Abstract
This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials ...of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression—primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit–risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.
The Marxist and socialist ideas that spread throughout the world following the Russian Revolution of 1917 were also influential in bringing about changes in art and culture. Proletarian literature, ...which flourished in Japan in the 1920s and 1930s, was one such example. However, due to Japan’s particular historical circumstances, Japanese proletarian literature was in an ambivalent position between revolutionary literature by left-wing intellectuals and proletarian literature by and for the proletarian class in the pure sense. This article examines the chaos and friction implied by the term “proletarian” from three perspectives: the relationship between proletarian media and bourgeois media, the media distribution system, and the boundary between writers and readers. Through this examination, it clarifies that the approaches of Japanese proletarian media, while imitating bourgeois media to some extent, were unique in their potential to transform the boundary between writers and readers.
Diabetic nephropathy has been traditionally diagnosed based on persistently high albuminuria and a subsequent decline in glomerular filtration rate (GFR), which is widely recognized as the classical ...phenotype of diabetic kidney disease (DKD). Several studies have emphasized that trajectories of kidney function in patients with diabetes (specifically, changes in GFR and albuminuria over time) can differ from this classical DKD phenotype. Three alternative DKD phenotypes have been reported to date and are characterized by albuminuria regression, a rapid decline in GFR, or non-proteinuric or non-albuminuric DKD. Although kidney biopsies are not typically required for the diagnosis of DKD, a few studies of biopsy samples from patients with DKD have demonstrated that changes in kidney function associate with specific histopathological findings in diabetes. In addition, various clinical and biochemical parameters are related to trajectories of GFR and albuminuria. Collectively, pathological and clinical characteristics can be used to predict trajectories of GFR and albuminuria in diabetes. Furthermore, cohort studies have suggested that the risks of kidney and cardiovascular outcomes might vary among different phenotypes of DKD. A broader understanding of the clinical course of DKD is therefore crucial to improve risk stratification and enable early interventions that prevent adverse outcomes.
Inflammation is a protective response to remove dangerous stimuli from the body. The multiprotein complex called the inflammasome regulates inflammation through the cleavage of proinflammatory ...cytokines into mature forms. Shahzad et al. unravel the importance of the Nlrp3 inflammasome, especially activated in glomerular resident cells, in diabetic nephropathy. They also show the role of mitochondrial reactive oxygen species as a mediator to activate the inflammasome in diabetic conditions. Targeting the inflammasome could be a promising approach for diabetic nephropathy.
Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a ...gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
Proteinuria has been considered to be the hallmark of diabetic kidney disease and to precede renal function loss. However, it has become clear that a substantial proportion of patients either with ...type 1 diabetes or type 2 diabetes have renal function loss without proteinuria, known as nonproteinuric diabetic kidney disease. Despite increasing recognition of the prevalence of nonproteinuric diabetic kidney disease, data on this phenotype of diabetic kidney disease is sparse. This review describes ever known clinical and pathological manifestations, renal prognosis, and mortality in patient with nonproteinuric diabetic kidney disease.
Recent studies have revealed that the gut microbiota plays a crucial role in maintaining a healthy, as well as diseased condition. Various organs and systems, including the kidney, are affected by ...the gut microbiota. While the impacts of the gut microbiota have been reported mainly on chronic kidney disease, acute kidney injury (AKI) is also affected by the intestinal environment. In this review, we discussed the pathogenesis of AKI, highlighting the relation to the gut microbiota. Since there is no established treatment for AKI, new treatments for AKI are highly desired. Some kinds of gut bacteria and their metabolites reportedly have protective effects against AKI. Current studies provide new insights into the role of the gut microbiota in the pathogenesis of AKI.
The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such ...as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m2, regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non‐diabetic kidney disease as being crucial in all stages of diabetic nephropathy.
Introduction
This study aimed to examine the effect of high-load resistance training (HLRT) on bone mineral density (BMD) in patients with osteoporosis and osteopenia using a meta-analysis.
Materials ...and methods
We searched for randomized controlled trials (RCTs) on HLRT in patients with osteoporosis and osteopenia from medical databases. Our meta-analysis was performed with the primary endpoints being the standardized mean difference (SMD) of the change in BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH). The robustness of the results was assessed by subgroup analysis. Heterogeneity factors were examined by meta-regression. Publication bias was evaluated using a funnel plot.
Results
We selected nine RCTs, with 259 patients in the HLRT group (women, 55.2%) and 236 patients in the control group (women, 62.7%). The HLRT group showed a significant increase in BMD in the LS SMD = 1.40, 95% confidence interval (CI) = 0.68–2.12,
p
< 0.001,
I
2
= 90%, the FN (SMD = 0.86, 95% CI = 0.05–1.67,
p
= 0.04,
I
2
= 92%), and the TH (SMD = 1.26, 95% CI = 0.45–2.08,
p
= 0.002,
I
2
= 91%). Subgroup analysis confirmed the robustness of the results only in LS. Total sessions and a high risk of bias were identified as the factors of heterogeneity in FN and TH (
p
< 0.05). The funnel plot showed asymmetry in all measurement sites.
Conclusion
This study suggested that HLRT can be effective in increasing BMD, mainly of LS, in patients with osteoporosis and osteopenia. However, due to high heterogeneity and publication bias, additional studies with a low risk of bias should be conducted to generalize our findings.
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