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.

Development of a prognostic risk score to predict early mortality in incident elderly Japanese hemodialysis patients.

BACKGROUND: Information of short-term prognosis after hemodialysis (HD) introduction is important for elderly patients with chronic kidney disease (CKD) and their families choosing a modality of renal replacement therapy. Therefore, we developed a risk score to predict early mortality in incident elderly Japanese hemodialysis patients. MATERIALS AND METHODS: We analyzed data of incident elderly HD patients from a nationwide cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) to develop a prognostic risk score. Candidate risk factors for early death within 1 year was evaluated using multivariate logistic regression analysis. The risk score was developed by summing up points derived from parameter estimate values of independent risk factors. The association between risk score and early death was tested using Cox proportional hazards models. This risk score was validated twice by using an internal validation cohort derived from the JRDR and an external validation cohort collected for this study. RESULTS: Using the development cohort (n = 2,000), nine risk factors were retained in the risk score: older age (>85), yes = 2, no = 0; sex, male = 2, female = 0; lower body mass index (<20), yes = 2, no = 0; cancer, yes = 1, no = 0; dementia, yes = 3, no = 0; lower creatinine (<6.5 mg/dL), yes = 1, no = 0; lower albumin (<3.0 g/dL), yes = 3, no = 0; normal or high calcium (≥8.5 mg/dL), yes = 1, no = 0; and higher C reactive protein (>2.0 mg/dL), yes = 2, no = 0. In the internal and external validation cohorts (n = 739, 140, respectively), the medium- and high-risk groups (total score, 6 to 10 and 11 or more, respectively) showed significantly higher risk of early death than the low-risk group (total score, 0 to 5) (p<0.001). CONCLUSION: We developed a prognostic risk score predicting early death within 1 year in incident elderly Japanese HD patients, which may help detect elderly patients with a high-risk of early death after HD introduction.

IgG4-Related Membranous Nephropathy with Acute Nephrotic Syndrome During Successful Steroid Maintenance Treatment for Type 1 Autoimmune Pancreatitis.

BACKGROUND Immunoglobulin G4 (IgG4)-related diseases (IgG4-RD) are systemic fibroinflammatory diseases that can develop asynchronously in multiple organs. IgG4-related kidney disease (IgG4-RKD) is generally characterized by tubulointerstitial nephritis but can also manifest as membranous nephropathy without tubulointerstitial nephritis. IgG4-related membranous nephropathy can present as a phenotype of systemic disorders, including autoimmune pancreatitis-associated diabetes mellitus; however, its clinical features remain unclear. CASE REPORT A 56-year-old Japanese man presented to our university hospital with bilateral edema of his lower legs. He had received a diagnosis of type 1 autoimmune pancreatitis and associated diabetes mellitus 16 months prior. He was successfully treated with oral glucocorticoids 25 mg/day of prednisolone as an initial dose, followed by titration down to a maintenance dose (5 mg/day), without recurrence of autoimmune pancreatitis. The pancreas showed atrophy and required basal-bolus insulin therapy owing to insulin insufficiency. Massive proteinuria and hypoalbuminemia with nephrotic syndrome on examination led to a renal biopsy to investigate the etiology and diagnosis of IgG4-RKD. Methylprednisolone and cyclosporine A were successfully administered to ameliorate the proteinuria and control systemic IgG4-RD with IgG4-related membranous nephropathy. CONCLUSIONS Ig4-RKD occurred despite maintenance treatment with prednisolone monotherapy and was controlled with methylprednisolone and cyclosporine A. Measurement of clinical parameters, including proteinuria, was important, and a renal biopsy finally established the diagnosis of IgG4-RKD. IgG4-RKD can present with progressive glomerular lesions and can be latent in cases diagnosed with diabetic kidney disease, particularly in patients with insulin insufficiency.

Encapsulating Peritoneal Sclerosis in a Patient Receiving Peritoneal Dialysis and Glucocorticoid Therapy.

Encapsulating peritoneal sclerosis (EPS) is a fatal complication of peritoneal dialysis. A 68-year-old man undergoing peritoneal dialysis for 10 years started receiving daily 50 mg of glucocorticoids for idiopathic pulmonary sclerosis. At the transition to hemodialysis, a peritoneal biopsy was performed, which demonstrated mild histological changes, including no fibrin formation and mild T lymphocyte infiltration at the time of 6.5 mg glucocorticoids. However, five months later, he developed EPS when receiving 2.5 mg glucocorticoids. Afterward, over 5 mg daily glucocorticoids were required to avoid the recurrence of EPS. These findings suggest that glucocorticoids may conceal peritoneal inflammation, a main contributor to EPS.

Cardiovascular adverse events and prognosis in patients with haematologic malignancies and breast cancer receiving anticancer agents: Kurume-CREO Registry insights.

AIMS: Cancer treatment-related cardiovascular toxicity (CTR-CVT) is a growing concern in patients undergoing anticancer therapy. The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) risk assessment tools have been proposed for the baseline cardiovascular (CV) risk stratification of patients with cancer. This study investigated the incidence of CV adverse events in clinical practice, also using the HFA-ICOS risk tool. METHODS AND RESULTS: This single-centre, prospective, observational study was conducted at Kurume University Hospital from October 2016 to August 2021, including patients aged ≥20 years with haematologic malignancies or breast cancer who were receiving anticancer agents. Cardiovascular assessments were performed at enrolment and every 6 months until August 2021, with additional assessments for suspected CV adverse events. The primary endpoint was common terminology criteria for adverse events v4.0 Grade ≥2, and the secondary endpoints were all-cause and CV deaths. Of the enrolled 486 patients, CV adverse events occurred in 24.5, 15.8, 38.1, and 18.0% of patients with leukaemia, malignant lymphoma, multiple myeloma, and breast cancer, respectively. Patients at high or very high risk had a significantly higher incidence of CV events, according to the HFA-ICOS risk tool. Cardiovascular death occurred in 4 (0.8%) patients during follow-up. CONCLUSION: This study revealed that 16-38% of patients with haematologic malignancies and breast cancer developed CTR-CVT during follow-up, in which patients with high/very high risk were well predicted by the HFA-ICOS risk assessment tool. Monitoring and managing CV risk factors are essential for safe cancer therapy.

As the elderly population grows worldwide, cancer and cardiac diseases have become the leading causes of death in many countries, including Japan. With advances in cancer treatment, survival rates have improved, resulting in an increasing number of cancer survivors developing therapy-related cardiovascular (CV) problems. The study, conducted at Kurume University Hospital, examined 486 participants with haematologic malignancies and breast cancer. The result demonstrates CV adverse events in 12, 45, 24, and 16 patients with leukaemia, malignant lymphoma, multiple myeloma, and breast cancer, respectively. Heart failure and left ventricular systolic dysfunction were the most common adverse events. This study demonstrates the importance of monitoring patients with cancer for potential CV risks and highlights the need for further research to improve treatment protocols for those at higher risk. Key findings include This prospective study conducted in Japan revealed a high incidence of adverse cardiovascular (CV) events in patients with haematologic malignancies and breast cancer treated with anticancer agents but a low CV mortality rate during the mid-term follow-up period. Patients at high/very high risk, as determined by the Heart Failure Association-International Cardio-Oncology Society risk assessment tool, experienced a higher incidence of CV events and heart failure compared with those at low and moderate risks.

RAGE signaling regulates the progression of diabetic complications.

Diabetes, the ninth leading cause of death globally, is expected to affect 642 million people by 2040. With the advancement of an aging society, the number of patients with diabetes having multiple underlying diseases, such as hypertension, obesity, and chronic inflammation, is increasing. Thus, the concept of diabetic kidney disease (DKD) has been accepted worldwide, and comprehensive treatment of patients with diabetes is required. Receptor for advanced glycation endproducts (RAGE), a multiligand receptor, belonging to the immunoglobulin superfamily is extensively expressed throughout the body. Various types of ligands, including advanced glycation endproducts (AGEs), high mobility group box 1, S100/calgranulins, and nucleic acids, bind to RAGE, and then induces signal transduction to amplify the inflammatory response and promote migration, invasion, and proliferation of cells. Furthermore, the expression level of RAGE is upregulated in patients with diabetes, hypertension, obesity, and chronic inflammation, suggesting that activation of RAGE is a common denominator in the context of DKD. Considering that ligand-and RAGE-targeting compounds have been developed, RAGE and its ligands can be potent therapeutic targets for inhibiting the progression of DKD and its complications. Here, we aimed to review recent literature on various signaling pathways mediated by RAGE in the pathogenesis of diabetic complications. Our findings highlight the possibility of using RAGE-or ligand-targeted therapy for treating DKD and its complications.

Effect of dapagliflozin on the initial estimated glomerular filtration rate dip in chronic kidney disease patients without diabetes mellitus.

BACKGROUND: Dapagliflozin (DAPA), a sodium-glucose transporter 2 inhibitor (SGLT2i), attenuates kidney outcomes in patients with not only diabetes mellitus (DM) but also chronic kidney disease (CKD). SGLT2i-derived initial dip in estimated glomerular filtration rate (eGFR) has been considered to reduce excess glomerular pressure, followed by renal protection in patients with DM. However, whether DAPA confers the eGFR dip and its independent determinants for CKD patients without DM are unclear. METHODS: A total of 126 patients with CKD treated with 10 mg DAPA daily was retrospectively registered. After participants with missing data and DM were excluded, 51 participants were enrolled. RESULTS: An initial eGFR dip was observed 1 month after initiation of DAPA, which was sustained until 2 months. DAPA did not affect urinary protein excretion; however, serum uric acid was decreased, while hemoglobin level was increased. Multiple regression analysis revealed that eGFR at baseline was the only independent determinant of the initial dip of eGFR. The patients currently showing exacerbation of glomerular hyperfiltration exhibited the larger initial eGFR dip rather than those showing progressive renal dysfunction. The patients meeting exclusion criteria of DAPA-CKD trial exhibited same degree of the initial eGFR dip as others. CONCLUSIONS: DAPA causes an initial dip of eGFR in CKD patients without DM at 1 month after starting DAPA treatment. A higher eGFR at baseline predicts a large initial eGFR dip, which might be linked to the subsequent recovery in eGFR in CKD patients without DM.

Association of Baseline Renal Function with Mortality in Patients with Sepsis Requiring Continuous Renal Replacement Therapy for Acute Kidney Injury: A Single-Center Retrospective Study.

INTRODUCTION: To date, the prognosis of patients with sepsis and underlying chronic kidney disease (CKD) had been poor. However, the impact of preseptic renal function on the short-term prognosis of patients with extremely severe septic shock with acute kidney injury (AKI) that requires renal replacement therapy (RRT) is unclear. METHODS: Of the septic shock cases treated at the intensive care unit for ≥48 h, 131 adults who were diagnosed as septic AKI and underwent continuous venovenous hemodiafiltration were retrospectively analyzed. The relationships of demographic, clinical, and laboratory data with mortality were evaluated, and the independent risk factors for death were identified. RESULTS: The median age of the subjects was 73 (range, 63-80) years, and 76 (58%) were men. The rate of mortality was significantly higher among patients with CKD (n = 42) than in those without CKD (n = 89) (43% vs. 22%, p < 0.016). On univariate and multivariate logistic regression analyses, the associated factors and independent predictors of death were Sequential Organ Failure Assessment score (odds ratios [ORs] 1.151, 95% confidence intervals [CIs] 1.026-1.293, p = 0.017, and OR 1.129, 95% CI 1.003-1.271, respectively); baseline estimated glomerular filtration rate (OR 0.986, 95% CI 0.975-0.997, p = 0.016, and OR 0.983, 95% CI 0.970-0.996, respectively); and lactic acid (OR 1.094, 95% CI 1.005-1.190, p = 0.038, and OR 1.110 CI 1.015-1.215, respectively). CONCLUSION: Reduced baseline renal function may be a factor for poor short-term prognosis in severe septic AKI cases requiring RRT.

A nationwide cross-sectional analysis of biopsy-proven Fabry nephropathy: the Japan Renal Biopsy Registry.

BACKGROUND: Fabry disease (FD) is an X-linked inherited disease where renal complications are associated with a poor prognosis. However, little is known about the prevalence of Fabry nephropathy (FN) in patients with chronic kidney disease (CKD). We extracted FN data from the Japan Renal Biopsy Registry, analyzed the prevalence of FN, and examined the correlation between clinical characteristics and renal involvement according to sex differences and hemi- and heterozygosity in patients with FD. METHODS: A total of 38,351 participants who underwent renal biopsy were retrospectively enrolled, and FN was determined. The clinical characteristics of FD patients were examined based on sex differences. RESULTS: Twenty-nine patients (0.076%) (19 males and 10 females, mean age: 43.7 ± 15.5 years old) were diagnosed with FN. Median estimated urinary protein (UP) and mean eGFR levels were 0.9 [interquartile range (IQR) [0.7-1.6] g/gCr and 67.1 ± 36.8 mL/min/1.73 m2, respectively. Mean systolic blood pressure (SBP) was 126.4 ± 17.1 mmHg and diastolic blood pressure was 76.1 ± 12.6 mmHg. An inverse correlation between eGFR and logarithm UP levels was observed (r2 = 0.23, p = 0.02), SBP was positively associated with logarithm UP (r2 = 0.34, p = 0.004) overall and inversely associated with eGFR (r2 = 0.25, p = 0.007) regardless of sex, and SBP was an independent determinant of proteinuria (p = 0.004) and eGFR (p = 0.007). CONCLUSIONS: The prevalence of biopsy-proven FN was 0.076%. Since SBP is associated with eGFR regardless of zygosity, strict SBP control might be necessary to prevent progression to end-stage kidney disease in both male and female patients with FN.

Quantification and Visualization of Reliable Hemodynamics Evaluation Based on Non-Contact Arteriovenous Fistula Measurement.

The condition of arteriovenous fistula (AVF) blood flow is typically checked by using auscultation; however, auscultation should require a qualitative judgment dependent on the skills of doctors, and further attention to contact infection is required. For these reasons, this study developed a non-contact and non-invasive medical device to measure the pulse wave of AVFs by applying optical imaging technology. As a first step toward realization of the quantification judgment based on non-contact AVF measurement, we experimentally validated the developed system, whereby the hemodynamics of 168 subjects were visually and quantitatively evaluated based on clinical tests. Based on the evaluation results, the fundamental statistical characteristics of the non-contact measurement, including the average and median values, and distribution of measured signal-to-noise power ratio, were demonstrated. The clinical test results contributed to the future construction of quantified criteria for the AVF condition with the non-contact measurement.

New Estimation Formulas for Daily Sodium Intake in Hemodialysis Patients by a Duplicate Portion Method.

OBJECTIVE: Excess sodium intake is associated with volume overload and increased blood pressure. Therefore, to prevent future cardiovascular events, a sodium-restricted diet is strongly recommended for patients on maintenance hemodialysis (HD). However, only one formula for estimating dietary sodium intake in HD patients is available, and its validity has not been adequately evaluated. This study aimed to measure daily sodium intake using the duplicate portion method and provide a new formula for estimating dietary sodium intake. DESIGN AND METHODS: Nineteen Japanese patients undergoing HD were enrolled in this cross-sectional multicenter study. The daily sodium intake of these patients was measured directly using the duplicate portion method. Two formulas for estimating sodium intake were developed by stepwise regression analysis. Their validities were compared with the validity of the previous formula. Furthermore, using these new formulas, we estimated the daily consumption of sodium in a large number of Japanese HD patients. RESULTS: The previous formula underestimated true sodium intake using Bland-Altman diagrams. No significant correlation was noted between the measured sodium intake and the estimated intake (r = 0.30, P = .23, Fisher's Z-transformation). The new formulas 1 and 2, which included age, predialysis and postdialysis serum sodium levels, predialysis body weight, and interdialytic body weight gain, accurately estimated sodium consumption. The coefficients of correlation between the estimated values and the true sodium intake were r = 0.858 and r = 0.805, respectively. The simulation model using data from the Japanese Society for Dialysis Therapy showed that the distribution of the estimated sodium intake using the previous formula shifted left compared with that using the new formulas. CONCLUSIONS: The new formulas accurately estimated the daily sodium consumption in HD patients. Further longitudinal studies are required to determine whether the estimated sodium intake level calculated using the new formulas would serve as a potential marker and/or therapeutic target to prevent cardiovascular events in HD patients.

Screening of Fabry disease in patients with chronic kidney disease in Japan.

BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder caused by a deficiency in alfa-galactosidase A (α-Gal A) activity due to mutations in the GLA gene, has a prevalence of 0-1.69% in patients undergoing haemodialysis; however, its prevalence in patients with chronic kidney disease (CKD) Stages 1-5 is unknown. METHODS: Serum α-Gal A activity analysis and direct sequencing of GLA were used to screen for FD in 2122 male patients with CKD, including 1703 patients with CKD Stage 5D and 419 with CKD Stages 1-5. The correlation between serum α-Gal A activity and confounding factors in patients with CKD Stages 1-5 was evaluated. RESULTS: FD prevalence rates in patients with CKD Stage 5D and CKD Stages 1-5 were 0.06% (1/1703) and 0.48% (2/419), respectively. A patient with CKD Stage 5D exhibited a novel GLA mutation, p.Met208Arg, whereas two patients with CKD Stages 1-5 had c.370delG and p.Met296Ile. p. Met208Arg caused moderate structural changes in the molecular surface region near the substituted amino acid residue but did not affect the catalytic residues Asp170 and Asp231 in α-Gal A. Serum α-Gal A activity in patients with CKD Stages 1-5 was inversely correlated with age (P < 0.0001) but directly correlated with estimated glomerular filtration rate (P < 0.0001). CONCLUSIONS: FD prevalence was much higher in male patients with CKD Stages 1-5 than in those with CKD Stage 5D. FD screening in patients with CKD Stages 1-5 may improve patient survival, decreasing the number of patients with CKD Stage 5D.

Effects of Reducing L-Carnitine Supplementation on Carnitine Kinetics and Cardiac Function in Hemodialysis Patients: A Multicenter, Single-Blind, Placebo-Controlled, Randomized Clinical Trial.

L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (ß = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.

Dysbiosis-Related Advanced Glycation Endproducts and Trimethylamine N-Oxide in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a public health concern that affects approximately 10% of the global population. CKD is associated with poor outcomes due to high frequencies of comorbidities such as heart failure and cardiovascular disease. Uremic toxins are compounds that are usually filtered and excreted by the kidneys. With the decline of renal function, uremic toxins are accumulated in the systemic circulation and tissues, which hastens the progression of CKD and concomitant comorbidities. Gut microbial dysbiosis, defined as an imbalance of the gut microbial community, is one of the comorbidities of CKD. Meanwhile, gut dysbiosis plays a pathological role in accelerating CKD progression through the production of further uremic toxins in the gastrointestinal tracts. Therefore, the gut-kidney axis has been attracting attention in recent years as a potential therapeutic target for stopping CKD. Trimethylamine N-oxide (TMAO) generated by gut microbiota is linked to the progression of cardiovascular disease and CKD. Also, advanced glycation endproducts (AGEs) not only promote CKD but also cause gut dysbiosis with disruption of the intestinal barrier. This review summarizes the underlying mechanism for how gut microbial dysbiosis promotes kidney injury and highlights the wide-ranging interventions to counter dysbiosis for CKD patients from the view of uremic toxins such as TMAO and AGEs.

Inhibitory effects of RAGE-aptamer on development of monocrotaline-induced pulmonary arterial hypertension in rats.

BACKGROUND: The receptor for advanced glycation end products (RAGE), a transmembrane receptor belonging to the immunoglobulin superfamily, is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with pulmonary arterial hypertension (PAH) and is implicated in the etiology of PAH. Recently, we reported that RAGE-aptamer, a short and single-stranded DNA directed against RAGE, inhibited an inappropriate increase in cultured PASMCs in PAH. The aim of this study was to determine the efficacy of RAGE-aptamer in monocrotaline-induced PAH in rats. METHODS AND RESULTS: Rats were assigned to either an untreated control group, a group that received continuous subcutaneous administration of RAGE-aptamer immediately after monocrotaline injection, or a group that received control-aptamer immediately after monocrotaline injection. All rats survived 21 days after injection of monocrotaline and control-aptamer or RAGE-aptamer. Injection of monocrotaline with continuous subcutaneous delivery of control-aptamer resulted in higher right ventricular systolic pressure compared with controls. This increase was attenuated by continuous subcutaneous delivery of RAGE-aptamer. The proportion of small pulmonary arteries with full muscularization was greater in the monocrotaline and control-aptamer group than in the control group. Continuous subcutaneous delivery of RAGE-aptamer significantly reduced the percentage of small pulmonary arteries with full muscularization. CONCLUSIONS: Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for PAH.