Effects of Oral Semaglutide on Renal Function in Diabetic Kidney Disease: A Short-term Clinical Study.

BACKGROUND/AIM: In the SUSTAIN-6 trial, semaglutide reduced the risk of worsening nephropathy in patients with type 2 diabetes. The objective of this retrospective study was to elucidate the effect and safety of oral semaglutide (Rybelsus®) in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Six patients with DKD received 3 mg/day semaglutide orally. The observation period was 9.0±5.0 months. Changes in estimated glomerular filtration rate (eGFR), urinary protein, fasting blood glucose, and hemoglobin A1c were studied from 6 months before the administration of oral semaglutide until 6 months after administration. RESULTS: The change in eGFR over the 6 months prior to semaglutide administration was -1.2±1.6 ml/min/1.73 m2, showing a trend for a decrease; although not statistically significant, the change at 6 months after oral semaglutide initiation showed improved eGFR (1-50.7±1.8 ml/min/1.73 m2). Proteinuria was not reduced after treatment with oral semaglutide. No significant adverse effects (including retinopathy) were observed in any patient during the study. CONCLUSION: Despite the small sample size and short observation period, oral semaglutide was found to be a relatively well-tolerated drug for patients with DKD.

Effect of Sacubitril/Valsartan on Patients Having Heart Failure With Preserved Left Ventricular Ejection Fraction Undergoing Hemodialysis: A Long-term Observational Study.

BACKGROUND/AIM: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin-angiotensin-aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. PATIENTS AND METHODS: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. RESULTS: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. CONCLUSION: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.

Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease.

Background: In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods: This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results: IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions: This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.

Multicentric IL-5-positive Castleman Disease With Nephrotic Syndrome Relapsed After Rituximab Treatment.

BACKGROUND/AIM: To date, no reports of interleukin (IL)-5-producing Castleman disease with nephrotic syndrome and moreover no reports of relapse after remission with rituximab treatment, have been published. CASE REPORT: A 67-year-old male presented to the Osaka Medical and Pharmaceutical University Hospital with a history of low-grade fever, papules, and nephrotic syndrome. Lymph nodes were palpated in the inguinal region. The patient showed anemia, eosinophilia, polyclonal hypergammaglobulinemia, and elevated interleukin (IL)-6 levels. Patient's serum IL-5 and IL-6 levels were measured using ELISA and immunohistochemical staining of lymph nodes was performed with antibodies specific to CD134. Histological examination confirmed diagnosis of a plasma cell variant of Castleman disease. After a total of four weekly doses of rituximab, urinary protein disappeared, and skin symptoms improved. However, one month after rituximab treatment, the skin rash worsened again, and eosinophils and IL-5 were elevated significantly. CONCLUSION: This is the first report of recurrent Castleman disease with direct evidence of increased serum IL-5. It may be reasonable to use rituximab, an anti-CD20 antibody for treating the disease, however, for IL-5-producing cases the effect of rituximab may be partial.

Effects of incretin-based therapeutic agents including tirzepatide on renal outcomes in patients with type 2 diabetes: A systemic review and meta-analysis.

Background: This meta-analysis was conducted to investigate the effects of incretin-based therapeutic agents, including the latest agent tirzepatide, on renal outcomes in patients with type 2 diabetes. Methods: MEDLINE (via PubMed) and Cochrane databases were searched for studies involving incretin-based therapeutic agents up to July 2022. Randomized and controlled trials comparing incretin-based therapeutic agents with placebo or other antidiabetic agents, and reporting renal outcomes were selected. The inclusion criteria were items related to the effects on albuminuria and the kidney-specific composite outcomes. A network meta-analysis was conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Twelve trials consisting of 75,346 participants were included in this meta-analysis. Glucagon-like peptide-1 (GLP-1) receptor agonists reduced the risk of the kidney-specific composite outcome by 21% (HR 0.79, 95% CI 0.75-0.85), and worsening albuminuria by 24% (HR 0.76, 95% CI 0.71-0.82). In particular, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide remarkably reduced the risk of the kidney-specific composite outcome by 45% (HR 0.55, 95% CI 0.40-0.77), and worsening albuminuria by 62% (HR 0.38, 95% CI 0.24-0.61). Conclusions: Among incretin-based therapeutic agents, tirzepatide was associated with a significantly reduced risk of diabetic kidney disease.

Case Report: IgG4-related kidney disease complicated by interstitial pneumonia.

Immunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disorder characterized by tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. We report the case of an 84-year-old male who presented with a history of dyspnea on exertion and cough. The lymph nodes were palpated in the axilla. Urinalysis revealed mild proteinuria and increased levels of NAG and ß2-microglobulin. Blood tests showed hyperglobulinemia with a marked elevation of serum IgG4 levels. Chest computed tomography showed bilateral ground-glass and reticular opacities in the lower and peripheral portions of the lungs. Ga-67 scintigraphy showed kidney uptake. The patient was diagnosed with IgG4-related kidney disease based on the renal pathology indicative of typical tubulointerstitial nephritis with extensive IgG4-positive plasma cell infiltration. The patient was treated with prednisolone and showed a prompt response in his clinical condition. The patient achieved normalization of serum IgG4 levels 6 months after the initiation of treatment. Although IgG4-related disease is thought to be potentially associated with organ fibrosis, there are few reports on combination of interstitial pneumonia and IgG4-related kidney disease. Our case report presents a possible pattern of IgG4-related disease.

Effect of finerenone on diabetic kidney disease outcomes with estimated glomerular filtration rate below 25 mL/min/1.73 m2.

Background: In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial, finerenone reduced the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes, while in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial, it improved renal and cardiovascular outcomes in patients with advanced CKD. However, no previous studies have assessed patients with CKD and type 2 diabetes with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods: Nine patients with CKD and type 2 diabetes who received finerenone 10 mg/day were analyzed retrospectively. Changes in eGFR, urinary protein, and serum potassium levels were studied from 1 year before administration of finerenone until 6 months after administration. Results: The mean baseline eGFR slope was -7.63 ± 9.84 (mL/min/1.73 m2/year). After finerenone treatment, the mean eGFR slope significantly improved -1.44 ± 3.17 (mL/min/1.73 m2/6 months, P=0.038). However, finerenone treatment did not significantly reduce proteinuria. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed a significantly slower decline in eGFR. Furthermore, aside from the present study, no reports have indicated the effectiveness of finerenone in patients with advanced CKD with an eGFR below 25 mL/min/1.73 m2. As confirmed in our clinical trials, the finding that finerenone is effective in a wide range of renal functions can be generalized to clinical practice. However, sample size in this study was small. Thus, further large-scale investigations will be needed.

Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells.

Many therapeutic antibodies (Abs) and mRNA vaccines, both targeting SARS-CoV-2 spike protein (S-protein), have been developed and approved in order to combat the ongoing COVID-19 pandemic. In consideration of these developments, a common concern has been the potential for Ab-dependent enhancement (ADE) of infection caused by inoculated or induced Abs. Although the preventive and therapeutic effects of these Abs are obvious, little attention has been paid to the influence of the remaining and dwindling anti-S-protein Abs in vivo. Here, we demonstrate that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. Although sera collected from mRNA-vaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. None of the sera examined exhibited neutralizing activity against infection with the Omicron strain. Rather, some ADE of Omicron infection was observed in some sera. These results suggest the possible emergence of adverse effects caused by these Abs in addition to the therapeutic or preventive effect.

The potential of COVID-19 patients' sera to cause antibody-dependent enhancement of infection and IL-6 production.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many vaccine trials have been initiated. An important goal of vaccination is the development of neutralizing antibody (Ab) against SARS-CoV-2. However, the possible induction of antibody-dependent enhancement (ADE) of infection, which is known for other coronaviruses and dengue virus infections, is a particular concern in vaccine development. Here, we demonstrated that human iPS cell-derived, immortalized, and ACE2- and TMPRSS2-expressing myeloid cell lines are useful as host cells for SARS-CoV-2 infection. The established cell lines were cloned and screened based on their function in terms of susceptibility to SARS-CoV-2-infection or IL-6 productivity. Using the resulting K-ML2 (AT) clone 35 for SARS-CoV-2-infection or its subclone 35-40 for IL-6 productivity, it was possible to evaluate the potential of sera from severe COVID-19 patients to cause ADE and to stimulate IL-6 production upon infection with SARS-CoV-2.

3D Printing of Anisotropic Bone-Mimetic Structure with Controlled Fluid Flow Stimuli for Osteocytes: Flow Orientation Determines the Elongation of Dendrites.

Although three-dimensional (3D) bioprinting techniques enable the construction of various living tissues and organs, the generation of bone-like oriented microstructures with anisotropic texture remains a challenge. Inside the mineralized bone matrix, osteocytes play mechanosensing roles in an ordered manner with a well-developed lacunar-canaliculi system. Therefore, control of cellular arrangement and dendritic processes is indispensable for construction of artificially controlled 3D bone-mimetic architecture. Herein, we propose an innovative methodology to induce controlled arrangement of osteocyte dendritic processes using the laminated layer method of oriented collagen sheets, combined with a custom-made fluid flow stimuli system. Osteocyte dendritic processes showed elongation depending on the competitive directional relationship between flow and substrate. To the best of our knowledge, this study is the first to report the successful construction of the anisotropic bone-mimetic microstructure and further demonstrate that the dendritic process formation in osteocytes can be controlled with selective fluid flow stimuli, specifically by regulating focal adhesion. Our results demonstrate how osteocytes adapt to mechanical stimuli by optimizing the anisotropic maturation of dendritic cell processes.