Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank.

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

Lysophosphatidylcholine mediates fast decline in kidney function in diabetic kidney disease.

Some patients with diabetic kidney disease (DKD) show a fast progression of kidney dysfunction and are known as a "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for fast decline. Here, we performed a comprehensive metabolomic analysis of patients with stage G3 DKD and identified increased urinary lysophosphatidylcholine (LPC) in fast decline. This was confirmed by quantification of urinary LPC using mass spectrometry and identified urinary LPC containing saturated fatty acids palmitic (16:0) and stearic (18:0) acids was increased in FDs. The upsurge in urinary LPC levels was correlated with a decline in estimated glomerular filtration rate after 2.5 years. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our in vitro studies also confirmed LPC-mediated lipotoxicity in cultured proximal tubular cells. LPC induced accumulation of lipid droplets via activation of peroxisome proliferator-activated receptor-δ followed by upregulation of the lipid droplet membrane protein perilipin 2 and decreased autophagic flux, thereby inducing organelle stress and subsequent apoptosis. Thus, LPC (16:0) and (18:0) may mediate a fast progression of DKD and may serve as a target for novel therapeutic approaches.

Lysine demethylase 2B regulates angiogenesis via Jumonji C dependent suppression of angiogenic transcription factors.

Vascular endothelial growth factor (VEGF) signaling plays a central role in vascular development and maintenance of vascular homeostasis. In endothelial cells (ECs), VEGF activates the gene expression of angiogenic transcription factors (TFs), followed by induction of downstream angiogenic responsive genes. Recent findings support that histone modification dynamics contribute to the transcriptional control of genes that are important for EC functions. Lysine demethylase 2B (KDM2B) demethylates histone H3K4me3 and H3K36me2/3 and mediates the monoubiquitination of histone H2AK119. KDM2B functions as a transcriptional repressor in somatic cell reprogramming and tumor development. However, the role of KDM2B in VEGF signaling remains to be elucidated. Here, we show that KDM2B knockdown enhances VEGF-induced angiogenesis in cultured human ECs via increased migration and proliferation. In contrast, ectopic expression of KDM2B inhibits angiogenesis. The function of KDM2B may depend on its catalytic Jumonji C domain. Genome-wide analysis further reveals that KDM2B selectively controls the transcription of VEGF-induced angiogenic TFs that are associated with increased H3K4me3/H3K36me3 and decreased H2AK119ub. These findings suggest an essential role of KDM2B in VEGF signaling in ECs. As dysregulation of VEGF signaling in ECs is involved in various diseases, including cancer, KDM2B may be a potential therapeutic target in VEGF-mediated vasculopathic diseases.

Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia.

Renal tubulointerstitial hypoxia is recognized as a final common pathway of chronic kidney disease and is considered a promising drug target. However, hypoxia in the tubules is not well examined because of limited detection methods. Here, we devised a method to visualize renal tubular oxygen tension with spatial resolution at a cellular level using the cell-penetrating phosphorescent probe, BTPDM1 (an iridium-based cationic lipophilic dye), and confocal phosphorescence lifetime imaging microscopy to precisely assess renal hypoxia. Imaging with BTPDM1 revealed an oxygen gradient between S1 and S2 segments in mouse kidney. We also demonstrated that our microscopy system can detect subtle changes of hypoxemia and reoxygenation, and the acquired phosphorescence lifetime can be converted to partial pressure of oxygen. This new method allows, for the first time, visualization of intravital oxygen gradients at the renal surface with high spatial resolution. Thus, the confocal phosphorescence lifetime imaging microscopy platform, combined with BTPDM1, will promote an accurate understanding of tissue hypoxia, including renal hypoxia.

Pathophysiology and therapeutics of premature ageing in chronic kidney disease, with a focus on glycative stress.

Chronic kidney disease (CKD) is a major concern in public health. The pathology of CKD includes premature ageing in the kidney and vessels, which results in a high risk of cardiovascular events and end-stage renal disease. Many factors are involved in premature ageing in CKD, including hormonal imbalance, glycative stress, nitrogenous metabolites, and oxidative stress. Of these, the most important role in premature ageing in CKD is played by glycative stress, namely a massive and unfavourable glycation state, since the kidney is responsible for the clearance of advanced glycation endproducts (AGEs). In an animal model, overexpression of glyoxalase I (GLO-1), a detoxifier of AGEs, has been found to alleviate premature ageing in the kidney and vessels. Both lifestyle changes and drug therapy have shown promise in overcoming premature ageing. Promising drug therapies include a GLO-1 activator and an absorbent against glycotoxin and nitrogenous metabolites.

Glycative Stress and Its Defense Machinery Glyoxalase 1 in Renal Pathogenesis.

Chronic kidney disease is a major public health problem around the world. Because the kidney plays a role in reducing glycative stress, renal dysfunction results in increased glycative stress. In turn, glycative stress, especially that due to advanced glycated end products (AGEs) and their precursors such as reactive carbonyl compounds, exacerbates chronic kidney disease and is related to premature aging in chronic kidney disease, whether caused by diabetes mellitus or otherwise. Factors which hinder a sufficient reduction in glycative stress include the inhibition of anti-glycation enzymes (e.g., GLO-1), as well as pathogenically activated endoplasmic reticulum (ER) stress and hypoxia in the kidney. Promising strategies aimed at halting the vicious cycle between chronic kidney disease and increases in glycative stress include the suppression of AGE accumulation in the body and the enhancement of GLO-1 to strengthen the host defense machinery against glycative stress.

Capacity for the management of kidney failure in the International Society of Nephrology North and East Asia region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA).

Globally, there remain significant disparities in the capacity and quality of kidney care, as evidenced by the third edition of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA). In the ISN North and East Asia region, the chronic kidney disease (CKD) burden varied widely; Taiwan had the heaviest burden of treated kidney failure (3679 per million population [pmp]) followed by Japan and South Korea. Except in Hong Kong, hemodialysis (HD) was the main dialysis modality for all other countries in the region and was much higher than the global median prevalence. Kidney transplantation services were generally available in the region, but the prevalence was much lower than that of dialysis. Most countries had public funding for kidney replacement therapy (KRT). The median prevalence of nephrologists was 28.7 pmp, higher than that of any other ISN region, with variation across countries. Home HD was available in only 17% of the countries, whereas conservative kidney management was available in 50%. All countries had official registries for dialysis and transplantation; however, only China and Japan had CKD registries. Advocacy groups for CKD, kidney failure, and KRT were uncommon throughout the region. Overall, all countries in the region had capacity for KRT, albeit with some shortages in their kidney care workforce. These data are useful for stakeholders to address gaps in kidney care and to reduce workforce shortages through increased use of multidisciplinary teams and telemedicine, policy changes to promote prevention and treatment of kidney failure, and increased advocacy for kidney disease in the region.

Acetate attenuates kidney fibrosis in an oxidative stress-dependent manner.

Short-chain fatty acids (SCFAs) are the end products of the fermentation of dietary fibers by the intestinal microbiota and reported to exert positive effects on host physiology. Acetate is the most abundant SCFA in humans and is shown to improve acute kidney injury in a mouse model of ischemia-reperfusion injury. However, how SCFAs protect the kidney and whether SCFAs have a renoprotective effect in chronic kidney disease (CKD) models remain to be elucidated. We investigated whether acetate and other SCFAs could attenuate the kidney damage. In in vitro experiments, cell viability of acetate-treated human kidney 2 (HK-2) cells was significantly higher than that of vehicle-treated in an oxidative stress model, and acetate reduced cellular reactive oxygen species (ROS) production. In mitochondrial analysis, the MitoSOX-positive cell proportion decreased, and transcription of dynamin-1-like protein gene, a fission gene, was decreased by acetate treatment. In in vivo experiments in mice, acetate treatment significantly ameliorated fibrosis induced by unilateral ureteral obstruction, and the oxidative stress marker phosphorylated histone H2AX (γH2AX) was also reduced. Further, acetate treatment ameliorated dysmorphic mitochondria in the proximal tubules, and ROS and mitochondrial analyses suggested that acetate improved mitochondrial damage. Our findings indicate a renoprotective effect of acetate in CKD.

Kidney Podocyte Zebra Bodies after Lung Transplantation for Lymphangioleiomyomatosis.

A 55-year-old woman showed progressive renal dysfunction after unilateral deceased-donor lung transplantation for lymphangioleiomyomatosis. A kidney biopsy showed a striped pattern of interstitial fibrosis, suggesting calcineurin inhibitor toxicity, and zebra body accumulation predominantly in the podocytes, characteristics of Fabry disease. Nevertheless, she had no extra-renal symptoms of the disease, and gene testing identified no known pathogenic variant or exon deletion. Our case report and literature review suggest that this atypical lysosomal inclusion may be phospholipidosis induced by sertraline. Potential underlying etiologies linking zebra body deposits may be not only hereditary but also drug-induced phospholipidosis.

Alpha 7 nicotinic acetylcholine receptors signaling boosts cell-cell interactions in macrophages effecting anti-inflammatory and organ protection.

Activation of the cholinergic anti-inflammatory pathway (CAP) via vagus nerve stimulation has been shown to improve acute kidney injury in rodent models. While alpha 7 nicotinic acetylcholine receptor (α7nAChR) positive macrophages are thought to play a crucial role in this pathway, their in vivo significance has not been fully understood. In this study, we used macrophage-specific α7nAChR-deficient mice to confirm the direct activation of α7nAChRs in macrophages. Our findings indicate that the administration of GTS-21, an α7nAChR-specific agonist, protects injured kidneys in wild-type mice but not in macrophage-specific α7nAChR-deficient mice. To investigate the signal changes or cell reconstructions induced by α7nAChR activation in splenocytes, we conducted single-cell RNA-sequencing of the spleen. Ligand-receptor analysis revealed an increase in macrophage-macrophage interactions. Using macrophage-derived cell lines, we demonstrated that GTS-21 increases cell contact, and that the contact between macrophages receiving α7nAChR signals leads to a reduction in TNF-α. Our results suggest that α7nAChR signaling increases macrophage-macrophage interactions in the spleen and has a protective effect on the kidneys.

Potential progression biomarkers of diabetic kidney disease determined using comprehensive machine learning analysis of non-targeted metabolomics.

Diabetic kidney disease is the main cause of end-stage renal disease worldwide. The prediction of the clinical course of patients with diabetic kidney disease remains difficult, despite the identification of potential biomarkers; therefore, novel biomarkers are needed to predict the progression of the disease. We conducted non-targeted metabolomics using plasma and urine of patients with diabetic kidney disease whose estimated glomerular filtration rate was between 30 and 60 mL/min/1.73 m2. We analyzed how the estimated glomerular filtration rate changed over time (up to 30 months) to detect rapid decliners of kidney function. Conventional logistic analysis suggested that only one metabolite, urinary 1-methylpyridin-1-ium (NMP), was a promising biomarker. We then applied a deep learning method to identify potential biomarkers and physiological parameters to predict the progression of diabetic kidney disease in an explainable manner. We narrowed down 3388 variables to 50 using the deep learning method and conducted two regression models, piecewise linear and handcrafted linear regression, both of which examined the utility of biomarker combinations. Our analysis, based on the deep learning method, identified systolic blood pressure and urinary albumin-to-creatinine ratio, six identified metabolites, and three unidentified metabolites including urinary NMP, as potential biomarkers. This research suggests that the machine learning method can detect potential biomarkers that could otherwise escape identification using the conventional statistical method.

Renal-limited ANCA-associated vasculitis during erlotinib treatment for lung carcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had clinical success in the treatment of non-small cell lung carcinoma (NSCLC). An effect of this drug on kidney has not been clarified and the occurrence of glomerulonephritis related to EGFR-TKI has rarely been reported. We present the case of a 71-year-old man with NSCLC who developed proteinuria and microscopic hematuria with the rise in a titer of MPO-ANCA, when 2 years and 3 months passed since the initiation of erlotinib, one of oral EGFR-TKI. Two serial biopsies support that ANCA-associated vasculitis may have been modified by the persistent use of erlotinib. We initiated intravenous pulse therapy with methylprednisolone followed by oral prednisone. The proteinuria has decreased and serum CRP was normalized. However, the serum creatinine level and hematuria did not change during the treatment period. While EGFR inhibition is implicated in protective control for glomerulonephritis, it may exacerbate vasculitis. Close monitoring of the kidney function and urinary findings is required during the use of EGFR inhibitors, such as erlotinib, because it may cause renal adverse events.

Analysis of inflammatory cytokines and estimated glomerular filtration rate decline in Japanese patients with diabetic kidney disease: a pilot study.

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6Rß, sCD163, sIL-6Rα, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m2/year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

A distinctive distribution of hypoxia-inducible factor-1α in cultured renal tubular cells with hypoperfusion simulated by coverslip placement.

Chronic hypoxia in the renal tubulointerstitium plays a key role in the progression of chronic kidney disease (CKD). It is therefore important to investigate tubular hypoxia and the activity of hypoxia-inducible factor (HIF)-1α in response to hypoxia. Rarefaction of the peritubular capillary causes hypoperfusion in CKD; however, the effect of hypoperfusion on HIFs has rarely been investigated. We induced hypoperfusion caused by coverslip placement in human kidney-2 cells, and observed an oxygen gradient under the coverslip. Immunocytochemistry of HIF-1α showed a doughnut-shaped formation on the edge of a pimonidazole-positive area, which we named the "HIF-ring". The oxygen tension of the HIF-ring was estimated to be between approximately 4 mmHg and 20 mmHg. This result was not compatible with those of past research showing HIF-1α accumulation in the anoxic range with homogeneous oxygen tension. We further observed the presence of a pH gradient under a coverslip, as well as a shift of the HIF ring due to changes in the pH of the culture medium, suggesting that the HIF ring was formed by suppression of HIF-1α related to low pH. This research demonstrated that HIF-1α activation mimics the physiological state in cultured cells with hypoperfusion.