Chronic kidney disease-associated pruritus (CKD-aP), one of the most common and intolerable complications in hemodialysis patients, not only seriously affects patients' quality of life and physical and mental health, but also increases the risk of long-term mortality. The pathogenesis of CKD-aP remains unclear, and immune-inflammatory dysregulation, imbalance of endogenous opioid system, abnormal accumulation of metabolites, xerosis, abnormal histamine level as well as hyperparathyroidism, have all been shown to be associated with pruritus. There is a lack of satisfactory and effective treatment strategies for CKD-aP, which mainly include pharmacological treatment, non-pharmacological treatment and dialysis modality modification. This article mainly reviews recent advances in the pathogenesis and pharmacological treatment of pruritus among hemodialysis patients.

Polycystic kidney disease (PKD) is a hereditary kidney disease characterized by the formation of numerous cysts in the kidneys, which progressively impairs renal function over time. PKD is primarily divided into two types: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), with ADPKD being more prevalent. Current treatments primarily focus on symptom relief and disease progression delay, lacking a curative approach. However, the development of gene editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-Cas9) and adeno-associated virus (AAV) vectors has offered new therapeutic possibilities for ADPKD and ARPKD. These include approaches like antisense oligonucleotides (ASO), adenovirus-mediated gene knockdown, CRISPR- Cas9, Pkd1 gene enhancement therapy, and the use of induced pluripotent stem cells (iPSCs), which have shown potential efficacy in animal models and early clinical studies. Despite facing technological challenges, ethical and legal issues, and high costs, gene therapy presents an unprecedented hope for PKD treatment. Future interdisciplinary collaboration and international cooperation are essential for developing more effective treatment strategies for PKD patients.

BACKGROUND: Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted. METHODS: We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored. RESULTS: Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2-5] loci vs. 5 [3-5] loci, P  = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P  = 0.024). On the other hand, those with decreased CD4 + /CD8 + T-cell ratio developed more fever (0.8 [0.7-1.2] vs. 1.4 [1.1-2.2], P  = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932-0.995, P  = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859-0.975, P  = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control. CONCLUSIONS Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.
Humans ; Leukocytes, Mononuclear ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Leukemia, Myeloid, Acute/therapy* ; Unrelated Donors ; Granulocyte Colony-Stimulating Factor ; Graft vs Host Disease

Objective:To investigate the injury effect of hyperoxali acid on human arterial endothelial cells (HAECs) and its mechanism.Methods:HAECs were divided into intervention group and control group according to whether oxalic acid was used for intervention. The cells in the intervention group were stimulated with 30, 100, 200 and 300 μmol/L oxalic for different time. The effect of oxalic acid on the proliferation of HAECs was detected by MTT colorimetry. The change of cell cycle was analyzed by flow cytometry. The content of intracellular calcium was detected by fluorescence detection technology. The protein and mRNA expressions of cell cycle and anion transporter-related proteins were detected by Western blotting and fluorescence quantitative PCR. Besides, JAK2/STAT3 signaling pathway-related proteins were measured by Western blotting.Results:MTT colorimetry results showed that the intervention groups with high concentration of oxalic acid (100, 200, 300 μmol/L) could significantly inhibit the proliferation of HAECs, which was significantly different from the control group (all P<0.05). Fluorescence detection showed that the contents of intracellular calcium of HAECs in the intervention groups with high concentration of oxalic acid (100, 200, 300 μmol/L) were significantly higher than those in the control group after 48 hours ( P<0.05, P<0.001, P<0.001, respectively). Flow cytometry showed that the proportion of S phase of cells in the 200 μmol/L oxalic acid intervention group was significantly higher than that in the control group ( P<0.05). The results of Western blotting and PCR showed that the relative protein and mRNA expressions of anion transporter-related proteins slc26a1, slc26a5, slc26a11 in the intervention groups were higher than those in the control group (all P<0.05). Western blotting showed that the expression of p-JAK2 and p-STAT3 in the intervention groups after 24 hours were significantly higher than those in control group (all P<0.05). Conclusions:Hyperoxalic acid may enter HAECs through transporters slc26a1, slc26a5 and slc26a11 to inhibit cell proliferation and increase the intracellular calcium concentration. The mechanism may be through the activation of JAK2/STAT3 signaling pathway. Therefore, oxalic acid may be one of the uremic toxins leading to atherosclerosis.

Objective: To screen the chronic kidney disease (CKD) patients among the high-risk groups in Jing'an district of Shanghai, and provide suggestions for the screening and analysis of CKD. Methods: Retrospective analysis was used to analyze the disease status of high-risk groups of CKD who participated in community screening from July 2016 to November 2018. A total of 25 199 subjects underwent two laboratory examinations at intervals of more than 3 months. The CKD was diagnosed in high-risk groups according to the diagnostic criteria, and the patients with CKD were classified and stratified. The screening population was divided into groups according to gender, age and medical history to compare the difference in the detection rate of CKD. Results: There were 788 CKD patients diagnosed previously in this screening population, and 3 713 CKD patients were confirmed by this district-level hospitals screening. Potential CKD patients were 4.71 times as many as previously known CKD patients. The CKD detection rate was 14.73%. The CKD detection rate of female high-risk group was higher than that of male (16.00% vs 13.00%, χ²=44.213, P<0.001). The CKD detection rate in the elderly group (≥65 years old) was higher than that in the non-elderly group (14.94% vs 13.76%, χ²=4.001, P=0.046). The CKD detection rate in high-risk group with hypertension, hyperuricemia and family history of chronic nephritis was significantly higher than those in the group without such diseases (all P<0.05). Conclusions The number of patients detected in high-risk groups of CKD is 4.71 times as much as previously known patients, indicating that it is very necessary to carry out CKD screening in community high-risk group. Women, elder, hypertension, hyperuricemia, and a family history of chronic nephritis are independent risk factors for patients at high risk of CKD.

Objective:To explore the role and mechanism of C3a-C3a receptor (C3aR) in the progression of autosomal dominant polycystic kidney disease (ADPKD).Methods:Renal tissues of ADPKD patients and PKD1 knockout mice were collected. Then the expression of C3a-C3aR, Ki67 and F4/80 in renal tissues was observed. Macrophages were stimulated with lipopolysaccharide (LPS) and interleukin 4 respectively. The expression of C3aR, TNF-α, typing markers and related signal pathway proteins was detected in each group. PKD1 knockout mice were treated with C3aR inhibitor SB290157 (1 mg/kg). Renal pathology, cyst-related indicators and renal function were observed. Results:The expression of C3a and C3aR in ADPKD was up-regulated (both P<0.05); C3aR and F4/80 were co-located in the kidney of polycystic kidney disease (PKD) mice, indicating that C3aR was mainly expressed on membrane of macrophages. In vitro, the expression of C3aR was up-regulated in M1 macrophages ( P<0.05). After the stimulation of C3a, the expression of iNOS, TNF-α and IL-6 mRNA in M1 macrophages were up-regulated (all P<0.05), as well as the secretion of TNF-α, indicating that C3a not only affected the expression of inflammatory factors of M1 macrophages, but also affected the inflammatory microenvironment. In addition, C3a significantly activated Akt in M1 macrophages ( P<0.05). Compared with the control group, the treatment group showed a decrease in C3a-C3aR as well as serum BUN, Scr, cyst index, and two kidneys weight/body weight (2KW/BW) (all P<0.05), and ADPKD related pathway protein expression such as p-ERK and p-P65 was significantly down-regulated (all P<0.05). Conclusions:The increased C3a in polycystic kidney tissue causes infiltration and activation of macrophages through C3aR, and then promotes ADPKD progression. The mechanism may be mediated by Akt activation and increased TNF-α production. C3aR antagonist is a potential research direction in the treatment of ADPKD.

Objective To screen Oxalobacter formigenes (OxF) from fresh feces of healthy adults,and study its effect on the the prevention of calcium oxalate kidney stones.Methods OxF was screened and cultured from fresh feces of healthy adults.The rat model of calcium oxalate stone was established by esophageal gavage of 0.8％ of ethylene glycol.Rats were divided into a control group and four groups of rats with ethylene glycol-induced calcium oxalate kidney stones according to random number table.Three groups were treated with 106 CFU,107 CFU,108 CFU viable OxF every day,respectively,for 4 weeks.The blood and 24-hour urine samples were collected to detect the serum creatinine,urea nitrogen,serum and urine calcium,phosphorus,magnesium and urine oxalate every week.At the end of the 4th week,the rats were sacrificed and the kidney tissues were stained with HE and Yasue.The deposition and content of calcium oxalate crystals were observed under a light microscope.Results The bacteria strain isolated from fresh feces of healthy adults was 100％ as same as the known ATCC35274 bacteria strain,which means the strain screened is OxF.Among the 5 groups,there were no significant differences in body weight,Scr,BUN,serum calcium,blood magnesium,blood phosphorus,urinary magnesium and urinary phosphorus.The 24-hour urinary calcium excretion in the model group was significantly lower than that of the control group (P ＜ 0.05).After intervention with OxF solution,the 24-hour urinary calcium excretion in the 108 CFU OxF group was significantly higher than that in the model group (P ＜ 0.05),while there was no significant difference between the other intervention groups and the model.The oxalic acid excretion of 106 CFU OxF group and 107 CFU OxF group was lower than that of the model,but the difference did not reach statistical significance (P＞ 0.05).The 24 h oxalic acid excretion in the 108 CFU OxF group was significantly lower than that of the model at the end of first week (P ＜ 0.05),and continued to decrease for the next 3 weeks.After 4 weeks of intervention,no crystal formation was observed in the control group under the deflection microscope,but a large amount of calcium oxalate crystals were formed in the renal cortex and renal medulla.The crystals were piled up and connected to each other.Yasue staining coincided with the calcium oxalate crystal in the same part of the kidneys.Compared with the model,there was no significant change in the score of calcium oxalate crystal in the kidneys of 106 CFU OxF group and 107 CFU OxF group,while the score of calcium oxalate crystal in the kidneys of 108 CFU OxF group was significantly lower (P ＜ 0.05).Conclusions OxF are successively screened from healthy adults.Daily administration of 108 CFU OxF can safely and effectively reduce the urinary oxalic acid excretion,prevent the formation of calcium oxalate crystals and inhibit the formation of stones in kidneys of rats.

Objective To investigate the changes of thyroid function and carotid atherosclerosis in patients on maintenance hemodialysis (MHD).Methods A total of 110 stable MHD patients undergoing hemodialysis for at least three months were enrolled in the study.Serum free-T3 (FT3), free-T4 (FT4) and thyroid stimulating hormone (TSH) concentrations were measured by electrochemiluminescence.Plasma levels of homocysteine (Hcy) and C-reactive protein (CRP) were detected.Clinical data and biochemical indicators were collected.These patients were divided into thyroid dysfunction group and euthyroidism group.Prevalence of atherosclerosis was detected by carotid ultrasonography.The associations between the changes of thyroid function and carotid atherosclerosis were analyzed by Logistic regression model.Results Among these 110 patients, 42 (38.18％) patients had thyroid dysfunction.Hcy and CRP concentrations were significantly higher in thyroid dysfunction group than those in euthyroidism group (P ＜ 0.05).The intima-media thickness, number of plague and arteriostenosis of carotid were higher in thyroid dysfunction group than those in euthyroidism group (P ＜ 0.05).Multivariate logistic regression analysis showed that increased Hcy and CRP, decreased serum FT3 were independent risk factors for carotid atherosclerosis.Conclusions Thyroid dysfunction with low serum FT3 is frequently found in MHD patients.In MHD patients, FT3 is closely correlated to carotid atherosclerosis.

Objective To explore the role of Hippo pathway in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD),and find potential targets for drug therapy.Methods By means of immunofluorescence staining,Western blotting,Real-time PCR,the differences of sublocalization,expression and phosphorylation level about Hippo pathway molecules in Han:SPRD (cy/+) and ADPKD patients compared with the control were observed.Knockdown Yes kinaseassociated protein (YAP),transcriptional coactivator with PDZ binding motif (TAZ) and large tumor suppressor kinase1 (LATS1) in cystic lining epithelium cell line WT9-12 were took by siRNA interference,and then their effects on cell proliferation,apoptosis and cell cycle were assessed.Results In cystic lining epithelium of Han:SPRD(cy/+),decreased expression of LATS1 and increased expression of YAP were found compared with the control,and the immunofluorescence of YAP was distributed both in cytoplasm and nucleus,while distribution and expression level of TAZ were without significant variance.Abnormal mRNA expressions of Hippo pathway components in ADPKD patients were found (P ＜ 0.05).Down-regulation of LATS1 in WT9-12 cells could prohibit phosphorylation of YAP,and prompted proliferation and cell division.Knockdown YAP in WT9-12 cells could inhibited cell proliferation by arresting cell cycle in G0/G1 phase,but down-regulating TAZ showed no significant differences in proliferation and cell cycle.Conclusions Altered Hippo signaling exists in ADPKD,and YAP activation may be one leading cause of autosomal dominant polycystic kidney disease onset.In vitro,knockdown YAP in WT9-12 cells can inhibit cell proliferation by arresting cell cycle and depressing cell division,suggesting the expression level and activity of YAP are potential targets for ADPKD treatment.

Objective To observe the impact of heparanase on glomerular endothelium glycocalyx during sepsis and to investigate the prevention of glycocalyx injury.Methods C57/BL6 mice were injected with lipopolysaccharide (LPS) or tumor necrosis factor-α(TNF-o) and sacrificed one hour later.Glomerular endothelium glycocalyx traced with lanthanum was observed by transmission electron microscope(TEM).Western blotting was used to observe heparanse protein expression of renal cortex tissue.Human renal glomerular endothelial cells (HRGECs) were stimulated with TNF-α and active heparanase protien expression was detected by Western blotting.Mice were administrated with heparin sodium or heparinase Ⅲ and renal endothelium glycocalyx was observed by TEM.Urine during twenty-four hours was collected to measure urinary albumin and creatinine.The ratio of albumin to creatinine was calculated and compared among groups.Results The glomerular endothelium glycocalyx of LPS group and TNF-α group was degradated and the one of podocyte was integrated.Renal cortex tissue heparanase protein expression was significantly increased since one hour after LPS injection (P ＜ 0.01).The protein expression of activited heparanase of HRGECs which were stimulated with TNF-α was increased (P ＜ 0.05).Administration of heparin sodium which could inhibit the activity of heparanase could prevent the glycocalyx form degradation.The ratio of urine albumin to creatinine of heparin sodium group was decreased compared with LPS group (P ＜ 0.05) and the ratio of heparinase Ⅲ group was higher than control group(P ＜ 0.01) as a result of degradation of glomerular endothelium glycocalyx.Conclusions During the early stage of sepsis,TNF-α can induce glomerular endothelium heparanase to increase and active,and consequently the glycocalyx is degradated which leads to albuminuria.Inhibition of heparanase can protect glomerular endothelium glycocalyx and prevent albuminuria.