The effect of active acupoints versus inactive acupoints in treating hypertension is not well documented. Metabolic phenotypes, depicted by metabolomics analysis, reflect the influence of external exposures, nutrition, and lifestyle on the integrated system of the human body. Therefore, we utilized high-performance liquid chromatography tandem mass spectrometry to compare the targeted metabolic phenotype changes induced by two different acupoint treatments. The clinical outcomes show that active acupoint treatment significantly lowers 24-hour systolic blood pressure but not diastolic blood pressure, as compared with inactive acupoint treatment. Furthermore, distinctive changes are observed between the metabolomics data of the two groups. Multivariate analysis shows that only in the active acupoint treatment group can the follow-up plasma be clearly separated from the baseline plasma. Moreover, the follow-up plasma of these two groups can be clearly separated, indicating two different post-treatment metabolic phenotypes. Three metabolites, sucrose, cellobiose, and hypoxanthine, are shown to be the most important features of active acupoint treatment. This study demonstrates that metabolomic analysis is a potential tool that can be used to efficiently differentiate the effect of active acupoints from inactive acupoints in treating hypertension. Possible mechanisms are the alternation of hypothalamic microinflammation and the restoration of host-gut microbiota interactions induced by acupuncture. A randomized controlled trial demonstrated that acupuncture as an add-on treatment can significantly reduce 24-hour ambulatory blood pressure for essential hypertension (EH) patients2. Other studies have indicated that acupuncture might be particularly effective to lower blood pressure in prehypertension and stage I hypertension3. In addition, acupuncture has been shown to be helpful for patients with EH by improving the circadian blood pressure rhythm, which is a main indicator of EH-associated target organ damage4. Systematic reviews have found that acupuncture is associated with a low adverse event rate6. Basic studies show that acupuncture may reduce sympathetic outflow and reflex elevations in blood pressure by regulating neurotransmitters in the rostral ventrolateral medulla (rVLM), arcuate, and ventrolateral periaqueductal grey (vlPAG), thereby lowering blood pressure7. Enhanced NO/NOS activity also plays an important role in the therapeutic effect of acupuncture for hypertension8. However, acupoint selection is still controversial, since it is still debatable as to whether some acupoints are more specific to certain diseases (termed ‘active acupoints’) than others (‘inactive acupoints’). This is especially true for the treatment of hypertension treatment. For example, two studies compared different acupoint selection protocols and yielded opposite results9, confusing researchers and clinicians. Studies by Longhurst et al. addressed the difference in efficacy between active and inactive points, highlighting that the acupoint and meridian may lie within the line of nerve innervations. They went on to explain that stimulating acupoints triggers nervous reflexes, transferring the acupuncture signals to the central nervous system, yielding cardiovascular regulation12. However, existing relevant studies are insufficient to form any solid conclusions.The history of acupuncture for treating cardiovascular diseases (CVD) is profound. Today, acupuncture is still one of the most popular alternative therapies for hypertension13. In systems biology14, metabolomics may enable a comprehensive elucidation of the biological change within a living organism caused by environmental exposures15, such as nutrition or lifestyle. As such, metabolomics is used to systematically characterize the change in a metabolic profile and selecting metabolites is considered a critical tool in understanding the possible mechanism behind blood pressure regulation. Recently, metabolic dysfunction in patients with hypertension has been increasingly emphasized20. Studies demonstrate that by using metabolomic analysis, new disease biomarkers and novel metabolic pathways associated with the pathogenesis of hypertension can be identified22. Because acupuncture is a holistic therapy that exerts comprehensive therapeutic effects, its influence may involve a dynamic, network-wide alternation of multiple target genes, proteins, or metabolites28. It is therefore of great significance to elucidate the mechanism of acupuncture effects with systematic biological approaches. As such, we applied metabolomics to separate the effects generated by active acupoint treatment versus inactive acupoint treatment. The present pilot study evaluates the clinical effect of two acupoint groups and quantifies 47 CVD-related metabolites in patients’ plasma. The active acupoints were selected based on expert opinions and the inactive acupoints were used for the control. The results show different clinical effects and different metabolic regulative effects between active acupoints and inactive acupoints in lowering blood pressure .Metabolomics, which has been developed to identify small molecular metabolites within human samples by using high-throughput analytical tools, is frequently employed to characterize metabolic features and explore new diseases mechanismsP > 0.05)  withdrew due to immigration reasons and three patients in the inactive acupoints treatment group (ITG) discontinued their treatment—two as a result of unsatisfactory blood pressure control and one from an unexpected hip bone fracture. 13 eligible patients completed the six-week treatment. Baseline comparison showed that the two groups were well-balanced in all clinical characteristics (5) Table .Table 1DP < 0.05). The average arterial blood pressure was significant reduced in the ATG (P < 0.05). While in the ITG, which delivered inactive acupoint treatment, neither systolic nor diastolic blood pressure was significantly changed (P > 0.05). Only the pulse rate was significantly reduced in the ITG (P > 0.05). In addition, when looking at the follow-up blood pressures, active acupoints treatment can be seen to significantly lower systolic blood pressure and DBP variation, but not diastolic blood pressure, as compared with inactive acupoint acupuncture (P < 0.05).After the six-week acupuncture treatment, changes in the EH patients’ blood pressure in the two experimental groups varied Table . Both syAccording to the results of the fold change (threshold >=2) analysis and the t-tests (threshold =<0.05), eight key plasmatic metabolites in the ATG, including sucrose, cellobiose, glycine, hypoxanthine, hexanoic acid, ketoglutaric acid, threonine, and uric acid, were significantly altered, and thus were selected as important features. However, in the ITG only one metabolite, ketoglutaric acid, showed significant change. The acupuncture-induced key plasmatic metabolite changes are listed in Table PCA and PLS-DA analysis demonstrates that the follow-up plasma of EH patients receiving active acupoint acupuncture can be separated from patients receiving inactive acupoint acupuncture, as shown in PLS-DA score plot Fig. . It demo29. This model is especially advantageous for research into complementary and alternative medicine, because not only does it efficaciously produce clinical evidence for decision making based on patient-centred outcomes, but it also sheds light on possible molecular mechanisms. The results show that active acupoints, selected on the basis of traditional theories, is more effective than disease-unrelated inactive acupoints in the lowering of blood pressure. Based on the metabolomic analysis, metabolic modulation may also play a significant role.In this study, we employ a combing omics and comparative effectiveness research model to address the controversy between active and inactive acupoints—an innovative, evidence-based clinical research decision-making model for Chinese medicine30. Active acupuncture stimulation might trigger afferent nerves innervated beneath active acupoints to transfer mechanical and biochemical signals to the brain areas responsible for blood pressure regulation, including the hypothalamus, rVLM, and vlPAG31. Studies have also confirmed that acupuncture can inhibit reflex hypertension through the opioid-mediated inhibition of glutamate in rVLM32. Therefore, glutamatergic suppression may further reverse the hypertensive effect of central TNF-α, which simultaneously recovers blood pressure and energy balance via inhibiting NF-κB and IKK β activation34  increases the risk of metabolic complications in overweight and obese subjects44. Another study suggests that a six-month daily intake of SSSDs increases ectopic fat accumulation and lipids, as compared with milk, diet cola, and water45. In our study, the plasma sucrose level was significantly reduced, suggesting that acupuncture may inhibit the duodenal absorption of sucrose, or accelerate its anabolism to improve metabolic abnormality.Moreover, sucrose, cellobiose, and hypoxanthine were considered signature metabolites of active acupoints for hypertension. Hypoxanthine is the precursor of uric acid—the end product of purine degradation in humans46. Cellobiose is a prebiotic ingredient in fermented products involving bifidobacterial47. Gut microbiota, as a major part of the commensal microbiome in humans, plays a significant role in maintaining intestinal hemostasis. It may also interact with human metabolism via enterohepatic circulation, as well as many other immunoendocrine mechanisms, and thus contribute to the maintenance of hemostasis. Various studies demonstrate that disruption of the gut microbiota (dysbiosis) is either causally or consequently associated with a variety of diseases, including Crohn’s disease, colon cancer, diabetes, metabolic syndrome, cardiovascular disease, stress and anxiety, food allergies, asthma, autism, hepatic encephalopathy, and eczema48. Mounting evidence supports the role of gut microbiota in the development and maintenance of hypertension49. Research indicates that short-chain fatty acids and other small molecular metabolites produced by gut microbiota bind to metabolite-sensing G-protein coupled receptors (GPCRs), such as GPR41, GPR43, and GPCR olfactory receptor 51E2 (humans)/Olfr78 (mice), to regulate blood pressure via controlling gut hemostasis, host metabolism, and immune response. Our previous study showed that in healthy males, acupuncture significantly increased concentrations of urinary hippuric acid50, which is a co-metabolite in humans and gut microbiota, and a possible biomarker of hypertension and obesity in humans52. Future studies are needed to explore this mechanism.Furthermore, gut-microbiota may participate in the blood pressure regulation mechanisms of acupuncture. This study finds that active acupoint treatment also reduces the level of cellobiose, which is fermented in the large intestine of humans53. It remains unclear if an increase of sample size will dilute this clinical efficacy. Moreover, there is a further need for the assessment of acupuncture’s long-term effect on hypertension. Mounting evidence shows that acupuncture has persisting therapeutic effects on chronic pain55. However, it is still largely unknown whether this effect remains when used for hypertension. Current research measures the immediate BP reduction following acupuncture treatment. For example, Flachskampf et al. reveals that the hypotensive effect of acupuncture could be time-dependent2. It also shows that the clinical efficacy detected at the completion of the treatment did not last for more than 3–6 months after treatment. These questions will be addressed in our future studies.It should be noted that the current comparison is only validated by this pilot study. Its power may be limited by the small sample size, even though the antihypertensive effect observed (systolic BP reduction: 8.2 mmHg) is equivalent to that of a relatively large trial (10.8 mmHg)In conclusion, metabolomic analysis is a potential tool that can be used to effectively differentiate the effect of active acupoints from inactive acupoints in treating hypertension. Possible mechanisms are the alternation of hypothalamic microinflammation and the restoration of host-gut microbiota interactions induced by acupuncture.This study has been ethically reviewed by the Sichuan Regional Ethical Review committee of the Teaching Hospital of Chengdu University of Traditional Chinese Medicine (NO. 2012KL-003). All trial procedures were designed and conducted in accordance with the Declaration of Helsinki. Patients’ right and beneficence were placed at the utmost place in this study. This study was registered in the NIH ClinicalTrial.gov Registry . Each eligible participant was informed about all the procedures, benefits as well as potential risks that they may encounter in this trial, and they are free to withdraw the study at any time without any specific reason. Before any trial process, the included participants were required to submit a written inform consent signed by oneself or their next of kin.56. Study participants were recruited from the third teaching hospital of Chengdu University of Traditional Chinese Medicine and its surrounding communities. Patients meet all inclusion criteria are included in this study, any violation of the exclusion criteria made participants excluded. Inclusion criteria: (1) aged between 45 and 75 years; (2) were diagnosed as stage I hypertension in the first visit, or used to be diagnosed as stage I hypertension in recent 1 year, but without any medication history; (3) without neurological, other cardiovascular, hepatic and renal disease, and other visceral diseases; (4) the basal metabolism rate of a patient, which was measured by the retrospective dietary questionnaire at baseline, should be approximately 1:1.4; (5) didn’t administer any drugs or herbs in at 15 days before the start of the study; (6) didn’t participate in any study other than this; (7) agreed to cooperate with researchers in all research procedures after they were introduced this study; and (8) provided with written informed consent. Exclusion criteria: (1) age ≤45 or age ≥75; (2) with hypertension which was secondary to other diseases, such as renal vascular disease, Cushing’s syndrome, hyperadrenocorticism and drug-induced hypertension; (3) had complicated cardiovascular, digestive, respiratory, urinary, blood, nervous, endocrine system and other severe primary diseases and failed to effectively control in clinic; (4) accompanied by epilepsy, sleep apnea hypopnea syndrome, etc.; (5) with psychiatric symptoms such as severe depression or anxiety ; (6) pregnant or lactating woman, or woman of reproductive age who was intended to conceive in recent 1 year; (7) with abnormality in laboratory test of blood biochemistry, or with contagious risks, such as HIV virus carrier, or patient with positive HBV superficial antigen; (8) with malignant tumor or other severe consuming diseases, or patient with infections or bleeding disorders; (9) alcoholics or drug abusers, or vegetarians; (10) used to suffer from acute diseases in recent 2 weeks, such as high fever, or gastritis; (11) used to administer any drug that may potentially impaired renal or hepatic function; (12) with cardiovascular disease that had been treated with acupuncture within recent three months; or (13) undergoing other clinical trials.Patients of essential hypertension were included and clear diagnosis of EH was made according to the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure, the JNC 7 reportThis study included the following procedures: patient recruitment, baseline information collection and blood sampling, randomization and allocation (1:1), treatment and outcome evaluation. The 24-hour ambulatory blood pressure was measured at baseline period and follow-up phase by an oscillometric device  within 24 hours before the commencement, and after the completion of acupuncture treatment, respectively. Venous blood was collected the day before acupuncture treatment and the second day of the final treatment at 8:00–9:00 a.m. with all the subjects having fasted for 12 hours. Fasting blood samples were collected into vacutainer tubes with heparin sodium and immediately cool to 4 °C. Then they were centrifuged within 2 h at 1500 rpm for 15 min. Plasma was separated, transferred to new vials, and immediately stored frozen (−80 °C) until preparation. The randomization procedure was done by an independent researcher with a random number table. Patients were not aware of which type of treatment they received. The primary outcome is the 24-hour ambulatory blood pressure change after treatment.57. In ATG, four acupoints, taichong (LR3), renying (ST9), taixi (KI3), and neiguan (PC6) were selected. While, for ITG, fengchi (GB20), waiguan (SJ5), yinlingquan (SP9), and xuehai (SP10) were stimulated. All acupoints were gently superficially inserted with filiform needles bilaterally. Patients have been induced to get Deqi sensation after slightly rotating, lifting and thrusting the needle. Then the needle tail was connected with Han’s acupoints nerve stimulator, HANS-200,  to maintain the Deqi sensation. The whole needle retention time is 30 min. In each group, patients received acupuncture treatment 3 times a week for a total of 6 weeks. All practitioners have at least 5 years’ clinical experience of acupuncture.After inclusion, patients were allocated to either ATG or ITG. The principle of active and inactive acupoints selection is based on a recent clinical trial67 that reported new biomarkers or important metabolites for EH and related cardiovascular diseases. LC-MS grade standard compounds were purchased from Sigma-Aldrich Company . We then detected their content by using the Multiple Reaction Monitoring (MRM) Mass-Spectrometry (MS) measurement. The analyzes for all the experiments were performed on a QTRAP5500 mass spectrometer  equipped with a Shimadzu UFLC system, which consisted of Shimadzu LC-20AD XR pumps and an SIL-HTC autosampler . Two microliters of each sample were injected on a Luna 5 μm, 150 mm × 4.6 mm HPLC column . The mobile phases were: (A) 0.01% heptafluorobutyric acid, 0.1% formic acid in water, and (B) 0.01% heptafluorobutyric acid, 0.1% formic acid in methanol. The needle-rinse solvent was methanol. The HPLC flow rate was set at 0.8 mL/min and eluted with a gradient of 2–40% solvent B for 6 min, 40% solvent B for 4 min, 40–90% solvent B for 0.5 min, 90% solvent B for 0.5 min, 90-2% solvent B for 1 min, and followed by 2% solvent B for 3 min. The column was re-equilibrated with 2% B for 1 min prior to the next injection. In QTRAP5500, the parameters were set to positive ionization mode, with curtain gas set at 40 psi, nebulizer gas at 60 psi, IonSprayTM voltage at 5500 V, ion source temperature at 600 °C, and CAD gas at medium and to negative ionization mode, with curtain gas set at 40 psi, nebulizer gas at 25 psi, IonSprayTM voltage at −4500 V, ion source temperature at 600 °C, and CAD gas at medium. The MRM transitions for the analyzes, declustering potential (DP), entrance potential (EP), collision energy (CE), and the collision cell exit potential (CXP) are listed in Supplementary Table 47 target metabolites -Lactic acid, L-Valine, L-Leucine, L-Proline, Betaine, Palmitic acid, Stearic acid, Glycine, (±)-a-Tocopherol, β-Sitoseterol, L-Tryptophan, DL-glyceraldehyde, Glycocholic acid, oleic acid, eicosanoic acid, hexanoic acid, Heptanoic acid, nonanoic acid, Galactose, Sucrose, Sorbitol, myoinositol, Fructose, Cellobiose, Urea, Isoleucine, Alanine, citric acid, Azelaic acid, Aspartic acid, 4-Hydroxybenzoic acid, Pimelic acid, L-Serine, Hypoxanthine, D-Homoserine, Uric acid, Trimethylamine oxide, Pentanedioic acid, Allantoin, Linoleic acid, Citrulline, Oxaloacetic acid, and Sorbose andα-ketoglutaric acid) were selected from previous studiesP < 0.05. As to target metabolomics analysis, we applied PCA and PLS-DA statistics to visualize the change of key metabolites’ distribution patterns after different treatment. Preliminary data were median-normalized, log-transformed and pareto-scaled prior to being introduced to the online software MetaboAnalyst . PCA was applied to show the distribution pattern of samples, and to detect data outlier to exclude. PLS-DA is a supervised statistical method to which the separating information is already known. It helps to figure out important features contributing to separation. Variable Importance in Projection (VIP) scores estimate the importance of each variable in the projection used in a PLS model and is often used for variable selection. A variable with a VIP Score equivalent to or greater than 1 (one) can be considered important in given model. In this case, we applied a VIP score threshold 1.5. Important features were selected by VIP score with threshold 1.5, t-tests with threshold 0.05, and fold-change analysis with threshold 2.Comparisons of clinical characteristics between ATG and ITG were performed by using the unpaired t-test. While for the comparison of baseline indices with post-treatment indices, the paired t-test was applied. The significance level for comparison is Supplementary dataset


GDNF, and the “rearranged during transfection” proto-oncogene, RET, in kidney and urinary tract development, variations in these genes are proposed to be candidates for medullary sponge kidney. Hyperparathyroidism is observed in a few patients with medullary sponge kidney, but the exact pathogenesis of this association is unknown. This case report highlights the coexistence of these two conditions associated with RET polymorphism, which contributes toward the understanding of the pathogenesis of medullary sponge kidney.Medullary sponge kidney is a rare renal malformation, which usually manifests as nephrocalcinosis, renal tubular acidosis, and recurrent urinary tract infections. Medullary sponge kidney is often associated with renal developmental anomalies and tumors, and its exact pathogenesis is not yet clearly explained. Given the key role of the interaction of glial cell line-derived neurotrophic factor gene, GDNF and RET genes were determined by Sanger sequencing. Two RET polymorphisms were found in our patient, one was nonsynonymous c.2071G>A  located in exon 11, the other was synonymous c.2712C>G.  located in exon 15.A 52-year-old Chinese woman with recurrent renal stones presented to our hospital. Subsequently she was diagnosed as having medullary sponge kidney and tertiary hyperparathyroidism and underwent parathyroidectomy. Genomic DNA was isolated from lymphocytes and the RET G691S/S904S polymorphism in this patient, but additional studies are required to explore the role of the RET gene in medullary sponge kidney with hyperparathyroidism.We demonstrated a case of medullary sponge kidney combined with tertiary hyperparathyroidism, which contributes to further understanding of the pathogenesis of this disease. Besides, we also found  GDNF and RET genes, which play a key role in kidney and urinary tract development, maybe reasonable candidates for MSK. Hyperparathyroidism is observed in a few patients with MSK, but the exact pathogenesis of this association is unknown [GDNF and RET gene variations, which contributes to further understanding of the pathogenesis of this disease.Medullary sponge kidney (MSK) is a nephropathy which usually manifests as nephrolithiasis, renal tubular acidosis, concentration defects, medullary cystic dilatations, and recurrent urinary tract infections. Its incidence is 1/20,000 to 1/5000 in the general population, 3 to 5% in patients with kidney stones, and up to 20% in patients with recurrent kidney stones , 5. Thus unknown . In the 2CP) 17.8 mmol/L, creatinine 249 μmol/L, serum parathyroid hormone (PTH) 1147 pg/ml  of her kidney showed MSK and polycystic kidney disease  37.5 °C, pulse (P) 82/minute, respiratory rate (R) 20/minute, blood pressure (BP) 130/80 mmHg, weight (W) 51 kg, and height (H) 154 cm. Respiratory movement and cardiac examination were normal. On abdominal examination no masses or tenderness were noted on both light and deep palpation. Her liver and spleen were not palpable. A sensory and motor system examination did not reveal any abnormality. Her neurological reflexes were normal. A routine urine examination showed: white blood cell 87/hpf (WBC2+), red blood cell 34/hpf (RBC2+), and pH 7. 0. A routine blood test showed: hemoglobin (Hb) 95 g/L. Her serum potassium was 3.2 mmol/L, calcium 2.92 mmol/L, phosphate 1.3 mmol/L, carbon dioxide combining power , red blood cell 27/hpf (RBC1+), and pH 7. 5. A routine blood test showed: Hb 88 g/L. Her serum potassium was 3.1 mmol/L, calcium 2.83 mmol/L, phosphorus 1.21 mmol/L, COnum Fig. . Parathynum Fig. . After s2CP 15.6 mmol/L, serum creatinine 766 μmol/L, and PTH 766.4 pg/ml  and pH 7.0. A routine blood test showed: Hb 76 g/L, potassium 4.0 mmol/L, calcium 2.09 mmol/L, phosphorus 2.37 mmol/L, CORET proto-oncogene are also present in 97% of individuals with multiple endocrine neoplasia (MEN) 2A (MEN2A). In order to explore the possible genetic mechanisms, we analyzed the GDNF and RET genes in this patient. After obtaining informed consent from our patient, genomic DNA was extracted from peripheral blood leukocytes by standard phenol–chloroform procedures. All 20 exons and flanking splice sites of the GDNF and RET genes were amplified by polymerase chain reaction (PCR) with the primers listed in Table RET polymorphisms were found in this patient, one was nonsynonymous c.2071G>A  located in exon 11 . Fabris et al.  showed tet al. . Some pret al. , 6, but et al. . In our GDNF and RET genes, which play a key role in the kidney–urinary tract development and nephrogenesis, might be the reasonable candidates for MSK. Torregrossa et al. [GDNF and RET genes of 55 patients with sporadic MSK and found eight patients with MSK had heterozygous variations of GDNF gene c.-45G>C, c.-27 + 18G>A. RET encodes a receptor tyrosine kinase, expressed primarily in neural crest and urogenital precursor cells. It is a developmentally important gene, required for kidney morphogenesis, maturation of peripheral nervous system lineages, and for differentiation of spermatogonia. In RET knockout mice, the loss of the RET protein results in anomalies of renal embryogenesis, which indicates that the RET protein is required for the development of the urinary excretory system. Primary hyperparathyroidism (PHPT) may occur as part of a complex syndrome or as an isolated disorder. Syndromic PHPT includes MEN types 1 to 4 (MEN1 to MEN4). RET gene mutations were also found in 97% of patients with MEN2A, who have an increased risk for parathyroid adenoma or hyperplasia, medullary carcinoma of the thyroid, and pheochromocytoma [et al. [RET C634Y mutation. In addition, sporadic forms of parathyroid tumors may arise because of somatic gene abnormalities. To date, reports have shown that more than 10% of patients with hyperparathyroidism may have a germline mutation involving the MEN1, RET, cell division cycle 73 (CDC73), calcium-sensing receptor (CASR), cyclin-dependent kinase inhibitor (CDNK1B), or PTH genes. Thakker [RET gene polymorphisms G691S (exon 11) and S904S (exon 15) were identified, but no GDNF variants were found. It was shown that the nonsynonymous RET G691S polymorphism is able to increase downstream signaling compared with RET wild type [RET pathogenic genes in MTC is enhanced by the presence of G691S, suggesting a possible modifier role of this nonsynonymous RET polymorphism [RET are in linkage disequilibrium with each other. Robledo et al. [RET in 104 patients with MEN2A, and found the homozygous for these polymorphisms were, on average, 10 years younger at the time of diagnosis compared with heterozygous and wild-type homozygous, indicating that the G691S/S904S variants of RET have a modifier effect on the age at onset of MEN2A. However, the exact mechanism of RET G691S/S904S polymorphism in the pathogenesis of MSK and hyperparathyroidism still remains to be uncovered.As MSK is considered a congenital disease, it is speculated that the a et al.  analyzed [et al.  reported Thakker  suggesteild type , 13. Mormorphism , 15. Premorphism  have shoo et al.  analyzedet al. [Considering the pivotal role of incomplete dRTA in MSK, Fabris et al.  recommenet al. . The proRET G691S/S904S polymorphism in this patient, but additional studies are required to explore the exact mechanism of the RET gene in MSK with hyperparathyroidism.We demonstrated a case of MSK combined with tertiary hyperparathyroidism, which further expands the pathophysiology of this disease. Early recognition of MSK symptoms has important clinical implications for the prevention of further progress of the disease. Besides, we also found


To The Editor:Eosinophils play an important pathogenic role in pulmonary and systemic conditions, including eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.A; see www.jacionline.org). The initial transit of radiolabeled eosinophils through the lung was similar in all subjects (B and C). We generated a “first-pass” transit curve to calculate the time taken for the initial bolus of eosinophils to transit from the right ventricle across the pulmonary circulation (see www.jacionline.org). This value was constant across all study groups (B). The 45-minute blood recovery values (D) did not differ between the study groups and, importantly, were comparable to published levels for unmanipulated radiolabeled eosinophils from healthy volunteers, indicating that the reinjected eosinophils were nonactivated.E-G).To determine the initial distribution of eosinophils, and to ensure that the reinjected cells had not been activated, planar gamma camera imaging was performed following injection of technetium-99m–labeled eosinophils. These scans were performed in healthy volunteers, patients with asthma, and patients with focal eosinophilic inflammation  and Patlak-Rutland analysis undertaken (see www.jacionline.org). As shown in I, pulmonary uptake was significantly increased in patients with focal eosinophilic inflammation  compared with healthy volunteers (0.0003 mL/min/mL). There was a trend toward increased pulmonary uptake in patients with asthma . However, conversion of this rate of uptake to an absolute whole lung eosinophil migration value by multiplying with the peripheral blood eosinophil count revealed the full extent of eosinophil accumulation by the lungs; patients with focal eosinophilic lung inflammation and subjects with asthma had higher rates of eosinophil migration compared with healthy volunteers (32 eosinophils/min/mL) (J). The extent of eosinophil migration in patients with asthma did not correlate with lung function or fractional nitric oxide (Feno) (see www.jacionline.org).To measure the time-dependent uptake of radiolabeled eosinophils from the blood into the lungs (“pulmonary uptake”), serial images were acquired using SPECT/CT , H and P/min/mL) , J. The 2) or nonobese (body mass index < 30 kg/m2) , and compared their eosinophil uptake. As shown in B, pulmonary uptake was increased in obese patients with asthma (0.001 mL/min/mL) compared with nonobese patients with asthma . This effect was not explained by an increase in the early retention of eosinophils in the lung because the first-pass mean transit time was faster in eosinophils of obese patients with asthma compared with eosinophils of nonobese patients with asthma (P = .038) (C). Furthermore, the 45-minute postinjection eosinophil recovery values and peripheral blood eosinophil counts were also similar . In a parallel but separate group of subjects with asthma (D), stratified in an identical manner to the SPECT/CT cohort, the bronchial submucosal eosinophil count was significantly elevated in obese patients with asthma compared with nonobese patients with asthma (P = .024) (E and F). The epithelial eosinophil count, sputum eosinophil count, peripheral blood eosinophil count, Feno levels, and IgE levels were not significantly different between patients with asthma with and without obesity  , C. Furth asthma , D, stra = .024) , E and F obesity  and E4.Fin vivo imaging of eosinophils will inform the development of these therapies, and shed light on the mechanisms controlling eosinophil migration.The impact of antieosinophil therapies on eosinophil trafficking is poorly understood. Inhaled corticosteroids are the mainstay treatment for asthma and reduce the number of eosinophils in sputum and bronchial biopsies. Biological therapies such as mepolizumabWe quantified eosinophil uptake from the blood to the lungs and demonstrated increased eosinophil migration to the lungs in our cohort with asthma relative to healthy controls. Although eosinophil migration in part reflects the peripheral blood eosinophil count, our methodology localizes inflammation and quantifies the migration to the “whole lung” parenchyma, providing information that cannot be obtained from the blood cell count alone.eno and peripheral eosinophil count. Second, although we have previously published a rigorous assessment of the reinjected eosinophils,Our study has some limitations. First, 50% of our cohort with asthma (studied in the imaging protocol) was recruited from primary care, and hence had not undergone in-depth phenotyping, and only 3 patients with asthma had a clearly eosinophilic phenotype based on FIn conclusion, SPECT/CT imaging using radiolabeled eosinophils provides evidence that eosinophil uptake can be quantified in the lungs and is enhanced in obese patients with asthma compared with nonobese patients with asthma. This finding has important implications for the role of eosinophils in obese patients with asthma and for selecting patients for targeted therapy in the context of type 2 inflammation.


Blood pressure (BP) is currently the main hemodynamic parameter used to assess the influence of fluid removal during hemodialysis session. Since BP is dependent on cardiac output (CO) and total peripheral resistance (TPRI), investigating these parameters may help to better understand the influence of fluid removal on patient’s hemodynamics. We used a novel non-invasive whole-body bio-impedance cardiography device, recently validated in hemodialysis patients, to examine mechanisms of intradialytic hemodynamics in a Chinese dialysis population.Chronic hemodialysis patients in Sichuan Provincial People’s Hospital were enrolled. Demographic data and dialysis prescriptions were collected. Hemodynamic measurements were made pre-treatment, every 20 min during treatment and immediately after treatment in each random dialysis session. These included blood pressure, cardiac index (CI), total peripheral resistance (TPRI) and cardiac power index (CPI). Patients were divided into 5 hemodynamic groups as per their major hemodynamic response to fluid removal: low CPI, low TPRI, high TPRI, High CPI and those with normal hemodynamics.Twenty-seven patients were enrolled, with 12 (44.4%) males. The average age was 65 ± 12 y. The average body mass index (BMI) was 23.7 ± 3.9 kg/m2. 12 (44.4%) patients were diabetic. Three hundred twenty-four hemodynamic measurements were made. Weight, BMI, total fluid removal, pretreatment systolic BP, CI, TPRI and CI differed significantly among the 5 hemodynamic groups.11.1% of patients had low CPI, 25.9% had low TPRI, 18.5% had high CPI, 3.7% had high TPRI and 40.7% had normal hemodynamics. Hemodynamic differences among the 5 subgroups were significant.This technology provides multi-dimensional insight into intradialytic hemodynamic parameters, which may be more informative than blood pressure only. Using hemodynamic parameters to describe patients’ status is more specific and accurate, and could help to work out specific and effective therapeutic actions according to underlying abnormalities. Fluid loading and removal, inherent aspects of chronic hemodialysis, are critical in patients’ care and determining outcomes. Adverse response to fluid management causes obvious symptoms, decreases quality of life, requires multiple actions of healthcare professionals and increases costs to the healthcare system. However, details of fluid management and its immediate consequence are limited by lack of information concerning intradialytic hemodynamics, largely because there are few practical methods to accurately measure the two decisive elements of blood pressure, viz. cardiac output and total peripheral resistance. Accurate measurement of cardiac output and total peripheral resistance requires the pulmonary artery catheterization determined cardiac output (CO) thermodilution technique , which ir = 0.92 which was maintained during fluid removal in maintenance hemodialysis treatments [These intradialytic non-invasive measurements provide opportunities to learn the full pattern of hemodynamic responses to fluid removal during hemodialysis and to intervene specifically according to deviations from normal. A novel non-invasive whole-body bio-impedance cardiography device  has been used recently to assess this in chronic hemodialysis patients . The deveatments . In addieatments .In this study, we examined the mechanisms of intradialytic hemodynamics, including cardiac output, peripheral resistance and cardiac power, in a Chinese dialysis population, in order to evaluate different hemodynamic statuses in this population, and to provide evidence for possible specific preventive and interventional actions, particularly in the management of hypotensive episodes.Twenty-seven chronic hemodialysis patients on regular dialysis for at least 3 months in the hemodialysis center of Sichuan Provincial People’s Hospital in China were investigated. Written informed consent was obtained prior to any procedure of the study during June to September 2016. All patients received 3 maintenance hemodialysis treatment per week. The study was approved by the Institutional Review Board of the hospital and followed the ethical standards of the committee on human experimentation in our institution.2). Hemodynamic measurements in these patients were made using the device , pre-treatment, every 20 min during treatment and immediately post-treatment in one random dialysis session for each individual. Blood pressure was measured at the same time as NICaS measurements. Mean arterial pressure (MAP) was calculated as (systolic blood pressure (SBP) + 2*diastolic blood pressure (DBP))/3. Dialysis prescriptions including treatment duration and total fluid removal (TFR) were recorded. Ultrafiltration rate (UFR) was expressed as fluid removal volume per kg weight per hour.Demographic data including gender, age, height, weight, dialysis vintage and comorbidity of diabetes was collected. Body mass index (BMI) was calculated as weight (kg) divided by height squared  , 4. It i5*m2 , 10 and 2), TPRI (1600–3000 dyn*Sec/cm5*m2) and CPI (0.45–0.85 W/m2).Each patient was studied during one random hemodialysis treatment. Treating clinicians were blinded to the measured data. For graphical representation, a graph with CI on the x-axis and MAP on the y-axis was shown in Fig. After normal hemodynamics were established, patients with abnormal hemodynamics were grouped as experiencing intradialytic hypotension (IDH), defined as systolic blood pressure (SBP decreased by> 20 mmHg or MAP decreased by > 10 mmHg), and non IDH. They were further divided into 4 hemodynamic groups  as follows:2.High TPRI with MAP ≥88 mmHg and CI < 3.25 l/min/m2.High CPI with MAP≥88 mmHg and CI ≥ 3.25 l/min/m2.Low CPI with MAP< 88 mmHg and CI < 3.25 l/min/m2.Low TPRI with MAP < 88 mmHg and CI ≥ 3.25 l/min/mThe MAP and CI measurements of each patient were plotted see Fig.  in 3 meaP < 0.05 was considered statistically significant.All statistical analyses were performed using MicroSoft Excel version 2010 . Quantitative data was expressed as mean ± standard deviation (SD). Qualitative data was expressed as number and percentage. Comparisons were made between/among groups by chi square test or ANOVA test. All tests were two-tailed. 2. 12 (44.4%) patients were diabetes. There were totally 324 measurements, including 27 measurements at baseline, 270 measurements made every 20 min during treatment and 27 measurements immediately after treatment. See Table 2 vs 64 ± 12 kg and 22.6 ± 3.2 kg/m2, p = 0.015 and 0.010 respectively). Patients in the non IDH group had been on dialysis longer than those in IDH groups . Significant changes were not found in treatment duration, total fluid removal (TFR), ultrafiltration rate (UFR) and pretreatment hemodynamics between the two groups. The percentage of diabetic patients in the non IDH group (42.9%) was not significantly different from that in the IDH group (50.0%). When patients were grouped as per the 5 hemodynamic subgroups, weight and BMI were significantly different among the groups (p < 0.001 and p = 0.030 respectively), with patients in the low CPI group had the highest weight and BMI. Patients in the low CPI group and high TPRI group had significantly higher TFR (p = 0.010). Pretreatment SBP, CI, CPI and TPRI differed significantly among groups . See Table The study population consisted of 27 patients, with 12 (44.4%) males. The average age was 65 ± 12 years, and the average BMI was 23.7 ± 3.9 kg/mThis study utilized a novel non-invasive regional impedance cardiography technology to illustrate the hemodynamic status of chronic hemodialysis patients during dialysis treatments with fluid removal. The results showed no significant pretreatment hemodynamic differences between IDH and non IDH patient groups. In addition, both IDH patients and non IDH patients returned to normal ranges of blood pressure, cardiac index, cardiac power index and total peripheral resistance post dialysis session. Patients were divided into hemodynamic groups as per highest and lowest intradialytic hemodynamic changes. The highest or lowest intradialytic hemodynamic measurement point in each treatment was selected as the point with the largest difference from the normal values of MAP and CI.In healthy subjects, CI and TPRI can correctly adjust according to the change in each other, maintaining a BP in the normal range and therefore stable hemodynamics. However, in a chronic hemodialysis patient, often with impaired cardiac function, reduced vessel elasticity, or decreased autonomic function, ultrafiltration and decompensation to either decrease in CI or TPRI by various mechanisms may cause a significant BP drop during dialysis. Cardiac insufficiency may result predominantly from hypertensive myocardial, valvular disease or coronary artery disease . Both syReliance on blood pressure monitoring cannot differentiate specific mechanisms of intradialytic IDH and IH episodes. However, hemodynamic measurements can discriminate patients on the basis of their cardiac power and peripheral resistance and provide opportunities for intervention. When blood pressures routinely fall, specific prophylaxis become practical during the actual treatment. Patients with low CPI or low TPRI or both changes combined may all present with decreased BP; however, their underlying causes are different, requiring different interventions. Even in the situation when patients do not have IDH symptoms, hemodynamic analysis can indicate an abnormal change in cardiac function or in peripheral resistance as well as compensatory changes in other functions.Reduction in cardiac power during dialysis can be as a result of reduction in preload, which may be due to hypovolemia as such, or complicated by diastolic dysfunction. Normally in this instance, the cardiac power reduction is compensated for by vasoconstriction. However, in the hemodialysis patient, the compensation is often insufficient to maintain stable hemodialysis, manifesting as a consequent BP decrease. With on-line hemodynamic monitoring regularly, decisions can be made to reduce ultrafiltration rate when a reduction in cardiac power is observed, before the blood pressure falls or to increase target weight to prevent hypovolemia. In addition, even baseline hemodynamic information, can promote specific actions targeting the underlying hemodynamic abnormality. For patients with impaired cardiac function, examinations to evaluate cardiac function, such as electrocardiograph and echocardiograph are valuable in choosing appropriate cardiotonic drugs. For patients with low TPRI (vasodilatation), dialysate temperature can be reduced or adrenergic agonists (e.g. Midodrine) can be prophylactically prescribed. Salt restriction to reduce interdialytic weight gain may also be helpful. For patients with high cardiac power (high BP and high CI), target weight could be gradually reduced. For patients with high TPRI (vasoconstriction), provision of non-dialyzable vasodilator drugs such as ARBs may be useful.The study has several limitations. First, the sample size of 27 patients is small. However, the gender and age composition of IDH group did not differ from the non IDH group. Further studies with larger sample sizes may help to limit selection bias. Secondly, this study is cross- sectional designed. Future interventional studies designed to test IDH patients’ response to different treatments according to their hemodynamic categorization will provide useful information.This non-invasive whole-body bio-impedance cardiography technology provides insight into hemodynamic trends during dialysis. Knowledge of cardiac output index and the calculated parameters of cardiac power index and total peripheral resistance enable a multi-dimensional hemodynamic categorization, which is likely to be more informative than the current indirect dimension provided by blood pressure only. This technology may provide useful information for clinicians to make specific decisions according to underlying abnormal findings, such as increasing target weight for patients with low CPI, increasing ultrafiltration for patients with high CPI, prescribing adrenergic agonists to patients with low TPRI (vasodilatation) and vasodilators for patients with high TPRI.


Additionally, there was a significant positive association between BMISDS and SBP in the SGHD group , but no association between these variables was observed in the non-SGHD group. Thus, SGHD patients had a higher SBP than non-SGHD patients. BMISDS is a significant factor for higher SBP in SGHD patients but not in non-SGHD patients.Blood pressure (BP), especially systolic BP (SBP), is higher in adult growth hormone deficiency (AGHD) patients than in normal controls. Additionally, obesity is a known risk factor for hypertension, and growth hormone deficiency (GHD) is an important cause of short stature. For children with GHD, attention has been directed solely towards height. Few studies have assessed its potential impact on BP. Here, we investigated the effect of body mass index standard deviation score (BMISDS) on BP in children with short stature. This study included 736 children with short stature divided into two groups based on peak growth hormone (GH) level in GH provocation tests . We found that SBP was significantly higher in the SGHD group than in the non-SGHD group ( All these factors may accelerate atherosclerosis and promote higher cardiovascular morbidity, and untreated AGHD is widely accepted to lead to cardiovascular diseases (CVDs), whereas growth hormone (GH) treatment has beneficial metabolic effects in these patients2. On the other hand, the situation in children is less clear, as few studies have investigated metabolic abnormalities and their association with CVD in children. A recent review by De Leonibus C suggested that the development of atheromatous plaques begins early in childhood in the context of GH deficiency (GHD)3. Thus, understanding the risk factors for GHD in children is important for preventing disease and reducing morbidity caused by GHD.Adult growth hormone deficiency (AGHD) is associated with a metabolic profile similar to that of metabolic syndrome, which is defined by the clustering of obesity, dyslipidemia, glucose intolerance, and hypertension4. Obesity is the excessive accumulation or expansion of adipose tissue. Population studies revealed that GH influences body composition6 and that GHD is associated with weight gain and a higher body mass index (BMI) in children and adults7. Basic research further showed that GH could reduce adipose tissue mass by regulating adipokine secretion, cellular senescence, the immune cell profile, angiogenesis, and lipid droplet formation8.In the general population, obesity is a known risk factor for hypertension. Obesity contributes to the development of hypertension via several interconnected and complex pathways, such as inflammation, oxidative stress, insulin resistance, and neurohormonal and humoral dysfunction10. However, these data were obtained from heterogeneous cohorts of adult patients with GHD of varying etiologies and durations. How BP changes in children with GHD is unknown, and the relationship between BMI and BP in children with GHD remains unclear.Blood pressure (BP), especially systolic BP (SBP), was reported to be higher in AGHD patients than in normal controls11. According to the criteria for SGHD12, this study defined SGHD as a GH peak <5 ng/ml. In this study, we sought to investigate the relationship between BMI standard deviation score (BMISDS) and SBP in children with SGHD.GHD is a common cause of linear growth restriction in children, and the diagnosis of GHD mainly relies on clinical manifestations combined with the GH provocation test. There are significant differences in body composition and metabolic traits between patients with severe GHD (SGHD) and the general populationp = 0.035), weight (p < 0.001), BMI (p < 0.001), BMISDS (p < 0.001), insulin-like growth factor-1 standard deviation score (IGF-1SDS) (p = 0.002), triglyceride (TG) (p = 0.023), total cholesterol (TC) (p < 0.001) and low-density lipoprotein cholesterol (LDL-C) (p = 0.008) than the non-SGHD group. However, there was no significant difference between groups in diastolic BP (DBP), sex, age, height, height standard deviation score (HtSDS), IGF-1, insulin-like growth factor-binding protein-3 (IGFBP-3), fasting plasma glucose (FPG), high-density lipoprotein cholesterol (HDL-C) or bone age (BA).Seven hundred thirty-six patients aged 10.2 ± 3.5 years, including 516 boys and 220 girls, were enrolled in this study. The demographic, anthropometric, and clinical characteristics of the 736 patients stratified according to GH peak in the GH provocation test are shown in Table p = 0.042).Univariate analysis was performed to assess the relationship between each variable and BP. As shown in Table p < 0.001) (Table p < 0.001), but there was no association in the non-SGHD group . To further confirm the findings, we adjusted the models for TG, TC, HDL-C, LDL-C, FPG, IGF-1SDS and IGFBP3 and found an independent association between BMISDS and SBP in the SGHD group  but not in the non-SGHD group . Furthermore, a test of the interaction between GH peak and BMISDS was statistically significant (p = 0.001).Given the above results showing that BMISDS was significantly associated with SBP , and all methods were performed in accordance with the guidelines of the Declaration of Helsinki. All of the families of the patients were informed of the aims of the study, and written informed consent was obtained from the parents of the patients.22. BMI was calculated as the ratio between body weight in kilograms and height in meters squared. The stage of puberty was assessed by physical examination according to Tanner staging23; prepuberty was defined24 as a testicular volume less than 4 ml and no pubic hair in boys and as no breast development or pubic hair in girls.Height and weight were measured by a designated individual using the same measuring instrument in the morning with allowable error ranges of 0.1 cm and 0.1 kg, respectively. BP was measured in the seated position by one of two pretrained physicians using an electronic sphygmomanometer with an appropriately sized cuff for the arm of a child, and the average of three measurements was used for analysis. HtSDS was calculated based on the normal range of Chinese children25.To assess GH secretion, Ldopa  and insulin  were administered orally or subcutaneously after overnight fasting. Blood samples were collected at 0, 30, 60, 90, and 120 min after administration to obtain serum GH concentrations at each time point. GH was measured using a chemiluminescence method  with an analytical sensitivity of 0.010 µg/L. Serum IGF-1 and IGFBP-3 levels were measured by the chemiluminescence immunometric method ; the intra- and interassay coefficients of variation (CVs) were 3.0% and 6.2% for IGF-1 and 4.4% and 6.6% for IGFBP-3. Measures of liver function , AST, and gamma-glutamyl transferase (GGT)) and kidney function , and UA), lipid profiles , and FPG were obtained by a biochemical autoanalyzer . Measures of thyroid function, including free T3 (FT3), free T4 (FT4), thyroid-stimulating hormone (TSH), gonadotropin, cortisol, and adrenocorticotropic hormone (ACTH), were determined by a luminescence immunoassay system . IGF-1SDS and BMISDS were calculated according to a previous studyhttps://www.r-project.org;) and EmpowerStats . Normally distributed variables are expressed as the mean ± standard deviation (SD); non-normally distributed variables are presented as the median (quartile). Categorical data are expressed as percentages. To compare differences between two groups, Student’s t-test was used for normally distributed variables, the Kruskal-Wallis test was used for non-normally distributed variables, and the chi-square test and Fisher’s exact test were used for categorical variables. A univariate model was used to examine whether BMISDS and other anthropometric and biochemical variables were associated with SBP and DBP. Then, the association between BMISDS and SBP in each subgroup defined by GH peak was estimated using a multivariate linear regression model adjusted for pertinent variables, and the interaction of GH peak with BMISDS was tested. A two-tailed P value ≤0.05 was considered to indicate statistical significance in all analyses.All statistical analyses were performed with R statistical software (


Clinical outcomes of patients with end-stage kidney disease (ESKD) secondary to membranous nephropathy (MN) have not been well described. This study aimed to evaluate patient and/or allograft outcomes of dialysis or kidney transplantation in patients with ESKD secondary to MN.st December 2013. Outcomes of MN were compared to other causes of ESKD. In a secondary analysis, outcomes of MN were compared to all patients with ESKD due to other forms of glomerulonephritis.All adult patients with ESKD commencing renal replacement therapy in Australia and New Zealand from January 1998 to December 2010 were extracted retrospectively from ANZDATA registry on 31Of 32,788 included patients, 417 (1.3%) had MN. Compared to other causes of ESKD, MN experienced lower mortality on dialysis  and following kidney transplantation , had a higher risk of death-censored kidney allograft failure  but comparable risk of overall kidney allograft failure . Similar results were obtained using competing-risk regression analyses. MN patients were significantly more likely to receive a kidney transplant  and to experience primary kidney disease recurrence in the allograft . Compared to other forms of glomerulonephritis, MN experienced comparable dialysis and transplant patient survival, but higher rates of kidney transplantation, primary renal disease recurrence and death-censored allograft failure.MN was associated with superior survival on dialysis and following kidney transplantation compared to patients with other causes of ESKD, and comparable patient survival compared to patients with other forms of glomerulonephritis. However, patients with MN exhibited a higher rate of death-censored allograft loss as a result of primary kidney disease recurrence. Membranous nephropathy (MN) is one of the most common types of glomerular disease and accounts for up to 20–40% of nephrotic syndrome in adults –3. It isThe aim of this study was to evaluate patient and/or allograft outcomes of dialysis or kidney transplantation in patients with ESKD secondary to MN, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry.st December 2013. And only those with enough data as listed in the following covariates part were analyzed. Patients were initially categorized into two groups according to the cause of ESKD: MN and all other causes. MN was diagnosed by kidney biopsy and clinical criteria ) for continuous variables that were not normally distributed. Characteristics of ESKD secondary to MN were compared to those of ESKD due to other causes using Pearson’s chi-square for categorical variables, two-tailed unpaired t-tests or Mann-Whitney tests for continuous variables, depending on data distribution.Time-to-event outcomes were analyzed using multivariable Cox proportional hazards regression. Patient survival on dialysis was censored for kidney function recovery, loss to follow-up, kidney transplantation and end of study. Patient survival for kidney transplant recipients was censored for allograft failure, loss to follow-up and end of study. Death-censored kidney allograft survival was censored for death, loss to follow-up and end of study. Covariates included in the Cox models were age, gender, racial origin, dialysis era or transplant era, first RRT treatment, smoking status, body mass index (BMI), late referral , and comorbidities recorded at registry entry . Donor type and the number of previous kidney transplants were additional covariates examined for the survival analysis of transplant patients. Proportional hazards assumptions were checked by formal hypothesis testing and graphically display of Schoenfeld residuals. In view of the possibility of informative censoring due to differential competing-risk rates between patients with and without MN, sensitivity analyses were performed using a competing-risk approach: kidney transplantation and kidney function recovery were competing events in the survival analysis for patients on dialysis; kidney transplantation was the competing risk for dialysis-independent kidney function recovery; patient death was the competing risk in kidney allograft survival and allograft failure was the competing risk for patient survival after kidney transplantation. Statistical analysis was performed using Stata version 14.0 . P values <0.05 were considered to be statistically significant.st January 1998 and 31st December 2010, 32,865 adult patients started RRT for ESKD in Australia and New Zealand. Of these, 77 patients were excluded due to data gaps , MN patients were more likely to be older (median age: 61 vs 55 years old), male (74% vs 63%) and Caucasian (87% vs 75%) with a greater comorbidity burden  and likelihood of choosing peritoneal dialysis (PD) as the first RRT (30% vs 26%). Also, they were less likely to be referred late to renal units (18% vs 24%) .There were 169 deaths (44%) amongst MN patients (132 per 1000 patient-years) on dialysis compared to 17,947 (57%) patients with ESKD from other causes . There was no difference in the causes of death between MN and other causes of ESKD . RespectWhen patients with MN were compared to patients with other forms of GN, comparable survival was observed in both Cox regression analysis  and competing risk analysis .Recovery of kidney function occurred in 10 MN patients (3%), 523 patients with other causes of ESKD  and 134 patients with other Glomerulonephritis . MN was not associated with kidney function recovery in either Cox regression analysis  patients with MN and 6,907 (22%) patients with other ESKD causes during the study period (p<0.001). There was no significant difference in the median time from dialysis commencement to first kidney transplant  compared to patients with ESKD from other causes. However, MN patients were significantly more likely to undergo kidney transplantation compared to patients with ESKD from other causes  patients with MN received 172 kidney allografts during the study period. Respective unadjusted first allograft survival rates at 1, 5, and 10-years were 98%, 92% and 76% in patients with MN and 97%, 92% and 82% in patients with other causes of ESKD. The risk of first allograft loss was not significantly associated with MN   or compeThe unadjusted patient survival rates for transplant patients at 1, 5 and 10-years were 97%, 95%, 89% for MN, and 98%, 92%, 80% for other ESKD, respectively. The causes of death were shown in When patients with MN were compared to patients with other forms of GN, no significant difference in patient survival was observed using either Cox regression analysis  or competing-risk analysis .This retrospective, multicenter, two- countries registry analysis demonstrated that MN was independently associated with lower mortality, higher transplantation rates and comparable dialysis-independent kidney function recovery during dialysis treatment compared with other causes of ESKD. Following first kidney transplantation, MN was associated with comparable overall allograft survival, higher recurrence and inferior death-censored allograft survival but better patient survival compared to other ESKD. When only patients with ESKD secondary to glomerulonephritis were taken into consideration, the outcomes of patients with MN were similar to those with other forms of GN, except that MN was associated with higher rates of kidney transplantation, higher primary kidney disease recurrence rates after transplantation and inferior death-censored allograft survival.Preceding studies of clinical outcomes in patients with MN have primarily focused on earlier stages of chronic kidney disease prior to reaching ESKD , 11–14. Interestingly, 3% of patients commencing dialysis for ESKD secondary to MN experienced kidney recovery and were able to stop dialysis. Whilst the frequency of this event was not significantly different to that experienced by patients with other causes of ESKD or other forms of glomerulonephritis, the findings do support those of the previous ANZDATA registry analyses , 16 and Nonetheless, patients with ESKD due to MN were significantly more likely to receive kidney transplantation compared to patients with other ESKD or other glomerulonephritis. This finding was perhaps not altogether surprising given that patients with MN were less likely to be referred late to a renal service and demonstrated less comorbidity burden. However, even after adjustment for these variables, MN patients were still significantly more likely to undergo kidney transplantation, suggesting some residual confounding factors. These results contrast with the findings of a USRDS study in which patients with MN were significantly less likely to receive transplantation compared to those with IgA nephropathy  . HoweverFollowing kidney transplantation, patients with MN experienced worse death-censored graft survival rates compared to patients with other causes of ESKD or patients with other forms of glomerulonephritis. Similar results were reported by Moroni et al  in whichA significant factor underpinning the reduced allograft survival rate in patients with MN was the relatively frequent recurrence of MN in the kidney allograft. In the present study, the biopsy-proven recurrence rate of MN after kidney transplantation was 11.4% after a median time period of 3.6 years, which was at the lower end of the range in the literature 7%-44%) %-44% 7,–27. The . The 27.Despite poorer death-censored graft survival, overall patient survival in patients with MN was superior to that of patients with other causes of ESKD and similar to that of patients with other forms of glomerulonephritis, such that overall allograft failure was comparable amongst these groups. Similar graft survival between MN and other GN were found in a previous smaller ANZDATA Registry study involving 81 transplant patients with MN   and a TaThe strengths of this study included its large sample size and inclusiveness. These strengths should be balanced against the study’s limitations, which included heterogeneity in ESKD care and limited depth of collected information. Even though adjustment was made for a number of demographic, clinical and RRT variables, residual confounding was possible. The ANZDATA Registry does not collect information on the reasons for recovery of renal function, presence of nephrotic syndrome, anti-PLA2R antibody measurements or immunosuppressive treatment of post-transplant recurrence. Some patients with MN may have had secondary MN. The frequency of MN recurrence in kidney allografts may have been under-estimated as not all MN patients who experienced kidney allograft failure may have received a kidney biopsy.In conclusion, MN was associated with superior survival on dialysis and following kidney transplantation compared to patients with other causes of ESKD, but higher rates of death-censored allograft loss as a result of MN recurrence. Compared to patients with other forms of glomerulonephritis, patients with MN have comparable dialysis and kidney transplant outcomes, except for higher death-censored graft failure and disease recurrence rates. These findings should be used to better inform shared decision-making by patients with MN and clinicians regarding ESKD care.S1 TableAbbreviations: ESKD, End-stage kidney diseases; RRT, Renal replacement therapy; ATSI, Aboriginal and Torres Strait Islander; MPI, Maori and Pacific Islander; BMI, body mass index.(DOC)Click here for additional data file.S2 TableAbbreviations: ESKD, End-stage kidney disease; RRT, Renal replacement therapy.(DOC)Click here for additional data file.S3 Tablea Fisher’s test result. Abbreviations: ESKD, End-stage kidney diseases; MN, Membranous nephropathy; ATSI, Aboriginal and Torres Strait Islander; MPI, Maori and Pacific Islander; RRT, Renal replacement therapy; BMI, body mass index; EBV, Epstein-Barr Virus; CMV, Cytomegalovirus.(DOC)Click here for additional data file.S4 TableAbbreviations: MN, Membranous nephropathy; ESKD, End-stage kidney disease; GN, Glomerulonephritis.(DOC)Click here for additional data file.S5 Tablea Fisher’s test result. b For difference of chronic rejection between patients with ESKD secondary to membranous nephropathy and other ESKD. Abbreviations: ESKD, End-stage kidney disease(DOC)Click here for additional data file.S1 Fig(a) Unadjusted curve. (b) Adjusted curve by demographic and comorbidity indices. The difference between the 2 groups were not significant .(TIF)Click here for additional data file.S2 FigThe difference between the 2 groups was not significant (p = 0.14).(TIF)Click here for additional data file.S3 Fig(a) Unadjusted curve. (b) Adjusted curve by demographic and comorbidity indices. The difference between the 2 groups was significant (TIF)Click here for additional data file.S4 Fig(a) Kaplan–Meier survival curve. (b) Survival curve adjusted for demographic, comorbidity and allograft indices. The difference between the 2 groups was not significant .(TIF)Click here for additional data file.S5 FigThe difference between the 2 groups was significant (p = 0.02).(TIF)Click here for additional data file.S6 FigThe difference between the 2 groups was significant (p = 0.03).(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DTA)Click here for additional data file.


Breast arterial calcification (BAC) may be a predictor of cardiovascular events and is highly prevalent in persons with end-stage kidney disease. However, few studies to date have examined the association between mild-to-moderate kidney function and proteinuria with BAC.We prospectively enrolled women with no prior cardiovascular disease aged 60 to 79 years undergoing mammography screening at Kaiser Permanente Northern California between 10/24/2012 and 2/13/2015. Urine albumin-to-creatinine ratio (uACR), along with specific laboratory, demographic, and medical data, were measured at the baseline visit. Baseline estimated glomerular filtration rate (eGFR), medication history, and other comorbidities were identified from self-report and/or electronic medical records. BAC presence and gradation (mass) was measured by digital quantification of full-field mammograms.2, with 85.7% having uACR ≥30 mg/g and 3.3% having uACR ≥300 mg/g. The prevalence of any measured BAC (>0 mg) was 27.9%. Neither uACR ≥30 mg/g nor uACR ≥300 were significantly associated with BAC in crude or multivariable analyses. Reduced eGFR was associated with BAC in univariate analyses , but the association was no longer significant after adjustment for potential confounders. Results were similar in various sensitivity analyses that used different BAC thresholds or analytic approaches.Among 3,507 participants, 24.5% were aged ≥70 years, 63.5% were white, 7.5% had eGFR <60 ml/min/1.73mAmong women without cardiovascular disease undergoing mammography screening, reduced eGFR and albuminuria were not significantly associated with BAC. Arterial calcification is a prominent predictor of cardiovascular morbidity and mortality, and is common among patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD).–5 SeveraBreast arterial calcification (BAC) can be observed on routine mammography and is considered to be primarily medial calcification. Prior stSimilar to coronary artery calcification, BAC has been found to be more prevalent among patients with advanced CKD or ESRD treated with chronic dialysis, although limited evidence exists for an independent or graded relationship between less severe kidney dysfunction and BAC., 19–21 TToward that end, we explored the independent association between measures of kidney function and damage with a novel, continuous measure of BAC mass in women with no prior cardiovascular disease undergoing screening mammography.The source population was based in Kaiser Permanente Northern California (KPNC), a large, integrated healthcare delivery system that currently provides comprehensive care for >4.2 million members. The KPNC membership is highly representative of the local surrounding and statewide population in terms of age, gender and race/ethnicity. Nearly aThis study was approved by the institutional review boards of Kaiser Permanente Northern California and University of California, Irvine, and all participants provided written informed consent.The MultIethNic study of brEast aRterial calcium gradation and cardioVAscular disease (MINERVA) is a prospective cohort study of women aged 60 to 79 years without known clinical cardiovascular disease who were receiving regular mammography screening. PatientsOur primary predictors of interest were eGFR calculated using the CKD-EPI equation based onOur main outcome was BAC measured by analysis of full-field digital mammograms . Standard digital mammograms were acquired by trained mammography technicians and transmitted using a secure FTP connection to a workstation for image analysis at the Department of Radiological Sciences, University of California, Irvine. Using mediolateral oblique and craniocaudal projections, arterial calcium mass was quantified (in mg) in each projection and then summed to obtain an estimate of total BAC burden.International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes and supplemented with laboratory test results , outpatient vital signs, and/or prescribed medications using electronic health record-based data that were linked at the individual-patient level into the Kaiser Permanente Northern California Virtual Data Warehouse (KPNC VDW) as previously described and validated.[Demographic characteristics, social history and lifestyle factors, and selected comorbidities were obtained through the self-administered questionnaire at the baseline visit. Laboratory results, including serum calcium, high sensitivity C-reactive protein (hs-CRP), glycosylated hemoglobin (HbA1C), hemoglobin, low density lipoprotein (LDL) cholesterol, phosphorous, parathyroid hormone (PTH), and vitamin D, were also collected at the baseline visit. Other relevant cardiovascular and medical comorbidities were defined by diagnostic or procedure alidated.–39 Diabe2 tests for categorical variables.All analyses were conducted using SAS, version 9.3 . Baseline characteristics were compared across presence (BAC >0 mg) or absence (BAC = 0 mg) of BAC using ANOVA for continuous variables and χ2, and uACR was classified as a binary variable using two primary cutoffs: ≥30 mg/g and ≥300 mg/g, which is consistent with clinical microalbuminuria and macroalbuminuria, respectively. We also examined the association between kidney dysfunction and BAC >0 mg stratified by race/ethnicity.We next conducted nested logistic regression models for two thresholds of BAC (>0 and BAC ≥10 mg), as well as ordinal logistic regression using tertiles of the BAC distribution among the subset of patients with BAC >0 mg. We categorized eGFR as a binary variable at <60 vs. ≥60 mL/min/1.73 mThe series of nested models progressively adjusted for additional categories of potential confounders and explanatory variables. Sociodemographic variables included age, race, educational attainment, household income, marital status, and whether the patient was born in the US. Lifestyle factors included use of alcohol in the past year, smoking status, and hours of physical activity per week. Reproductive history included age at menarche, age periods stopped, polycystic ovary syndrome, receipt of menopausal hormone therapy, history of breastfeeding, and number of children. Prior history of cardiovascular risk factors and diseases, ascertained from records in the KPNC VDW, included atrial fibrillation or flutter, mitral and/or aortic valvular disease, diabetes mellitus, hypertension, and dyslipidemia, as well as ankle-brachial index measured at the baseline visit. Medical history identified from the MINERVA baseline survey included prior migraine, gout, osteoporosis, osteoarthritis, depression, self-reported health status, and parental history of stroke, heart failure, and heart attack. Other medical history identified from the VDW records included hyperthyroidism, hypothyroidism, cirrhosis, chronic lung disease, and hospitalized bleeds. Baseline medication use included prior receipt of angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers, diuretics, aldosterone receptor antagonists, alpha blockers, antiarrhythmic agents, nitrates, other vasodilators, non-aspirin antiplatelet agents, statins, other lipid-lowering agents, anti-diabetic agents, and non-steroidal anti-inflammatory drugs based on pharmacy dispensing within 30 days before or on the baseline visit date. Lastly, we hypothesized that a category of potential biological mediators may help to explain any observed independent relationship between kidney function or damage with BAC; this included systolic blood pressure, body mass index, waist circumference, and calcium, hs-CRP, HBA1c, hemoglobin, LDL cholesterol, phosphorous, parathyroid hormone, and vitamin D levels.In a sensitivity analysis using linear regression, we modeled log-transformed BAC ) because the distribution of BAC among participants was non-normally distributed. To account for the high prevalence of patients with no detected BAC, we fit loess curves for continuous eGFR, log(uACR) and log(BAC + 0.05) among only those with BAC >0 mg.Lastly, we conducted another sensitivity analysis using a case-control approach matching CKD patients to non-CKD patients at a 1:1 ratio on age group  and race category . After matching, odds ratios and corresponding McNemar’s exact 95% confidence limits were calculated.Table 1). Women with any measured BAC were more likely than women with no BAC to be older; have lower educational attainment and mean household income; to have used alcohol in the past year; had more children; had a prior history of gout, osteoporosis, atrial flutter or fibrillation, hypertension, chronic lung disease, and hospitalized bleeds; have a higher systolic blood pressure, and have a lower baseline eGFR level.Among 5,145 enrolled participants, we identified a final analytic sample of 3,507 women who met eligibility criteria. Approximately two thirds of the sample was white, with a majority having at least a bachelor’s degree (73.3%), mean household income greater than $60,000/year (66.0%), married (54.7%), born in the US (78.3%), drank alcohol in the past year (79.9%), and non-smokers (61.3%) and a low prevalence of uACR ≥300 mg/g (3.3%). The prevalence of any measured BAC (>0 mg) was 27.9% and 7.5% had BAC >10 mg, with the distribution of BAC mass highly right-skewed among the overall population as well as among the subset with non-zero BAC mass . Examples of minimal, mild, and severe BAC can be seen in Fig 2.At entry, 7.5% of participants had CKD, defined as an eGFR of <60 mL/min/1.73 mp = 0.002) and 10 mg (p = 0.01) thresholds (Table 2).Among uACR categories, BAC prevalence using either cutoff was not significantly different. However, patients with CKD had significantly higher unadjusted prevalence of BAC at both the 0 mg (Table 3).We next conducted logistic regression models for to examine the association of uACR and eGFR with BAC using both thresholds. We found that there was no significant univariate association of uACR ≥30 mg/g with BAC, and results did not materially change after serial adjustment for several categories of potential confounders or mediators (Table 4). However, these associations were attenuated and no longer statistically significant with the addition of sociodemographic characteristics (Table 4). Additional adjustment for other potential confounders or mediators did not materially affect the observed associations. We observed a stronger unadjusted association between CKD and BAC >0 mg among 412 black participants , but this association was attenuated and no longer significant after adjustment for sociodemographic characteristics. There was no significant crude association between CKD and BAC in Hispanic or Asian/Pacific Islander participants. In sensitivity analyses using linear regression analyses between continuous eGFR or log-transformed uACR with log-transformed BAC, we also found no significant associations. In the case-control analysis, the 262 CKD patients were successfully matched to 262 non-CKD patients on age and race categories. Among CKD patients, 95 (36.3%) had BAC >0 mg and 30 (11.5%) had BAC >10 mg. Among non-CKD patients, 82 (31.3%) had BAC >0 mg and 24 (9.2%) had BAC >10 mg. The odds ratio for BAC >0 mg was 1.25 (95% CI: 0.85–1.83) and for BAC >10 mg was 1.28 (95% CI: 0.70–2.37), both indicating a non-statistically significant difference in BAC between CKD patients and non-CKD patients.In unadjusted models, we found that CKD was associated with higher odds of BAC >0 mg  and BAC >10 mg   was present in 28% of participants which was higher than reported in previous studies, and approximately 1 in 12 participants had BAC >10 mg. In addit2 increase 0.96, 95%CI:0.92–0.99).[2 and found that progression of BAC was not increased in patients with an eGFR ≥40 mL/min/1.73m2.[To date, few studies have examined the association of eGFR or albuminuria with BAC. Hassan et al. studied 292 patients with CKD or ESRD from 2006–2011, along with the same number of controls matched on age, race and diabetes status. Presence92–0.99). However,92–0.99). A more r14–18 Several potential mechanisms have been identified in which CKD may influence vascular calcification, including dysregulation of mineral bone metabolism, with recent studies suggesting osteogenic transdifferentiation in vascular smooth muscle cells leading to calcification, although this may not affect all vascular beds in the same manner.[Previous studies of kidney dysfunction suggest a positive association with intimal calcification of the coronary arteries and valves,–7, 10 bue manner., 11, 202 (89.2% of CKD patients). This may reduce the generalizability of our results to more advanced CKD populations. Our participants were derived from an integrated health care delivery system in northern California that is heavily focused on primary prevention as reflected by the relatively high use of antihypertensive and lipid-modifying therapies shown in While our findings support that kidney function and proteinuria may have differential associations with different arterial distributions, we believe that our findings should be considered in the context of several limitations. First, despite enrolling a diverse and well-characterized cohort, by design, we excluded patients with any known clinical CVD which likely affected the prevalence and severity of BAC as well as the representation of more severe CKD or albuminuria. In our cohort, we observed a relatively low presence of CKD (7.5%) with the majority of CKD patients having an eGFR between 45–59 mL/min/1.73mIn sum, among women with no known CVD undergoing regular mammography screening, we found that reduced eGFR and albuminuria were not significantly associated with BAC. Future studies should evaluate whether BAC influences the risk of future CVD events across the spectrum of kidney function.


Background Few reports have evaluated the relationship between changes in postprandial blood pressure and the severity of autonomic dysfunction in patients with type 2 diabetes. This was a cross-sectional study designed to investigate postprandial blood pressure changes in individuals without type 2 diabetes and patients with type 2 diabetes and mild or severe cardiac autonomic dysfunction. Methods Forty patients with type 2 diabetes mellitus and 20 individuals without type 2 diabetes participated in this study. Fifty-two participants underwent a meal tolerance test. Blood pressure  and central systolic blood pressure (cSBP)), electrocardiogram recordings, and blood samples were assessed before and after meal ingestion. Patients with diabetes were divided into two groups based on their coefficient of variation of R–R intervals (CVRR): a normal or mildly dysfunctional group  and a severely dysfunctional group . Results In the control group, bSBP and cSBP did not significantly change after meal ingestion, whereas both decreased significantly at 60 min after meal ingestion in the mild and severe groups. While blood pressure recovered at 120 min after meal ingestion in the mild group, a significant decrease in blood pressure persisted at 120 min after meal ingestion in the severe group. Conclusions Based on these results, adequate clinical attention should be paid to the risk of serious events related to postprandial decreases in blood pressure, particularly in patients with diabetes and severe cardiac autonomic dysfunction. Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, action, or both . Long-tePrevious studies have shown that the prevalence of hypertension is increased in patients with DM . Tight cA critical symptom of hypotension in patients with DM is postprandial hypotension (PPH) . PostpraFurther, for blood pressure measurements, the importance of measuring central systolic blood pressure (cSBP), as performed in this study, is that this measure is more closely related to cardiovascular events compared to peripheral blood pressure and is recognized by studies such as the Anglo-Scandinavian Cardiac Outcomes Trial Conduit Artery Function Endpoint (ASCOT-CAFE) study ,13. HoweGiven this gap in the existing research, we hypothesized that there might be a difference in the change in postprandial blood pressure in patients with T2DM and mild or severe cardiac autonomic dysfunction when measuring both brachial systolic blood pressure (bSBP) and cSBP and that there would be a positive correlation between the decrease in postprandial blood pressure and the severity of autonomic dysfunction.The purpose of the present study was as follows: (1) to investigate differences in the change in postprandial blood pressure in individuals without T2DM and patients with T2DM and mild or severe cardiac autonomic dysfunction by measuring brachial systolic blood pressure (bSBP) as well as cSBP; and (2) to clarify the relationship between changes in postprandial blood pressure and the severity of autonomic dysfunction.2), pregnancy, and treatment with a β-blocker. We also recruited 20 individuals without T2DM through advertisements at the Graduate School of Health Sciences, Kobe University . The only control group inclusion criterion was an age of 40–80 years. Control group exclusion criteria included pre-existing diabetes, cardiovascular disease, arrhythmias such as atrial fibrillation, pregnancy, being a night-shift worker, and smoking. The study was approved by the Ethics Committee of the Graduate School of Health Sciences, Kobe University . The purpose and risk of this study was explained to each participant before their written informed consent was obtained.This was a cross-sectional study, which included 40 patients with T2DM and 20 individuals without T2DM. Patients with T2DM were recruited from outpatients and inpatients at Akashi Medical Center  and Tatsuno Central Hospital . All patients were diagnosed according to the Japan Diabetes Society’s T2DM criteria . Study iAssessments began at 11:30. After 10 min of rest in a seated position, blood pressure and radial arterial waveforms were measured. The measurement of cSBP was performed simultaneously. An electrocardiogram (ECG) was then obtained while the patient was in a supine position. After this, intravenous blood samples were collected from the brachial vein. Starting at 12:00, participants were served a test meal . The participants were those who had completely consumed a meal within 15–20 min. The same set of measurements was then repeated at 60 (13:00) and 120 (14:00) minutes after the participants began their meal. During the measurement period, participants were allowed to drink only water (less than 500 mL) in addition to the test meal.Brachial systolic blood pressure, brachial diastolic blood pressure (bDBP), and cSBP were measured using a digital automated sphygmomanometer . Brachial systolic blood pressure and bDBP measurements were recorded using a cuff around the right upper arm. Pressure waveforms in the radial artery were recorded non-invasively using a tonometric approach. Early systolic pressure (SBP1), late systolic pressure (SBP2), and augmentation index (AI) were also measured and calculated automatically by the HEM-9000AI using the following equations: AI = (SBP2 − DBP)/(SBP1 − DBP), SBP2 (mmHg) = AI × (SBP − DBP) + DBP. Because Takazawa et al.  demonstr2. We divided the patients based on their CVRR into two groups: a normal or mild cardiac autonomic dysfunction  and a severe cardiac autonomic dysfunction . A CVRR value of 2% is considered the critical level below which diabetic autonomic neuropathy occurs [t-tests and Fisher’s exact test. Changes in measured variables following meal ingestion were examined using two-way ANOVAs for repeated measures and the Bonferroni post-hoc test. Pearson’s correlation analyses were performed to identify correlations between preprandial blood pressure (bSBP and cSBP), and the magnitude of postprandial change in bSBP over 1 or 2 h  or cSBP over 1 or 2 h , calculated by subtracting preprandial blood pressure from postprandial blood pressure. A correlation analysis was also used to assess any correlation between preprandial CVRR and the magnitude of postprandial blood pressure change .Data were expressed as the mean value ± standard error. Body mass index (BMI) was calculated using the following equation: BMI = body weight (kg)/height (m)y occurs . Differep-values, and the completeness of the models were assessed by the coefficients of determination. Statistical analyses were conducted using SPSS version 20 . A p-value of less than 0.05 was considered to indicate statistical significance.A stepwise multiple linear regression analysis was performed to evaluate the independent variables that were associated with the magnitude of postprandial change in blood pressure for all subjects. The independent variables were ∆bSBP1hr, ∆bSBP2hrs, ∆cSBP1hr, and ∆cSBP2hrs. The following factors were used as dependent variables: age, BMI, CVRR, bSBP, and plasma glucose at baseline. The effectiveness of the models was assessed by n = 12) and calcium channel blockers (n = 8). The mean CVRR in the severe group was 1.45 ± 0.11%, which was significantly lower than that in the mild group . In addition, the mean CVRR in the mild group was significantly lower than that in the control group (p < 0.05). There were no significant differences in age or measures of blood pressure, such as bSBP and cSBP, among the groups.During meal tolerance testing, plasma glucose significantly increased at 60 min in all groups A. Serum p < 0.01; from 131.8 ± 3.87 to 122.6 ± 3.22 mmHg in the severe group, p < 0.01). This decrease in bSBP recovered by 120 min in the mild group (134.3 ± 3.04 mmHg), whereas a significant decrease in bSBP persisted at 120 min in the severe group ; the decrease in cSBP recovered at 120 min in the mild group (138.1 ± 3.22 mmHg), whereas a significant decrease in cSBP persisted at 120 min in the severe group , whereas ∆bSBP2hrs was not. Similarly, ∆cSBP1hr was significantly and negatively correlated with cSBP at baseline , whereas ∆cSBP2hrs was not. ∆bSBP2hrs  and ∆cSBP2hrs  were significantly and positively correlated with CVRR, whereas ∆bSBP1hr and ∆cSBP1hr did not significantly correlate with CVRR.Pearson’s correlation analysis revealed that ∆bSBP1hr was significantly and negatively correlated with bSBP at baseline (As shown in The main findings of this study are as follows: (1) cSBP, as well as bSBP, decreased after meal ingestion in patients with T2DM and both mild and severe cardiac autonomic dysfunction; furthermore, the decline in bSBP and cSBP at 60 min after meal ingestion correlated with preprandial bSBP and cSBP, respectively. (2) Postprandial decreases in both bSBP and cSBP persisted longer in patients with T2DM and severe cardiac autonomic dysfunction, resulting in a magnitude of decline in bSBP and cSBP at 120 min after meal ingestion that was independently associated with CVRR. These results suggest that adequate clinical attention should be paid to possible serious events related to PPH, especially in patients with T2DM and severe cardiac autonomic dysfunction.In this study, bSBP decreased at 60 min after meal ingestion not only in patients with severe autonomic dysfunction but also in those with mild autonomic dysfunction, suggesting that a postprandial decrease in blood pressure might occur in the early stage of T2DM. In the present study, blood pressure was maintained and HR was increased in middle-aged individuals without diabetes after meal ingestion. The difference in postprandial decreases in blood pressure between individuals without T2DM and patients with T2DM could be attributed to differences in their compensatory response to postprandial hemodynamic change . That isOur study results are in concordance with those of previous studies. For instance, some studies have found that postprandial blood pressure was maintained in healthy participants despite vasodilation and splanchnic blood pooling caused by gastrointestinal vasoactive peptides ,18,19. IIn the present study, we found that ∆bSBP1hr significantly correlated with preprandial bSBP. Previous studies have made similar observations among elderly or hypertensive patients. For example, Vaitlevicius et al.  reportedAlthough the precise mechanisms which result in PPH have not been clearly elucidated, earlier studies ,29,30,31We also found that CVRR was independently related to ∆bSBP2hr and had a greater influence than bSBP. This suggests that more severe cardiac autonomic dysfunction might delay recovery from decreases in blood pressure. To the best of our knowledge, this study is the first to report that postprandial decrease in blood pressure persists longer in patients with T2DM and severe cardiac autonomic dysfunction. Furthermore, impaired sympathetic activation due to severe cardiac autonomic dysfunction might not increase peripheral resistance, which was diminished by vasodilation after meal ingestion. Masuda et al.  suggesteIn the present study, as with bSBP, cSBP also decreased in patients with both mild and severe autonomic dysfunction. The decrease in the severe group persisted for up to 120 min after meal ingestion. Therefore, we extended the findings observed in bSBP to cSBP. As mentioned above, in general, cSBP is recognized to be more closely related to cardiovascular events compared to peripheral blood pressure, as demonstrated by studies such as ASCOT-CAFE study . cSBP isOur study has some limitations that warrant discussion. First, we did not measure gastrointestinal hormones beyond insulin. Our results suggest that insulin might not play a major role in PPH in patients with T2DM. It is necessary to further investigate other hormonal mechanisms and the rate of gastric emptying and mesenteric blood flow to clarify additional potential mechanism of PPH. Second, as blood pressure was only measured for 120 min after meal ingestion, blood pressure recovery from hypotension was not observed in patients with severe autonomic dysfunction. While postprandial decreases in blood pressure recovered at 120 min after meal ingestion in patients with mild autonomic dysfunction, this decrease in blood pressure persisted in patients with severe autonomic dysfunction. Had we taken measurements for a longer period of time after meal ingestion, we might have been able to clarify the point at which postprandial hypotension recovers in patients with severe autonomic dysfunction. Third, the present study’s sample size was relatively small. In addition, we did not perform power calculations to determine the number of subjects. Fourth, in the control group, there was no established definition of CVRR, and an oral glucose tolerance test (OGTT) or HbA1c evaluation were not performed. In the control participants, the plasma glucose before meal ingestion was 99.3 ± 1.81 mg/dL, and none had levels exceeding 110 mg/dL, which is the criterion for impaired fasting glucose (IFG). Because we did not perform an OGTT in the control group, we cannot exclude the possibility that individuals with impaired glucose tolerance (IGT) were included. While this is a limitation, the plasma glucose at 120 min after meal ingestion was 108.5 ± 6.59 mg/dL, and no individuals had levels higher than 140 mg/dL. Therefore, we believe that it is unlikely that individuals with IGT were included in the control group and that the probability of misclassification bias is low. Finally, while numerous mechanisms may account for blood pressure reduction after meal ingestion, these remain poorly understood and worthy of additional investigation.The present study revealed that postprandial decreases in bSBP and also cSBP occurred in patients with T2DM and both mild and severe cardiac autonomic dysfunction. Furthermore, we found that postprandial decreases in blood pressure persisted for longer in patients with T2DM and severe cardiac autonomic dysfunction. In addition, cardiac autonomic dysfunction was associated with the magnitude of blood pressure decline at 120 min after meal ingestion. Given these findings, attention should be paid to the possible serious events related to PPH, especially in patients with T2DM and severe cardiac autonomic dysfunction.