Hepatic arterial infusion of autologous CD34+ cells for hepatitis C virus-related decompensated cirrhosis: A multicenter, open-label, exploratory randomized controlled trial.

Introduction: In this multicenter clinical study, we aimed to investigate the efficacy and safety of the transhepatic arterial administration of granulocyte-colony stimulating factor (G-CSF)-mobilized autologous peripheral blood (PB)-CD34+ cells compared with standard therapy in patients with decompensated cirrhosis type C. Methods: Patients were randomly assigned (2:1) to the CD34+ cell transplant (CD34+ cell) or standard-of-care (SOC) group and followed up for 52 weeks. The primary endpoints were the non-progression rate of Child-Pugh (CP) scores at 24 weeks post-enrollment and the safety of the protocol treatment. Results: Fourteen patients (CD34+ cell group: 10; SOC group: 4) were enrolled. CP scores at 24 weeks had a non-progression rate of 90% in the CD34+ cell group and 100% in the SOC group, with no significant difference between groups. Importantly, 4 out of 10 patients in the CD34+ cell group exhibited an improvement from decompensated to compensated cirrhosis, whereas all patients in the SOC group remained in decompensated cirrhosis. With regard to secondary endpoints, a trend toward increased serum albumin levels in the CD34+ cell group was noted. Serious adverse events (SAEs) occurred in three patients in the CD34+ cell group and in one patient in the SOC group. No causal relationship was observed between all SAEs and G-CSF, leukapheresis, or cell transplantation in the CD34+ cell group. No patients died and no hepatocellular carcinoma occurred within the study period. Conclusions: PB-CD34+ cell infusion therapy may have the potential to circumvent the decompensated stage of cirrhosis, thus avoiding the need for liver transplantation.

Artificial Intelligence Reporting Guidelines' Adherence in Nephrology for Improved Research and Clinical Outcomes.

The use of artificial intelligence (AI) in healthcare is transforming a number of medical fields, including nephrology. The integration of various AI techniques in nephrology facilitates the prediction of the early detection, diagnosis, prognosis, and treatment of kidney disease. Nevertheless, recent reports have demonstrated that the majority of published clinical AI studies lack uniform AI reporting standards, which poses significant challenges in interpreting, replicating, and translating the studies into routine clinical use. In response to these issues, worldwide initiatives have created guidelines for publishing AI-related studies that outline the minimal necessary information that researchers should include. By following standardized reporting frameworks, researchers and clinicians can ensure the reproducibility, reliability, and ethical use of AI models. This will ultimately lead to improved research outcomes, enhanced clinical decision-making, and better patient management. This review article highlights the importance of adhering to AI reporting guidelines in medical research, with a focus on nephrology and urology, and clinical practice for advancing the field and optimizing patient care.

A disease-specific iPS cell resource for studying rare and intractable diseases.

BACKGROUND: Disease-specific induced pluripotent stem cells (iPSCs) are useful tools for pathological analysis and diagnosis of rare diseases. Given the limited available resources, banking such disease-derived iPSCs and promoting their widespread use would be a promising approach for untangling the mysteries of rare diseases. Herein, we comprehensively established iPSCs from patients with designated intractable diseases in Japan and evaluated their properties to enrich rare disease iPSC resources. METHODS: Patients with designated intractable diseases were recruited for the study and blood samples were collected after written informed consent was obtained from the patients or their guardians. From the obtained samples, iPSCs were established using the episomal method. The established iPSCs were deposited in a cell bank. RESULTS: We established 1,532 iPSC clones from 259 patients with 139 designated intractable diseases. The efficiency of iPSC establishment did not vary based on age and sex. Most iPSC clones originated from non-T and non-B hematopoietic cells. All iPSC clones expressed key transcription factors, OCT3/4 (range 0.27-1.51; mean 0.79) and NANOG (range 0.15-3.03; mean 1.00), relative to the reference 201B7 iPSC clone. CONCLUSIONS: These newly established iPSCs are readily available to the researchers and can prove to be a useful resource for research on rare intractable diseases.

Therapeutic application of regeneration-associated cells: a novel source of regenerative medicine.

Chronic diseases with comorbidities or associated risk factors may impair the function of regenerative cells and the regenerative microenvironment. Following this consideration, the vasculogenic conditioning culture (VCC) method was developed to boost the regenerative microenvironment to achieve regeneration-associated cells (RACs), which contain vasculogenic endothelial progenitor cells (EPCs) and anti-inflammatory/anti-immunity cells. Preclinical and clinical studies demonstrate that RAC transplantation is a safe and convenient cell population for promoting ischemic tissue recovery based on its strong vasculogenicity and functionality. The outputs of the scientific reports reviewed in the present study shed light on the fact that RAC transplantation is efficient in curing various diseases. Here, we compactly highlight the universal features of RACs and the latest progress in their translation toward clinics.

Dialysis-related Amyloidosis Presenting as a Fever of Unknown Origin: Symptoms and Management.

A 74-year-old woman with a 34-year history of hemodialysis presented with an intermittent fever, which later coincided with recurrent bilateral shoulder and hip joint pain. Imaging studies suggested amyloid arthropathy, which was histologically confirmed by a synovial biopsy. Increasing ß2-microglobulin clearance during dialysis alone attenuated the intermittent fever and joint pain, but the symptoms did not disappear until the administration of prednisolone 10 mg/day. Reported cases of dialysis-related amyloidosis with a fever imply that changing to blood purification methods with high ß2-microglobulin clearance is crucial for controlling the condition long-term, whereas concurrent use of anti-inflammatory agents promptly alleviates the symptoms.

CD34 positive cells as endothelial progenitor cells in biology and medicine.

CD34 is a cell surface antigen expressed in numerous stem/progenitor cells including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which are known to be rich sources of EPCs. Therefore, regenerative therapy using CD34+ cells has attracted interest for application in patients with various vascular, ischemic, and inflammatory diseases. CD34+ cells have recently been reported to improve therapeutic angiogenesis in a variety of diseases. Mechanistically, CD34+ cells are involved in both direct incorporation into the expanding vasculature and paracrine activity through angiogenesis, anti-inflammatory, immunomodulatory, and anti-apoptosis/fibrosis roles, which support the developing microvasculature. Preclinical, pilot, and clinical trials have well documented a track record of safety, practicality, and validity of CD34+ cell therapy in various diseases. However, the clinical application of CD34+ cell therapy has triggered scientific debates and controversies in last decade. This review covers all preexisting scientific literature and prepares an overview of the comprehensive biology of CD34+ cells as well as the preclinical/clinical details of CD34+ cell therapy for regenerative medicine.

Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice.

BACKGROUND: There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD). AIM: To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice. METHODS: Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet. RESULTS: Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001). CONCLUSION: Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.

A novel low-density lipoprotein/fibrinogen apheresis method for chronic limb-threatening ischemia in patients with poor options for revascularization: A multicenter, single-arm clinical trial.

INTRODUCTION: Low-density lipoprotein (LDL) apheresis is a treatment option for patients with unhealed chronic limb-threatening ischemia (CLTI) after revascularization. The newly developed AS-25 is a direct hemoperfusion-type apheresis device that differs from conventional LDL apheresis therapy and is designed to specifically adsorb both LDL-C and fibrinogen. We evaluate the efficacy and safety of AS-25. METHODS: This study included 61 patients whose ulcers failed to heal after revascularization or were ineligible for revascularization. Of these, 50 were undergoing hemodialysis. The primary endpoint was the healing rate of a target lesion of interest (ulcer), using historical data as control. RESULTS: The ulcer healing rate of 45.9% was significantly higher than the historical data. No significant safety concerns were observed. CONCLUSIONS: AS-25 was effective in healing ulcers and preventing major amputation even in CLTI refractory patients on hemodialysis, thus showing potential clinical applicability and high significance. CLINICAL TRIAL REGISTRATION: UMIN study ID UMIN000020336.

Association of Hyperkalemia and Hypokalemia with Patient Characteristics and Clinical Outcomes in Japanese Hemodialysis (HD) Patients.

This study aimed to examine the characteristics and clinical outcomes of Japanese hemodialysis patients with dyskalemia. A retrospective study was conducted using a large Japanese hospital group database. Outpatients undergoing thrice-a-week maintenance hemodialysis were stratified into hyperkalemia, hypokalemia, and normokalemia groups based on their pre-dialysis serum potassium (sK) levels during the three-month baseline period. Baseline characteristics of the three groups were described and compared for the following outcomes during follow-up: all-cause mortality, all-cause hospitalization, major adverse cardiovascular events (MACE), cardiac arrest, fatal arrythmia, and death related to arrhythmia. The study included 2846 eligible patients, of which 67% were men with a mean age of 65.65 (SD: 12.63) years. When compared with the normokalemia group (n = 1624, 57.06%), patients in the hypokalemia group (n = 313, 11.00%) were older and suffered from malnutrition, whereas patients in the hyperkalemia group (n = 909, 31.94%) had longer dialysis vintage. The hazard ratios for all-cause mortality and MACE in the hypokalemia group were 1.47 (95% confidence interval [CI], 1.13-1.92) and 1.48 (95% CI, 1.17-1.86), respectively, whereas that of death related to arrhythmia in the hyperkalemia group was 3.11 (95% CI, 1.03-9.33). Thus, dyskalemia in maintenance hemodialysis patients was associated with adverse outcomes, suggesting the importance of optimized sK levels.

Relationship between Lower Extremity Peripheral Arterial Disease and Mild Cognitive Impairment in Hemodialysis Patients.

BACKGROUND: The link between arterial stiffness and mild cognitive impairment (MCI) in patients on hemodialysis (HD) has been receiving increased attention. The purpose of this study was to investigate the relationship between cognitive function and ankle brachial index (ABI) and toe brachial index (TBI) values in patients on hemodialysis. Of the 100 participants (mean age: 67.9 years; average history of hemodialysis: 7.3 years). Of these, 46.0% had MCI. The MoCA-J scores were significantly higher in the ABI ≥ 1.06 group. However, the MoCA-J scores divided into the two groups according to the TBI cutoff value were not significantly different. In a multiple regression model with the MoCA-J scores as the objective variable, the ABI was a significantly associated factor. This study indicates that a low ABI might be associated with MCI.

Malnutrition and Insulin Resistance May Interact with Metabolic Syndrome in Prevalent Hemodialysis Patients.

BACKGROUND: We sought to determine the prevalence of metabolic syndrome (Mets) and whether 100 cm2 of visceral fatty area (VFA) measured by computed tomography (CT) validates the criteria of waist circumference (WC) in hemodialysis (HD) patients. METHODS: The study comprised 141 HD patients. Mets was defined according to the criteria of Adult Treatment Panel III (ATP III) and the modified criteria of National Cholesterol Education Program (NCEP) that defines abdominal obesity as a WC of >=85 cm in men and >=90 cm in women. RESULTS: The prevalence of Mets was 31.9% in men and 13.6% in women. However, the prevalence of patients with a body mass index over 25 in all HD patients was only 11.2%. The visceral fatty area (VFA) measured by CT showed a strong positive correlation with WC. The patients with Mets, comparing with those without Mets, have significantly shorter duration of HD, higher high-sensitive C-reactive protein, and higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In the patients with Mets, there was a significant negative correlation between HOMA-IR and serum albumin levels. Multivariate logistic regression analysis showed that HOMA-IR and short duration of HD were chosen as independent risk factors for Mets. CONCLUSIONS: Mets is more prevalent in HD patients. In Japanese HD patients, 100 cm2 of VFA corresponded to a WC of 85 cm in men and 90 cm in women, thus confirming the validity of the modified criteria. HOMA-IR and serum albumin were significantly correlated in HD patients with Mets.

Transcranial Doppler Echography Measurement in Hemodialysis Patients: The Potential Role of Angiotensin II Receptor Blockades on Cerebrovascular Circulation.

BACKGROUND: Although hemodialysis (HD) patients have an elevated risk of strokes, there are few reports about transcranial doppler (TCD) echography measurements. It is well-known that angiotensin II receptor blockades (ARBs) protect against cardiovascular complications. In this study, we measured intracranial artery (ICA) velocity using TCD echography and studied the associated factors with its velocity in HD patients by a comparison with or without ARBs. METHODS: We conducted a cross-sectional study in a single hospital. We included 61 patients who had measurable ICA velocity by TCD echography. Among them, the ARB usage group consisted of 22 subjects, whilst the non-ARB usage group consisted of 39 subjects. RESULTS: Patients in the ARB (+) and ARB (-) groups did not show any difference in basic characteristics. ICA blood flow velocity in all intracranial arteries tended to show greater values in the ARB group than those in the non-ARB group. Particularly, blood velocity in the middle cerebral artery (MCA) (maximal flow velocity) statistically increased in the ARB group, respectively. In a univariate analysis, MCA maximum velocity was significantly associated with ARB usage (p = 0.011) and low hematocrit levels (p = 0.045). The multivariate analysis chose only ARB usage as an independent factor associated with left MCA maximum velocity (p = 0.022). CONCLUSIONS: We showed that dialysis patients with ARBs have significantly higher ICA blood velocity. ARBs might have a potential benefit for maintaining ICA blood flow in HD patients.

Impact of the 3% Oxygen Desaturation Index via Overnight Pulse Oximetry on Cardiovascular Events and Death in Patients Undergoing Hemodialysis: A Retrospective Cohort Study.

It is unclear whether the severity of sleep-disordered breathing (SDB) affects the risk of cardiovascular events and mortality in patients undergoing hemodialysis (HD). We determined the severity of SDB with the 3% oxygen desaturation index (ODI) via overnight pulse oximetry. This study was a retrospective cohort, observational study of 134 patients on maintenance HD at a single center. They were divided into four groups according to SDB severity (normal, mild, moderate, and severe), and were followed. The baseline characteristics of all patients were as follows: the median age was 67 (interquartile range, 59-75) years, 64.2% were men, 37.3% were diabetic, and the median duration of HD was 69 (29-132) months. During follow-up, major adverse cardiovascular events (MACEs) occurred in 71 patients and deaths in 60 (including 32 cardiovascular deaths). Severe SDB was an independent risk factor for MACEs (hazard ratio [HR] = 4.66, 95% confidence interval [CI] = 1.87-11.61, p = 0.001) and all-cause death (HR = 5.74, 95% CI = 1.92-16.70, p = 0.001). Severe SDB had a statistically significant impact on the risk of MACEs and mortality in patients undergoing HD. The severity of the 3% ODI via overnight pulse oximetry may be a useful marker as a risk factor for cardiovascular outcomes and mortality in these patients.

The Characteristics of Dialysis Membranes: Benefits of the AN69 Membrane in Hemodialysis Patients.

Patients undergoing hemodialysis (HD) experience serious cardiovascular complications, through malnutrition, inflammation, and atherosclerosis. Amputation for peripheral arterial disease (PAD) is more prevalent in patients undergoing HD than in the general population. In addition, revascularization procedures in dialysis patients are often associated with subsequent amputation and high mortality rates. To improve the prognosis of dialysis patients, malnutrition and inflammation must be properly treated, which necessitates a better understanding of the characteristics of dialysis membranes. Herein, the characteristics of several dialysis membranes were studied, with a special reference to the AN69 membrane, noting several similarities to low-density lipoprotein (LDL)-apheresis, which is also applicable for the treatment of PAD. Both systems (LDL-apheresis and AN69) have anti-inflammatory and anti-thrombogenic effects because they use a negatively charged surface for extracorporeal adsorptive filtration from the blood/plasma, and contact phase activation. The concomitant use of both these therapeutic systems may have additive therapeutic benefits in HD patients. Here, we reviewed the characteristics of dialysis membranes and benefits of the AN69 membrane in dialysis patients.

Impact of Arterial Calcification of the Lower Limbs on Long-Term Clinical Outcomes in Patients on Hemodialysis.

Lower limbs' arterial calcification is significantly associated with the clinical severity of lower extremity artery disease (LEAD) in patients undergoing hemodialysis (HD). However, the association between arterial calcification of the lower limbs and long-term clinical outcomes in patients on HD has not been elucidated. Calcification scores of the superficial femoral artery (SFACS) and below-knee arteries (BKACS) were quantitatively evaluated in 97 HD patients who were followed for 10 years. Clinical outcomes, including all-cause and cardiovascular mortality, cardiovascular events, and limb amputation were evaluated. Risk factors for clinical outcomes were evaluated using univariate and multivariate Cox proportional hazard analyses. Furthermore, SFACS and BKACS were divided into three groups (low, middle, and high), and their associations with clinical outcomes were evaluated using Kaplan-Meier analysis. SFACS, BKACS, C-reactive protein, serum albumin, age, diabetes, presence of ischemic heart disease, and critical limb-threatening ischemia were significantly associated with 3-year and 10-year clinical outcomes in the univariate analysis. Multivariate analysis showed that SFACS was an independent factor associated with 10-year cardiovascular events and limb amputations. Kaplan-Meier life table analysis showed that higher SFACS and BKACS levels were significantly associated with cardiovascular events and mortality. In conclusion, long-term clinical outcomes and the risk factors in patients undergoing HD were evaluated. Arterial calcification of the lower limbs was strongly associated with 10-year cardiovascular events and mortality in patients undergoing HD.

Association between zinc deficiency and aorta stiffness in non-diabetic hemodialysis patients.

OBJECTIVES: Zinc deficiency (Zn < 60 µg/dL) is known to play an important role for vascular calcification. However, little data is available regarding the association between zinc deficiency and aorta stiffness in dialysis patients. Thus, we studied the relationship between zinc deficiency and aorta stiffness in non-diabetic hemodialysis (HD) patients. METHODS: Of 150 patients receiving maintenance HD at our hospital, we included 79 non-diabetic HD patients (age: 70±11 years, 49 men) after excluding 71 diabetic HD patients. Zinc deficiency was defined as Zn <60 µg/dL during pre-HD blood sampling. The association between zinc deficiency and aorta stiffness was analyzed. Aorta stiffness was evaluated as brachial-ankle pulse wave velocity (baPWV). Other surrogate markers for cardiovascular complications were also measured. RESULTS: The zinc deficiency group (ZD group) included 45 patients (57.0%). Compared to the zinc non-deficiency group (ZND group), patients with ZD group were significantly older, higher levels of CRP and hypoalbuminemia. Moreover, they had significantly higher levels of baPWV, and lower levels of ankle-brachial pressure index (ABI) (p<0.05). After adjusting for hypoalbuminemia, and CRP, multivariate analysis showed that age and zinc level were independent predictors of baPWV. CONCLUSION: The study suggested that zinc deficiency may be an independent risk factor for aorta stiffness, even after adjusting for malnutrition and inflammation.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome.

Inflammation plays crucial roles in the regulation of pathophysiological processes involved in injury, repair and remodeling of the infarcted heart; hence, it has become a promising target to improve the prognosis of myocardial infarction (MI). Mesenchymal stem cells (MSCs) serve as an effective and innovative treatment option for cardiac repair owing to their paracrine effects and immunomodulatory functions. In fact, transplanted MSCs have been shown to accumulate at injury sites of heart, exerting multiple effects including immunomodulation, regulating macrophages polarization, modulating the activation of T cells, NK cells and dendritic cells and alleviating pyroptosis of non-immune cells. Many studies also proved that preconditioning of MSCs can enhance their inflammation-regulatory effects. In this review, we provide an overview on the current understanding of the mechanisms on MSCs and their secretome regulating inflammation and immune cells after myocardial infarction and shed light on the applications of MSCs in the treatment of cardiac infarction.

Impact of Contrast-Induced Nephropathy on Long-Term Renal Function after Coronary Angiography and Contrast-Enhanced Computed Tomography.

Background: It remains unclear whether contrast-induced nephropathy (CIN) has a prognostic impact on subsequent renal dysfunction and whether deteriorating renal function is a risk factor for CIN. This study aimed to evaluate the occurrence of CIN in patients with pre-existing renal dysfunction and investigate the long-term effects of worsening renal function after coronary angiography or contrast-enhanced computed tomography (CT). The prognostic factors of worsening renal dysfunction were also analyzed. Methods: This was a prospective cohort study of patients at risk for CIN, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 on coronary angiography or eGFR <45 mL/min/1.73 m2 on contrast-enhanced CT. Serum creatinine levels and the 2-year prognosis were evaluated. CIN was defined as an increase in serum creatinine level by more than 0.5 mg/dL or a 25% increase from the previous value within 72 hours after contrast administration. The primary endpoint was the proportion of patients who had serum Cr doubling or induction of dialysis within 2 years according to CIN occurrence. Results: Of the 410 patients, 19 patients developed CIN (8/142 patients on coronary angiography and 11/268 patients on contrast-enhanced CT), and 38 patients had worsened renal function (21/142 patients on coronary angiography and 17/268 patients on contrast-enhanced CT). CIN was not associated with worsening renal function at 2 years. Analysis by renal function at the time of coronary angiography or contrast-enhanced CT (i.e., eGFR ≥30 ml/min/1.73 m2 and eGFR ≤1.73 m2) found no between-group difference in the occurrence of CIN. Conclusions: CIN is not a prognostic risk factor for the long-term of chronic kidney disease after coronary angiography or contrast-enhanced CT. Pre-existing renal dysfunction is also not a risk factor for CIN, even if the eGFR is <30 ml/min/1.73 m2.