Role of TGFß-producing regulatory T cells in scleroderma and end-stage organ failure.

Regulatory T cells (Tregs) are crucial immune cells that initiate a tolerable immune response. Transforming growth factor-beta (TGFß) is a key cytokine produced by Tregs and plays a significant role in stimulating tissue fibrosis. Systemic sclerosis, an autoimmune disease characterized by organ fibrosis, is associated with an overrepresentation of regulatory T cells. This review aims to identify Treg-dominant tolerable host immune reactions and discuss their association with scleroderma and end-stage organ failure. End-stage organ failures, including heart failure, liver cirrhosis, uremia, and pulmonary fibrosis, are frequently linked to tissue fibrosis. This suggests that TGFß-producing Tregs are involved in the pathogenesis of these conditions. However, the exact significance of TGFß and the mechanisms through which it induces tolerable immune reactions during end-stage organ failure remain unclear. A deeper understanding of these mechanisms could lead to improved preventive and therapeutic strategies for these severe diseases.

Sex hormone binding globulin (SHBG) serum levels and insulin resistance in men on chronic hemodialysis.

BACKGROUND: In males with end stage renal disease biochemical hypogonadism is a frequent finding. Testosterone and sex hormone binding globulin (SHBG) have been associated with insulin resistance, a well-known condition in uremia. The aim of the present study was to investigate in males on chronic hemodialysis the relationship of testosterone and SHBG serum levels with insulin resistance. METHODS: In a cross-sectional study we enrolled men treated with chronic hemodialysis who did not suffer from an acute illness or other endocrinopathy, as well as primary hypogonadism, and were not hospitalised. Diabetes mellitus, diabetic nephropathy or previous transplantation were not exclusion criteria. As controls we used a community-based group of healthy males matched for age and Body Mass Index (BMI). We assessed the BMI (kg/m2) from body weight and height, the body fat content (%) by bioelectrical impedance and serum testosterone (ng/ml), SHBG (nmol/L) and estradiol (pg/ml) by standard methods. Testosterone < 3.25 ng/ml defined biochemical hypogonadism. In non-diabetic males, we calculated the homeostasis model assessment index (HOMA-R), an estimate of insulin resistance, from serum fasting insulin and glucose. RESULTS: 27 men (age 54.4 ± 19 years) on chronic hemodialysis (treatment duration 29.1 ± 14.4 months) and 51 healthy men (age 47.1 ± 9.6 years) were included. In men on hemodialysis vs. healthy men there were increased serum levels of SHBG (40.9 ± 26.9 vs. 27.6 ± 11.9 nmol/L; p = 0.031) and a significantly enhanced frequency of biochemical hypogonadism (22.2 vs. 3.9%; p = 0.011). In cases without diabetes (n = 22) a significant correlation was observed between the HOMA-R (r = -0.586, p = 0.004) and the fasting insulin levels (r = -0.650, p = 0.001) on the one hand and the serum SHBG levels on the other. CONCLUSIONS: Our findings confirm enhanced prevalence of biochemical hypogonadism in males on chronic hemodialysis. In non-diabetic cases the serum levels of SHBG correlated with serum insulin and insulin resistance.

Magnetic Resonance Imaging in Uremic Encephalopathy: Identifying Key Imaging Patterns and Clinical Correlations.

Background/Objectives: Magnetic Resonance Imaging (MRI) is essential in diagnosing neurological conditions, offering detailed insights into brain pathology. Uremic encephalopathy (UE) is a severe neurological disorder resulting from renal failure, characterized by cognitive impairments and brain abnormalities due to the accumulation of uremic toxins (UTs). Despite extensive research on UTs, there is a significant gap in the detailed characterization of MRI findings in UE patients. This study aims to bridge this gap by conducting a comprehensive literature review of cerebral MRI findings in UE. We hypothesize that specific MRI patterns correlate with the severity and clinical manifestations of UE, thereby enhancing diagnostic accuracy and improving patient outcomes. Methods: A literature review was performed using PubMed, Cochrane Library, and Google Scholar. The search terms included "uremic encephalopathy MRI", "uremia and kidney failure MRI", and "toxic and metabolic or acquired encephalopathies MRI". The inclusion criteria were original articles on UE and MRI findings published in English. Results: Common MRI sequences include T1-weighted, T2-weighted, FLAIR, and DWI. Frequent MRI findings in UE are cytotoxic and vasogenic brain edema in regions such as the basal ganglia and periventricular white matter. Patterns like the "lentiform fork sign" and basal ganglia involvement are key indicators of UE. Conclusions: MRI plays a crucial role in diagnosing UE by identifying characteristic brain edema and specific patterns. A comprehensive diagnostic approach, incorporating clinical, laboratory, and imaging data, is essential for accurate diagnosis and management. The study calls for larger well-designed cohorts with long-term follow-up to improve the understanding and treatment of UE.

Myoclonus, Uremia, and Delirium in a Liver Transplant Recipient: A Case Report and Literature Review.

BACKGROUND: Consultation-liaison (CL) psychiatrists are frequently asked to consult on various abnormal movements (1). CL psychiatrists can be instrumental in aiding the primary teams to identify and manage these movement disorders. In this manuscript, we provide an illustrative case of a patient presenting with myoclonus and offer a review on this important topic. Myoclonus accompanied by delirium represents a rare post-transplant complication and can be associated with heightened morbidity and mortality. The incidence of this complication in solid organ transplant recipients is scarcely documented, and its pathophysiology remains inadequately understood. Potential etiologies in the intensive care unit are numerous and likely multifactorial. The literature lacks detailed descriptions of the correlation and association between myoclonus and uremia. Management of this condition requires a multimodal approach, focusing on resolving underlying metabolic disturbances and providing symptomatic treatment. OBJECTIVE: This manuscript describes the clinical presentation of myoclonus in a liver transplant recipient accompanied by delirium and precipitated by uremia. We aim to highlight the diagnostic and therapeutic complexities, help providers distinguish myoclonus from other movement disorders, and aid appropriate management. METHODS AND RESULTS: We present a case of acute myoclonus in an elderly female liver transplant recipient precipitated by uremia and improved after continuous renal replacement treatment. In addition, we conducted a systematic review utilizing EMBASSE and PubMed of reported cases of myoclonus, delirium, and/or encephalopathy accompanied by uremia. We included 12 manuscripts in our review and discussed their findings. CONCLUSIONS: CL psychiatrists are frequently consulted for a range of movement disorders in the intensive care unit, including myoclonus. Accurate diagnosis and identification of contributing etiologies are critical in these cases. Management typically involves addressing the underlying disorder, such as using dialysis for uremia, alongside symptomatic treatment with benzodiazepines to mitigate the frequency and amplitude of myoclonus. This approach helps to alleviate both the physical burden and psychological distress associated with the condition. This case underscores the pivotal role of the CL psychiatrist within a complex multidisciplinary team, contributing to diagnostic precision and optimization of management strategies for movement disorders.

Agreement between lacrimal fluid and serum for detecting urea nitrogen and creatinine in dogs.

OBJECTIVE: To determine whether urea nitrogen and creatinine levels differ in lacrimal fluid (LF) and serum (SER) in nonazotemic (control) and azotemic dogs and whether there is an agreement between LF and SER. METHODS: A prospective observational study was performed at the Auburn University Small Animal Teaching Hospital between May 2023 and March 2024. Forty control and 38 azotemic dogs were enrolled. Twenty microliters of LF per eye was collected with microcapillary tubes, and 3 mL of blood was drawn. Bland-Altman plot and intraclass correlation coefficient (ICC) were used to evaluate the agreement between LF and SER. RESULTS: There was good agreement between LF and SER levels of urea nitrogen in the control group (Bland-Altman plot mean bias of -0.8108 ± 2.407 mg/dL; ICC of 0.874 [95% CI, 0.773 to 0.934]) and the azotemic group (Bland-Altman plot mean bias of -9.681 ± 23.89 mg/dL; ICC of 0.82 [95% CI, 0.658 to 0.906]). There was poor agreement between LF and SER concentrations for creatinine in the control and azotemic groups, with only 26 dogs with creatinine detectable in LF. CONCLUSIONS: Lacrimal fluid and SER concentrations of urea nitrogen showed good agreement in both the control and azotemic groups, whereas poor agreement was found for creatinine in both groups. CLINICAL RELEVANCE: Measurement of urea nitrogen in LF may provide an alternative to blood for diagnosing uremia. However, additional research is necessary before substituting LF for SER.

Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis.

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.

Adequacy of Dialysis and Incidence of Atrial Fibrillation in Patients Undergoing Hemodialysis.

BACKGROUND: Atrial fibrillation (AF) can lead to stroke, heart failure, and mortality and has a greater prevalence in dialysis patients than in the general population. Several studies have suggested that uremic toxins may contribute to the development of AF. However, the association between dialysis adequacy and incident AF has not been well established. METHODS: In this retrospective nationwide cohort study, we analyzed data from the Korean National Periodic Hemodialysis Quality Assessment from 2013 to 2015 of patients who received outpatient maintenance hemodialysis 3× a week. The main exposure was single pooled Kt/V (spKt/V), which is the dialysis adequacy index, and the primary outcome was the development of AF. For the primary analysis, patients were categorized into quartiles according to baseline spKt/V. The lowest quartile, representing the lowest adequacy, was used as the reference group. Fine-Gray subdistribution hazard models were used, treating all-cause mortality as a competing risk. RESULTS: Of 25 173 patients, the mean age was 60 (51-69) years, and 14 772 (58.7%) were men. During a median follow-up of 5.7 years, incident AF occurred in a total of 3883 (15.4%) patients. Participants with a higher spKt/V tended to have lower AF incidence. In survival analysis, a graded association was observed between the risk of incident AF and spKt/V quartiles: subdistribution hazard ratios and 95% CIs for the second, third, and the highest quartile compared with the lowest quartile were 0.90 (95% CI, 0.82-0.98), 0.84 (95% CI, 0.77-0.93), and 0.79 (95% CI, 0.72-0.88), respectively. CONCLUSIONS: This nationwide cohort study showed that a higher spKt/V is associated with a reduced risk of incident AF. These findings suggests that reducing uremic toxin burden through enhanced dialysis clearance may be associated with a lower risk of AF development in patients undergoing maintenance hemodialysis.

Risk factors for cardiovascular and cerebrovascular events in patients with uremia and hypertension during maintenance hemodialysis.

OBJECTIVES: This study aimed to investigate risk factors for major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with uremia and hypertension during maintenance hemodialysis (MHD). METHODS: Clinical data of patients with uremia and refractory hypertension admitted to Changzhou Fourth People's Hospital (Changzhou Tumor Hospital) from February 2018 to February 2022 were retrospectively collected and analyzed. All patients were treated with MHD and categorized into an MACCE group and a non-MACCE group according to whether MACCEs occurred during the treatment cycle. Univariate analysis and multivariate logistic regression analysis were applied to identify the risk factors for MACCEs in the patients during the treatment period. RESULTS: (1) A total of 156 patients were included in this study, among whom 75 patients were in the MACCE group and 81 in the non-MACCE group, with an MACCE incidence of 48.08%. (2) Diabetes, body mass growth rate, triglyceride (TG), N-terminal pro-brain natriuretic peptide (NT-proBNP), as well as the standard deviation (SD) and coefficient of variability (CV) for both systolic (SBP) and diastolic blood pressure (DBP) showed significant differences between the two groups, with P<0.05. (3) Diabetes, body mass growth rate ≥5.54%, TG≥1.40 mmol/L, NT-proBNP≥5.82 ng/L, SBP-SD≥13.52, SBP-CV≥8.63, DBP-SD≥8.14, and DBP-CV≥8.82 were found to be risk factors for MACCEs in the patients. CONCLUSIONS: The incidence of MACCEs in patients with uremia and hypertension during MHD was associated with diabetes, body mass growth rate, TG, NT-proBNP, SBP-SD, SBP-CV, DBP-SD, and DBP-CV.Early screening for high-risk patients and positive intervention measures should be given to reduce the risk of MACCEs to enhance the safety of dialysis procedures.

A Historical Perspective on Uremia and Uremic Toxins.

Uremia, also known as uremic syndrome, refers to the clinical symptoms in the final stage of renal failure. The definition of the term has changed over time due to an improved comprehension of the kidney's function and the advancement of dialysis technology. Here, we aim to present an overview of the various concepts that have developed regarding uremia throughout the years. We provide a comprehensive review of the historical progression starting from the early days of Kolff and his predecessors, continuing with the initial research conducted by Niwa et al., and culminating in the remote sensing hypothesis of Nigam. Additionally, we explore the subsequent investigation into the function of these toxins as signaling molecules in various somatic cells.

Renal candidiasis associated with papillary necrosis in a captive tiger (Panthera tigris).

A 14-year-old male tiger developed anorexia with elevated blood urea nitrogen and creatinine levels. The patient had a palpable abdominal mass and demonstrated neutrophilic leukocytosis and anaemia. Leukocytes, yeast and bacteria were present in the urine. The animal was non-responsive to therapy and was subsequently euthanised. Extensive acute renal papillary necrosis (RPN) with pyelonephritis, chronic nephritis and polycystic renal disease were evident during gross and microscopic pathology examinations. The histologic occurrence of fungal spores and pseudohyphae morphologically consistent with Candida species were observed within the necrotic papillary regions of the kidney and within multiple foci of mild parakeratotic hyperkeratosis present in the gingiva and tongue. Candida albicans along with a slight growth of Escherichia coli were recovered from kidney cultures. Possible contributory factors for the renal candidiasis and associated RPN include predisposing oral candidiasis, polycystic renal disease, ischaemic nephrosclerosis, age-associated or other forms of immunodeficiency and therapy with meloxicam, a non-steroidal anti-inflammatory drug. The absence of apparent lower urinary tract involvement coupled with the presence of intravascular renal 'Candida emboli' suggest that chronic oral candidiasis was the probable source of the kidney infection.

Clinical features, treatment, and outcomes of patients with carfilzomib induced thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is associated with carfilzomib, and knowledge of carfilzomib-induced TMA is based mainly on case reports. This study investigated the clinical characteristics of patients with carfilzomib-induced TMA and provided a reference for the rational use of carfilzomib. METHODS: Reports of carfilzomib-induced TMA were collected for retrospective analysis by searching the Chinese and English databases from inception to January 31, 2024. RESULTS: Sixty-six patients were included, with a median age of 63 years (range 39, 85). The median time to onset of TMA was 42 days (range 1, 1825) from initial administration, and the median number of cycles was 3 cycles (range 1, 15). Hemolytic anemia was recorded in 64 patients, with a median of 8.3 g/dL (range 4.6, 13). Sixty-three patients had thrombocytopenia with a median of 18 × 109/L (range 1, 139). The median value of increased LDH was 1192 IU/L (range 141, 5378). ADAMTS13 activity was normal in 41 (62.1 %) of the 42 patients. Mutations were found in 9 (13.6 %) of the 15 patients. Fifty-seven patients achieved a clinical response after discontinuing carfilzomib and receiving therapeutic plasma exchange (53.0 %), eculizumab (24.2 %), or hemodialysis (39.4 %). CONCLUSION: Carfilzomib-induced TMA is an important adverse event that should be considered in patients receiving carfilzomib for multiple myeloma with anemia, thrombocytopenia, and acute kidney injury. Withdrawal of carfilzomib and treatment with eculizumab have proven successful in some patients.

The serum levels of gasdermin D in uremic patients and its relationship with the prognosis: a prospective observational cohort study.

OBJECTIVE: This study aimed to explore the serum levels of gasdermin D (GSDMD) in uremic (end-stage kidney disease, ESKD) patients and their correlation with vascular calcification (VC) and clinical results. METHODS: This prospective observational cohort study enrolled 213 ESKD patients who were undergoing regular maintenance hemodialysis (MHD) for > 3 months in our hospital from August 2019 to July 2022. The abdominal aortic calcification score (AACS) was used to assess the VC condition of patients with ESKD. Serum GSDMD, caspase-1, interleukin (IL)-6, IL-1ß, IL-18 and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA). Demographic and clinical data were obtained. All patients were followed up for 1 year, and patients with major adverse cardiovascular events (MACE) were defined as having a poor prognosis. All data used SPSS 26.0 to statistical analyses. RESULTS: The serum total cholesterol (TC) levels of patients in the AACS > 4 group were significantly elevated compared with those in the AACS ≤ 4 group. In addition, ESKD patients with an AACS > 4 had significantly higher serum levels of GSDMD, caspase-1, IL-6, IL-18 and IL-1ß. Moreover, Pearson's analysis supported a positive correlation between GSDMD and caspase-1, IL-6, and IL-1ß. In addition, we found that GSDMD levels were positively correlated with the clinical data (AACS scores and serum TC levels) of patients with ERSD. Additionally, ROC curves showed that the serum levels of GSDMD could be a potential predictive biomarker of moderate/severe VC and prognosis in patients with ESKD. Finally, the results of logistic regression indicated that GSDMD and AACS scores were risk factors for poor prognosis in patients with ESKD. CONCLUSION: Serum GSDMD levels were remarkably elevated in patients with ESKD with moderate/severe calcification. In addition, serum levels of GSDMD could be a potential predictive biomarker of moderate/severe VC and prognosis in patients with ESKD.

IgG4-related disease presenting with acute kidney injury and tubulointerstitial nephritis.

Immunoglobulin G-4 related disease (IgG4-RD) is an immune-mediated, inflammatory disease that often involves multiple organ systems. IgG4-RD can be classified according to the organs involved. Type 1 IgG4-RD is related to acute pancreatitis and sclerosing cholangitis. Disease manifestation is also seen in the retroperitoneal region, pelvic organs, and orbital space. Here we describe a rare case of IgG4-RD causing isolated acute kidney injury.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

Progress in clinical application of external treatment of TCM in uremic pruritus / 国际中医中药杂志

Uremic pruritus (UP) is a common complication in patients with end-stage renal disease, which seriously reduces the quality of life of patients. Compared with the internal treatment of TCM, the external treatment of TCM for UP is simpler and more effective, and can avoid the first pass effect caused by oral drugs and may cause liver and kidney damage. The treatment methods mainly include external washing of TCM, medicated bath, fumigation, wet compress, enema, scraping, acupuncture, auricular point sticking, acupoint application, acupoint iontophoresis, autologous blood acupoint injection and so on. At present, most studies are based on the conventional treatment of Western medicine, and the addition of external treatment of TCM can improve the efficacy, and has certain advantages in improving itching symptoms, inflammatory indicators, sleep quality, anxiety and depression. Some studies have selected parathyroid hormone, blood phosphorus, CRP, IL-6, histamine, SCr, BUN, β2-microglobulin and other indicators to evaluate the efficacy. The results suggest that external treatment of TCM can improve the micro-inflammatory state of patients and protect renal function, but further mechanism research is needed. The existing research has the following problems: the clinical efficacy evaluation scale is not uniform, and it is difficult to compare and summarize horizontally; the relief of pruritus symptoms is based on the scale evaluation, which is subjective; the course of treatment is short, and the long-term efficacy and safety can not be evaluated; some studies do not specify the patients' syndrome type, which is difficult to reflect the advantages of TCM syndrome differentiation and treatment, and needed to be improved in the future.

Effects of echinacoside on renal injury in uremia rats and its mechanism / 中国药房

OBJECTIVE To investigate the effects of echinacoside （ECH） on renal injury in uremia （URE） rats and its mechanism. METHODS URE model of the rat was established by 5/6 nephrectomy. Successfully modeled rats were grouped into uremia group （URE group）， ECH low-dose [10 mg/（kg·d）] group， ECH medium-dose [20 mg/（kg·d）] group， ECH high-dose [40 mg/（kg·d）] group， ECH high-dose+anisomycin [p38 mitogen-activated protein kinase （p38 MAPK） pathway activator] group [ECH-H+Ani group， 40 mg/（kg·d） ECH +2 mg/（kg·d） anisomycin]， with a sham operation group， 12 mice in each group. Each drug group was given corresponding ECH intragastrically， while ECH-H+Ani group was further injected with anisomycin via the tail vein， once a day， for 8 consecutive weeks. The serum levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， IL-6， blood urea nitrogen （BUN）， β2-microglobulin （β2-MG）， serum creatinine （Scr）， neutrophil gelatinase-associated lipocalin （NGAL）， kidney injury molecule-1 （KIM-1）， cystatin C （Cys-C） and 24 h urine protein （24 h UP） as well as the levels of malondialdehyde （MDA） and superoxide dismutase （SOD） activity in renal tissue were all detected； pathological changes of renal tissue were observed； the rate of positive expression of α-smooth muscle protein （α-SMA） and E-cadherin， and the phosphorylation of p38 MAPK and nuclear factor-κB （NF-κB） p65 were determined in renal tissue of rats. RESULTS Compared with URE group， glomerular swelling， damage and necrosis of renal tubular epithelial cells and inflammatory cell infiltration were relieved significantly in ECH groups. The renal injury score， levels of TNF-α， IL-1β， IL-6， BUN， Scr， β2-MG， 24 h UP， NGAL， KIM- 1， Cys-C and MDA， the positive expression rate of α-SMA in renal tissue， the phosphorylation of p38 MAPK and NF-κB p65 were decreased in dose-dependent manner， while SOD activity and the positive expression rate of E-cadherin were obviously increased in dose-dependent manner （P＜0.05）. Anisomycin significantly attenuated the improvement effect of high-dose ECH on renal injury in URE rats （P＜0.05）. CONCLUSIONS ECH may inhibit inflammation and oxidative stress， enhance renal function， and improve renal injury in uremic rats by inhibiting the activation of p38 MAPK/NF-κB signaling pathway.

Deletion of the aryl hydrocarbon receptor in endothelial cells improves ischemic angiogenesis in chronic kidney disease.

Chronic kidney disease (CKD) is a strong risk factor for peripheral artery disease (PAD) that is associated with worsened clinical outcomes. CKD leads to the accumulation of tryptophan metabolites that are associated with adverse limb events in PAD and are ligands of the aryl hydrocarbon receptor (AHR), which may regulate ischemic angiogenesis. To test if endothelial cell-specific deletion of the AHR (AHRecKO) alters ischemic angiogenesis and limb function in mice with CKD subjected to femoral artery ligation. Male AHRecKO mice with CKD displayed better limb perfusion recovery and enhanced ischemic angiogenesis compared with wild-type mice with CKD. However, the improved limb perfusion did not result in better muscle performance. In contrast to male mice, deletion of the AHR in female mice with CKD had no impact on perfusion recovery or angiogenesis. With the use of primary endothelial cells from male and female mice, treatment with indoxyl sulfate uncovered sex-dependent differences in AHR activating potential and RNA sequencing revealed wide-ranging sex differences in angiogenic signaling pathways. Endothelium-specific deletion of the AHR improved ischemic angiogenesis in male, but not female, mice with CKD. There are sex-dependent differences in Ahr activating potential within endothelial cells that are independent of sex hormones.NEW & NOTEWORTHY This study provides novel insights into the mechanisms by which chronic kidney disease worsens ischemic limb outcomes in an experimental model of peripheral artery disease. Deletion of the aryl hydrocarbon receptor (AHR) in the endothelium improved ischemic angiogenesis suggesting that AHR inhibition could be a viable therapeutic target; however, this effect was only observed in male mice. Subsequent analysis in primary endothelial cells reveals sex differences in Ahr activating potential independent of sex hormones.

Single-cell RNA sequencing reveals transdifferentiation of parathyroid chief cells into oxyphil cells in patients with uremic secondary hyperparathyroidism.

The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease.

Assessing Cross-Sectional Association of Uremic Pruritus with Serum Heavy Metal Levels: A Single-Center Study.

(1) Background: Uremic pruritus (UP) is a common and taxing symptom in patients on maintenance hemodialysis (MHD). We have previously shown that blood lead levels (BLLs) and blood aluminum levels (BALs) were separately positively associated with UP in MHD patients. We also found that blood cadmium levels (BCLs) were positively associated with all-cause mortality and cardiovascular-related mortality in MHD patients. We wondered whether there is any correlation between BCLs and UP after adjusting for BLLs and BALs. (2) Methods: Patients enrolled in this study were all from three hemodialysis (HD) centers at Chang Gung Memorial Hospital, Lin-Kou Medical Center, including both the Taipei and Taoyuan branches. Correlations between UP and BLLs, BALs, BCLs, and other clinical data were analyzed. (3) Results: Eight hundred and fifty-three patients were recruited. Univariate logistic regressions showed that diabetes mellitus, hepatitis B virus infection, hepatitis C virus infection, HD duration, hemodiafiltration, dialysis clearance of urea, normalized protein catabolic rate, non-anuria, serum albumin levels, log (intact-parathyroid hormone levels), total serum cholesterol levels, serum low-density lipoprotein levels, log (blood aluminum levels), and log (blood lead levels) were associated with UP. Although log BCLs were not significantly associated with UP (p = 0.136) in univariate analysis, we still included log BCLs in multivariate logistic regression to verify their effect on UP given that our aim in this study was to verify associations between serum heavy metals and UP. Multivariate logistic regressions showed that log BLLs (OR: 27.556, 95% CI: 10.912-69.587, p < 0.001) and log BALs (OR: 5.485, 95% CI: 2.985-10.079, p < 0.001) were positively associated with UP. The other logistic regression, which stratified BLLs and BALs into high and low BLLs and BALs, respectively, showed that high BLLs or high BALs (low BLLs and low BALs as reference) (OR: 3.760, 95% CI: 2.554-5.535, p < 0.001) and high BLLs and high BALs combined (low BLLs and low BALs as reference) (OR: 10.838, 95% CI: 5.381-21.828, p < 0.001) were positively correlated with UP. (4) Conclusions: BLLs and BALs were positively correlated with UP. BCLs were not correlated with UP. Clinicians should pay more attention to the environmental sources of lead and aluminum to prevent UP.