxygen saturation, and MAP measured from a radial artery line, were transferred electronically to a computer with a 2-second time interval. If echocardiography, and thermodilution suggest that low cardiac output addition of an inotropic agent may be appropriate). The following agents may be considered: (a) milrinone (0.375–0.75 μg/kg per min) and (b) levosimendan (0.1 μg/kg per min). If an inotropic agent at maximal dose combined with vasopressors cannot maintain cardiac output, mechanical circulatory support may be considered.As part of the routine hemodynamic monitoring, a pulmonary artery catheter (PAC) is inserted via the internal jugular or subclavian vein under ultrasound guidance. During ICU stay, cardiac index, mixed venous oxygen saturation (SvO2) values will be recorded simultaneously during ICU stay, and values will be recorded every hour for 96 h or until arousal.At ICU arrival, patients will be implanted with a jugular bulb MD catheter and monitored for 96 h or until arousal. MD samples are collected in microvials and analyzed every 1 h at the bedside. Regional cerebral oxygen saturation will be monitored by using bifrontal NIRS . Right and left frontal regional oxygen saturation (rSO2) of 4.5–6.0 in all patients.Patients will be mechanically ventilated, sedated, and when necessary paralyzed with neuromuscular blocking agents to reduce shivering and subsequent heat generation and energy consumption. The study is targeting normal oxygenation (13–14 kPa) during TTM and mechanical ventilation. Ventilation is adjusted, targeting normocapnia of partial pressure of carbon dioxide . The TTM intervention period of 24 h commenced at the time of randomization by using an automated feedback device with temperature control to achieve a target core temperature of 36 °C. After TTM, patients are rewarmed to a core temperature of 37 °C with no more than 0.5 °C per hour. Phase 2 ends when sedation is withheld.Sedation is terminated after rewarming when the temperature is at least at 37 °C. Normothermia of 37 °C ± 0.5 °C is maintained until 72 h after the cardiac arrest as long as the patients are managed in the ICU and are unconscious. Nevertheless, weaning from ventilation will be attempted at the earliest possible time during this phase on the basis of typical procedures for discontinuation of mechanical ventilation. Blinded physicians perform a neurological evaluation of patients who remain in coma at 72 h or later after OHCA. The number of patients still comatose at 72 h after the end of TTM who underwent neurological prognostication will be reported. The number of patients who died before neurological prognostication and their presumed cause of death, including limitations in care and explanations for that, will be described. If judged by attending physicians to be indicated, electroencephalogram, somatosensory evoked potentials, and CT of the brain will be performed.This starts when invasive blood pressure measurement is discontinued during the ICU stay.Neurological outcome will be assessed at hospital discharge in accordance with the CPC scale , 32: CPCVital status and neurological status (CPC) were evaluated at 3 months after admission by clinical examination or telephone interview. Vital status will be evaluated at the end of the trial by using the Danish civil registration system. The SPIRIT timeline of progress through the phases of the parallel-randomized trial is shown in Fig. Patients at least 18 years old with sustained ROSC after OHCA are eligible for inclusion if complying with all the criteria presented in Table Patients will be implanted with a jugular bulb MD catheter  and monitored for 96 h or until arousal. The catheter allows energy-related metabolites to diffuse into the catheter reflecting accurate concentrations in the venous blood, CE marked according to the Medical Device Directive, 93/42/EEC. MD catheters are inserted in a retrograde direction into the jugular bulb, through a peripheral intravenous 17 GA cannula by using ultrasound guidance, as performed in a previous study . The posThe study is enrolling at one university hospital with experience in conducting clinical trials. All investigators have been qualified and are licensed in “good clinical practice” (GCP).Patients were not involved in setting the research hypothesis or end-points, nor were they implicated in the design of the study. There are no plans to include patients in the dissemination of results, nor will we publish results directly to patients.The study focuses on the following end-points:Comparing mean LP ratio differences within 48 h between blood pressure groups and comparing individual LP ratio measurements using longitudinal analysis.Primary end-pointAssociation between LP ratio and all-cause mortality during ICU stay adjusted for blood pressure groups2 of not more than 50% during ICU stayBetween-group difference in total duration (minutes) of cerebral desaturation defined as an absolute rSOBetween-group difference within 48 h in lactate, pyruvate, glutamate, glycerol, and glucose measured in jugular bulbAssociation between LP ratio and cardiac index adjusted for blood pressure groupsAssociation between LP ratio and survival to hospital discharge with poor neurological function (CPC 3–4) adjusted for blood pressure groups.Secondary end-pointsThe sample size was calculated on the basis of the primary hypothesis but taking into account only the mean LP ratio and not the individual measurements; this was due to insufficient information about interpretation variation in LP values; this implies a conservative error and hence the true power of the study is expected to be higher than in this calculation. The trial is designed as a randomized study, and we have chosen to power this study according to differences in the LP ratio. A difference of 30% between groups is defined as the minimal clinically relevant difference. Assuming an average LP ratio of less than 20 over 48 h in the high MAP group compared with more than 35 over 48 h in the low MAP group, we will need to include 46 patients in total to achieve a power of 0.9 using a patient-to-patient variation with standard deviation (SD) of 15 in LP ratio as motivated by an earlier study  in the pAnalyses will be performed in accordance with the intention-to-treat principle and will take into account patients lost to follow-up.A two-sided significance level of 0.05 will be applied to both primary and secondary end-points.t tests or Mann–Whitney U tests will be conducted for unpaired comparisons of numerical variables. A chi-squared or Fisher’s exact test will be conducted to examine differences between categorical variables.Unpaired Association between LP ratio and “poor” neurological outcome (CPC 3–4) will be assessed with chi-squared test and logistic regression. The overall expected rates of unfavorable neurological outcome (CPC 3–4) are 5–7%, observed in earlier studies , 35. TheAssociation between LP ratio and all-cause mortality will be assessed with chi-squared test and logistic regression.Receiver operating characteristic (ROC) curves will be constructed to determine the sensitivity and specificity of the LP ratio levels at each time point  for predicting outcomes.2 ≤ 50%) and unfavorable neurological outcome (CPC 3–4) and death will be assessed with chi-squared test and logistic regression.Association between total duration (in minutes) of cerebral desaturation .A flowchart of the study participants will be presented in accordance with the Consolidated Standards of Reporting Trials (CONSORT) diagram , 37.SexAgeComorbidities Previous percutaneous coronary interventionPrevious coronary artery bypass graftPrevious valvular surgeryImplantable cardioverter-defibrillator or pacemaker or bothLocation of cardiac arrestBystander-witnessed arrestBystander cardiopulmonary resuscitationShockable primary rhythmTime to basic life supportTime to advanced life supportTime to ROSCPre-hospital variablesFirst measured temperatureGlasgow Coma Scale scoreShock at admissionPresumed cause of cardiac arrest (cardiac/non-cardiac)Acute myocardial infarctionSerum pHSerum lactateEnd-tidal carbon dioxideBlood pressureResult of angiogramCardiac troponin (TnI) and creatine kinase-muscle/brain (CK-MB).Admission variablesThe predefined baseline variables are the following:t test. In case of non-normally distributed data, continuous variables will be presented as median (interquartile range) and a t test will be applied following logarithmic transformation if the transformed data are normally distributed; alternatively, the non-parametric Mann–Whitney test will be applied. Categorical variables will be presented as counts and percentages and differences will be analyzed with the chi-squared test or Fisher’s exact tests if counts below 10 are observed.Differences in baseline variables between blood pressure groups will be analyzed and presented in tables. Continuous variables will be presented as mean ± SD, and differences will be analyzed with the unpaired The mortality of patients who are admitted in a comatose state to an ICU following successful resuscitation after cardiac arrest remains significant. The necessity for early and accurate prognostic predictors is important, especially since sedation and TTM might change the neurological examination and postpone the recovery of motor response for several days. Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic variations after successful resuscitation are urgently required to assist more personalized post-resuscitation care and prognostication.Jugular bulb MD may provide a reliable global estimate of cerebral metabolic state and can be implemented as an entirely new and less invasive diagnostic tool for ICU patients after OHCA and has implications for early prognosis and treatment. The LP ratio assessed from MD of cerebral venous blood may play a critical role in detecting the early responses of post-resuscitation care and may predict in-hospital and long-term prognosis in patients affected by brain injury after cardiac arrest. In the future, this might optimize and individualize the treatment of post-cardiac arrest patients and potentially improve outcome.The end-point defined as the LP ratio during ICU stay is a surrogate marker for poor neurological outcome and death. The surrogate marker is used as an alternative to a hard end-point in order to power this study adequately. Previously, LP ratio studies have been shown to be a reliable marker for poor outcome after traumatic brain injury –26. HencJugular bulb MD may provide a reliable global estimate of cerebral metabolic state and can be implemented as an entirely new and less invasive diagnostic tool for ICU patients after OHCA and has implications for early prognosis and treatment.This pragmatic trial is addressing the effect of higher MAP on global cerebral metabolism in patients resuscitated from OHCA.Randomized controlled trial design minimizes the risk of selection bias.Clinicians are not blinded to data obtained at the bedside from jugular bulb MD, so all outcome assessors will be blinded to minimize the risk of bias.Until now, no established gold standard method assessing global cerebral energy state has existed. Therefore, it is not possible to compare jugular bulb MD with an established method already in clinical use.Protocol version 1.1. Date: March 8, 2018. The study is ongoing and currently enrolling. Recruitment began January 11, 2017, and is expected to be completed around January 8, 2020.Additional file 1: SPIRIT  2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*. (PDF 144 kb)Additional file 2: Informed consent. (PDF 183 kb)


Haemodialysis (HD) which is a form of renal replacement therapy commonly prescribed for patients with chronic kidney disease (CKD). However, it is not without deleterious haemodynamic responses which may occur either during or immediately after the termination of the procedure. These may include hypotension or hypertension.This was a retrospective study that reviewed chronic kidney disease (CKD) patients on maintenance haemodialysis at the renal unit of University of Calabar Teaching Hospital, Calabar, Nigeria. In all, 71 patients were reviewed but only 64 patients had complete data for analysis. Socio-demographic, clinical and biochemical data were obtained from the records in the dialysis unit.There were more males 38 (59.4%) than females 26 (40.6%) in the study. The mean age was 51.71±15.43 years and 43.04±14.03years for males and females respectively. The prevalence of intradialysis hypertension 29 (45.3%) was higher than that of intradialysis hypotension 20 (31.3%) and the commonest cause of CKD requiring haemodialysis was diabetic nephropathy. The factors associated with intradialysis hypotension were lower post-dialysis systolic blood pressure (PDSBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and less number of antihypertensive medications; while the factors associated with intradialysis hypertension were higher post-dialysis systolic blood pressure (SBP), MAP, greater number of antihypertensive medications and longer duration of haemodialysis.Our study shows that there are several modifiable factors associated with blood pressure fluctuations among CKD patients on maintenance haemodialysis in the renal unit of the University of Calabar Teaching Hospital, Calabar. Haemodialysis which is a form of renal replacement therapy is usually a treatment modality for patients with advanced chronic kidney disease. However, this therapy is not without deleterious haemodynamic responses which may occur either during or immediately after the termination of the procedure, and may include hypotension or hypertension , 2. The urea [Intradialytic hypotension precludes the delivery of an adequate dose of dialysis, as hypotension episodes lead to the compartment effect and result in suboptimal Kt/Vurea . Despiteurea , 11. Theurea , 7, 12. urea . The exaurea , 14. Theurea , 7, 12 bThis was a retrospective study that reviewed CKD patients who were on maintenance haemodialysis at the renal unit of the department of internal medicine, UCTH for a two-year period from January 2014 to December 2016. In all, 71 patients were reviewed but only 64 patients had complete data for analysis. Ethical approval was sought and obtained from the Health Research Ethical Committee (HREC) of the UCTH. Patients' medical records were reviewed and information regarding the patients demography, blood pressure measurements by automated machine attached to the dialysis bed, laboratory investigations and haemodialysis prescriptions were extracted from the dialysis records and entered into a data extraction template. Intradialytic hypertension was defined as follows: an increase in systolic BP, post-dialysis systolic blood pressure (SBP) >10mm/Hg from pre-dialysis to post-dialysis , 15, an The inclusion criteria: they included patients on maintenance haemodialysis and patients aged between 18 and above.The study population: the study population was divided into three. Patients with intradialysis hypotension, those with intradialysis hypertension and those with no significant blood pressure changes during dialysis. The last group was taken as control. Patients who had less than three sessions of haemodialysis were excluded.Data analysis: the data obtained were analysed using Statistical Package for Social Sciences (SPSS) version 18. Continuous variables were expressed as means and standard deviations for normally distributed data. Categorical variables were expressed as percentages. Independent sample t-test, Chi-square test, ANOVA and other statistical tests were used as appropriate. P <0.05 was considered to be significant.Limitations of the study: this study is not without some limitations related to the sample size and analysis. For example, we had a small sample size and some parameters such as serum albumin, cholesterol and parathyroid hormone levels were not assessed. Secondly, intradialysis blood pressure changes and their influence on even short term clinical outcomes were not assessed. Thirdly, given the retrospective nature of this present study and missing data, no conclusions regarding cause and effect can be made. Finally, the BP parameters were obtained from an average of three dialysis sessions; however, prior studies have used 1 week averages of routine dialysis BP recordings.In This study has shown that the duration of dialysis as well as an increased number of antihypertensive medication use significantly affect blood pressure changes in an advanced CKD cohort with a higher frequency of diabetic patients. There were more males with higher mean age, which portrays the tendency for the development of CKD in older males and the commonest cause of CKD in patients on maintenance HD is diabetic nephropathy. These findings are in keeping with other studies -21. Furtet al. in their investigation of incident hemodialysis patients, showed that elevated pre-dialysis SBP (>160mm/Hg) was associated with lower mortality, and low post-dialysis SBP (<110mm/Hg) was associated with increased mortality [et al. found that neither pre-dialysis nor post-dialysis SBP was significantly associated with all-cause mortality after controlling for demographics, comorbid conditions, and percentage of interdialytic weight gain [Our study demonstrates that haemodynamic responses during haemodialysis were associated with pre-dialysis or post-dialysis systolic BP, diastolic BP or MAP. These changes have been demonstrated in other studies to be strongly associated with hospitalization or death. , 3. Howeortality  but a stght gain . In thiset al. further evaluated the relationship between intradialytic hypertension and interdialytic ambulatory blood pressure [Our study showed that the duration of HD is longer in subjects with intradialysis hypertension, although hypotension has been shown to be associated with longer duration of HD . Our finpressure , 27.In conclusion, intradialysis hypotension and intradialysis hypertension are present in 31.3% and 45.3% of patients on maintenance haemodialysis respectively. On one hand, the factors associated with intradialysis hypotension were lower post-dialysis SBP, DBP, MAP and less number of antihypertensive medications, while on the other hand the factors associated with intradialysis hypertension were higher post-dialysis SBP, MAP, greater number of antihypertensive medications and longer duration of heamodialysis.Intradialysis blood pressure fluctuations such as hypotension and hypertension are common complications during haemodialysis;Risk factors for intradialysis hypotension includes diabetic CKD, CVD, severe anemia, age ≥65, and predialysis systolic blood pressure <100mm/Hg;On the other hand, the risk factors for intradialysis hypertension include older patients, lower dry weights, prescription of more antihypertensive medications, and lower serum creatinine levels.This study investigates intradialysis blood pressure fluctuations among advanced CKD patients on maintenance HD;Longer duration of haemodialysis is a risk factor for intradialysis hypertension.The authors declare no competing interests.


An increasing amount of evidence has demonstrated an association between an increase in the level of tumor necrosis factor superfamily 13 (TNFSF13) and immunoglobulin A nephropathy (IgAN) progression. We aimed to evaluate if the level of pre-transplant serum TNFSF13 is predictive of IgAN recurrence after kidney transplantation.This analysis was based on the clinical and laboratory data of 69 patients with IgAN who underwent first kidney transplantation with no evidence of mesangial IgA deposits in zero-time transplantation biopsy. We measured pre-transplant serum TNFSF13, total IgA, and galactose-deficient IgA1 levels.The recurrence rate of IgAN over a median follow-up duration of 5.1 years was 15.9% (11/69 patients), with a mean time to the first recurrence of 1.7 years. The high pre-transplant TNFSF13 level was associated with IgAN recurrence after kidney transplantation among patients who received a graft from a living related donor.This study highlights association of TNFSF13 levels in recurrent IgAN patients who undergo living related donor transplantation. Further research is needed to clarify mechanisms by which TNFSF13 affects the recurrence of IgA nephropathy. Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis , 2, and TNFSF13 gene knockout mice showed impaired IgA antibody responses to mucosal immunization [TNFSF13 transgenic mice showed enhanced T-cell independent humoral responses [TNFSF13 locus has recently been identified as a susceptibility gene in a Han Chinese genome-wide association study of IgAN patients [Tumor necrosis factor superfamily 13 (TNFSF13), also known as a proliferation inducing ligand (APRIL), is secreted from antigen-presenting cells and is engaged in adaptive and innate immune responses by binding to receptors on B and T cells , 10. An nization . Conversesponses . The TNFpatients . The hig2. Clinicopathologic recurrence of IgAN after kidney transplantation was defined as a clinically evident disease with deteriorating renal function and identification of mesangial IgA deposits on immunofluorescence staining with mesangial hypercellularity in allograft biopsy tissue [Between January 2011 and October 2015, 80 patients with biopsy-proven IgAN underwent kidney transplantation at our institution. Among these patients, we enrolled 69 who underwent first kidney transplantation and did not show mesangial IgA deposits on biopsy at the time of kidney transplantation and have allograft biopsy data within one year after transplantation. The following information was extracted from medical records for analysis: age, sex, renal replacement therapy, the donor age and sex, number of human leukocyte antigen (HLA) mismatches, ABO mismatch, donor type, desensitization treatment, induction treatments administered, withdrawal of steroid treatment and acute rejection events and trough level of tacrolimus within one year after kidney transplantation. Highly sensitized patients defined as having panel reactive antibody higher than 50% [y tissue . Renal f2. The samples were frozen at − 80 °C until analysis. Serum levels TNFSF13 were quantified using an enzyme-linked immunosorbent assay (ELISA) kit , based on previously published methods [Helix promatia agglutinin. Serum Gd-IgA1 levels were expressed in U/mL, where 1 U of Gd-IgA1 was defined as 10.0 μg of standard, and 1 U/mL was expressed as 1 U/ng IgA after normalization to total IgA levels. We purified Gd-IgA1 from an IgAN patient’s plasma using immobilized Jacalin  for the Gd-IgA1 method, as previously reported [Of the 69 IgAN patients initially enrolled in the study, serum samples at the time of kidney transplantation to quantify pre-transplant TNFSF13 levels were obtained from 62 patients. We also recruited the serum samples from non-ESRD IgAN patients who had eGFR > 30 mL/min/1.73 m methods . Serum Greported .with and without recurrent IgAN after kidney transplantation. The data are presented as the mean ± standard deviation (S.D) for continuous variables and as proportions for categorical variables. Differences between recurrent and non-recurrent group were evaluated using the t-test for normally distributed continuous variables and Mann-Whitney U test for non-normally distributed continuous variables. The chi-squared or Fisher’s exact test was used for categorical variables. A Cox regression model was used to calculate the unadjusted and adjusted hazard ratios (HRs) and the 95% confidence intervals (CIs) for the factors that were associated with IgAN recurrence after kidney transplantation. The interaction terms between TNFSF13 and adjusted variables were confirmed by Cox analysis. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM®SPSS® software, version 21.0 .Comparisons were performed between patients with than without IgAN recurrence (p = 0.056). Pre-transplant serum TNFSF13 levels in the study population were significantly higher than in the 382 patients with non-ESRD IgAN (mean 1.75 ± 11.94 ng/mL)  and 29 women who underwent first kidney transplantation for ESRD due to biopsy-proven IgAN. At the time of transplantation, their mean age was 43.7 years Table . Over a p = 0.620). There was a significant interaction between pre-transplant serum TNFSF13 levels with living related transplantation for recurrent IgAN (p = 0.018). Pre-transplant TNFSF13 levels were associated with an increased risk of IgAN recurrence among patients who received a graft from a living related donor after adjusting the recipient’s age and follow up duration (Table p = 0.025). Patients who received a graft from a living related donor were dichotomized based on the median pre-transplant serum TNFSF13 level (9.97 ng/mL). Recurrence-free survival was significantly lower among patients with a pre-transplant serum TNFSF13 level greater than median values  registry, which has accumulated data over 30 years, showed that recurrence of IgAN was 5.1, 15% at 5, 15 years after kidney transplantation . The ratThe present study has several limitations. The number of total subjects and events in the present study was too small to obtain the predictive value of TNFSF13 for recurrent IgAN. Relatively shorter follow up duration was also a limitation of the present study. TNFSF13 was only associated with living related transplantation, and the predictive value was not shown. Further studies in the sufficient number of cohorts are needed to confirm these findings and to show cut off values for the predictive value of TNFSF13.In summary, we identified an association between pre-transplant serum TNFSF13 levels and IgAN recurrence among patients who received a graft from a living related donor. Our findings suggest that there may be a possible role of TNFSF13 in IgAN recurrence among patients who undergo living related donor graft transplantation.This study provides evidence to suggest that pre-transplant serum TNFSF13 levels is associated with recurrent IgAN who had living related transplantation. Regarding the concern of recurrence of IgAN on graft function, these results require further studies to validate the role of TNFSF13 in the recurrence of IgAN.