In CKD, empagliflozin reduced kidney disease progression at a median 2 y, regardless of primary kidney disease type.

SOURCE CITATION: EMPA-KIDNEY Collaborative Group. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12:51-60. 38061372.

Combination of Fushengong decoction with Western medicine on patients with chronic renal failure: An observational study.

Chronic renal failure (CRF) causes a reduction in glomerular filtration rate and damage to renal parenchyma. Fushengong decoction (FSGD) showed improvement in renal function in CRF rats. This study aims to analyze the differentially expressed proteins in CRF patients treated with Western medicine alone or in combination with FSGD. Sixty patients with CRF recruited from Yongchuan Traditional Chinese Medicine Hospital affiliated to Chongqing Medical University were randomly assigned into control (treated with Western medicine alone) and observation groups (received additional FSGD treatment thrice daily for 8 weeks). The clinical efficacy and changes in serum Bun, serum creatinine, Cystatin C, and transforming growth factor beta 1 (TGF-ß1) before and after treatment were observed. We employed isotope relative labeling absolute quantification labeling and liquid chromatography-mass spectrometry to identify differentially expressed proteins and carried out bioinformatics Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Patients in the observation group showed greater clinical improvement and lower levels of serum Bun, serum creatinine, Cyc-c, and TGF-ß1 than the control group. We identified 32 differentially up-regulated and 52 down-regulated proteins in the observation group. These proteins are involved in the blood coagulation system, protein serine/threonine kinase activity, and TGF-ß, which are closely related to the pathogenesis of CRF. Protein-protein-interaction network analysis indicated that candidate proteins fibronectin 1, fibrinogen alpha chain, vitronectin, and Serpin Family C Member 1 were in the key nodes. This study provided an experimental basis suggesting that FSGD combined with Western medicine could significantly improve renal function and renal fibrosis of CRF patients, which may be through the regulation of fibronectin 1, fibrinogen alpha chain, vitronectin, Serpin Family C Member 1, TGF-ß, and the complement coagulation pathway (see Graphical abstract S1, Supplemental Digital Content, http://links.lww.com/MD/L947).

Rational Engineering of Escherichia coli Nissle 1917 as Live Biotherapeutic to Degrade Uremic Toxin Precursors.

Uremic toxins (UTs) are microbiota-derived metabolites that accelerate the progression of kidney damage in patients with chronic kidney disease (CKD). One of the major UTs involved in CKD progression is p-cresol-sulfate (PCS), derived from dietary l-tyrosine (l-Tyr). Here, we engineered a probiotic strain of Escherichia coli Nissle 1917, to convert l-Tyr to the nontoxic compound p-coumaric acid via tyrosine ammonia lyase (TAL). First, a small metagenomic library was assessed to identify the TAL with the greatest whole-cell activity. Second, accessory genes implicated in the import of l-Tyr and export of PCA were overexpressed to enhance l-Tyr degradation by 106% and 56%, respectively. Last, random mutagenesis coupled to a novel selection and screening strategy was developed that identified a TAL variant with a 25% increase in whole-cell activity. Taken together, the final strain exhibits a 183% improvement over initial whole-cell activity and provides a promising candidate to degrade l-Tyr mediated PCS accumulation.

Adenine-induced animal model of chronic kidney disease: current applications and future perspectives.

Chronic kidney disease (CKD) with high morbidity and mortality all over the world is characterized by decreased kidney function, a condition which can result from numerous risk factors, including diabetes, hypertension and obesity. Despite significant advances in our understanding of the pathogenesis of CKD, there are still no treatments that can effectively combat CKD, which underscores the urgent need for further study into the pathological mechanisms underlying this condition. In this regard, animal models of CKD are indispensable. This article reviews a widely used animal model of CKD, which is induced by adenine. While a physiologic dose of adenine is beneficial in terms of biological activity, a high dose of adenine is known to induce renal disease in the organism. Following a brief description of the procedure for disease induction by adenine, major mechanisms of adenine-induced CKD are then reviewed, including inflammation, oxidative stress, programmed cell death, metabolic disorders, and fibrillation. Finally, the application and future perspective of this adenine-induced CKD model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given the simplicity and reproducibility of this animal model, it remains a valuable tool for studying the pathological mechanisms of CKD and identifying therapeutic targets to fight CKD.

Effect modification of polypharmacy on incident frailty by chronic kidney disease in older adults.

BACKGROUND: Frailty and polypharmacy are common conditions in older adults, especially in those with chronic kidney disease (CKD). Therefore, we analyzed the association of polypharmacy and incident frailty and the effect modification by CKD in very old adults. METHODS: In non-frail individuals within the Berlin Initiative (cohort) Study, polypharmacy (≥ 5 medications) was assessed according to multiple definitions based on the number of regular and on demand prescription and over the counter drugs, as well as vitamins and supplements. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m2 and/or an albumin-creatinine ratio ≥ 30 mg/g. Incident frailty was assessed at follow-up using Fried criteria. Logistic regression was applied to assess (1) the association of different polypharmacy definitions with incident frailty and (2) effect modification by CKD. RESULTS: In this cohort study, out of 757 non-frail participants (mean age 82.9 years, 52% female, 74% CKD), 298 (39%) participants reported polypharmacy. Over the observation period of 2.1 years, 105 became frail. Individuals with polypharmacy had 1.96 adjusted odds (95% confidence interval (CI): 1.20-3.19) of becoming frail compared to participants without polypharmacy. The effect of polypharmacy on incident frailty was modified by CKD on the additive scale (relative excess risk due to interaction: 1.56; 95% CI 0.01-3.12). CONCLUSIONS: This study demonstrates an association of polypharmacy and incident frailty and suggests strong evidence for an effect modification of CKD on polypharmacy and incident frailty. Revision of prescriptions could be a target strategy to prevent frailty occurrence, especially in older adults with CKD.

Effects of glucose-lowering drugs on cardiovascular outcomes in patients with type 2 diabetes: an update.

INTRODUCTION: Over the last few years, there has been a substantial increase in the data available about the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in improving cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Very little new information is available for the other groups of glucose-lowering drugs. AREAS COVERED: This brief report summarizes the recent information about the respective benefits of the two newer groups of glucose-lowering drugs and the effects on cardiovascular risk factors that may be involved in these benefits. The articles reviewed were identified by a Medline search. EXPERT OPINION: Recent guidelines recommend SGLT2 inhibitors or GLP-1 RAs with proven cardiovascular disease benefits as potential first line treatment for patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) or those with high risk of ASCVD or with chronic kidney disease or heart failure. Both groups of drugs have been shown to reduce major adverse cardiovascular events, but the mechanisms vary between them. SGLT2 inhibitors are preferred for the treatment and prevention of heart failure and chronic kidney disease, whereas GLP-1 RAs are more effective in reducing body weight and improving glycemic control in patients with T2D.

Ambient heat exposure and kidney function in patients with chronic kidney disease: a post-hoc analysis of the DAPA-CKD trial.

BACKGROUND: Higher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis. METHODS: DAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: Climate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a -0·6% (95% CI -0·9% to -0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment. INTERPRETATION: Higher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression. FUNDING: None.

Metformin modulates autophagic pathway in renal fibrosis induced by carbon tetrachloride in adult male albino rats.

BACKGROUNDS: Chronic kidney disease (CKD) is a global public health problem. All progressive chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis. Exposure to high concentrations of carbon tetrachloride (including vapor) can destroy the kidneys. Autophagy played an important role in maintaining the homeostasis of organs. Impaired autophagy was frequently associated with renal damage and fibrosis. Recent data suggests that metformin protects against a variety of kidney disorders. AIM: To investigate the protective role of metformin on carbon tetrachloride induced renal damage via autophagy pathway. MATERIALS AND METHODS: Forty adult male albino rats were divided into four equal groups (10 rats, each); Group 1: control group. Group 2: olive oil group received olive oil 1.5 mg/kg twice weekly S.C for 12 weeks. Group 3: The ccl4 group, the rats were received ccl4 1.5 mg/kg twice weekly S.C for 12 weeks. Group 4: CCL4 and Metformin group received concomitant treatment of CCL4, 1.5 mg/kg twice weekly S.C and 100 mg/kg/day Metformin orally for 12 weeks. After sacrifice, kidneys were taken from all animal groups and processed for light and electron microscopy, immunological studies and biochemical tests. Statistical analysis was done. RESULTS: Administration of ccl4 resulted in histopathological changes in the kidney tissue in the form of areas of tissue destruction, inflammatory cell infiltration, congestion and fibrosis. Ultrastructurally, irregular thickening of GBM was observed. Improvement was noticed with concomitant treatment of ccl4 with metformin. CONCLUSION: Metformin administration can modulate histological and biochemical effects in the renal tissue induced by of ccl4.

Attenuating Renal Interstitial Fibrosis by Shenqi Pill via Reducing Inflammation Response Regulated by NF-κB Pathway In Vitro and In Vivo.

INTRODUCTION: One of the most significant clinical features of chronic  kidney disease is renal interstitial fibrosis (RIF). This study aimed  to investigate the role and mechanism of Shenqi Pill (SQP) on RIF. METHODS: RIF model was established by conducting unilateral  ureteral obstruction (UUO) surgery on rat or stimulating human  kidney-2 (HK-2) cell with transforming growth factor ß1 (TGFß1).  After modeling, the rats in the SQP low dose group (SQP-L), SQP  middle dose group (SQP-M) and SQP high dose group (SQP-H)  were treated with SQP at 1.5, 3 or 6 g/kg/d, and the cells in the  TGFß1+SQP-L/M/H were treated with 2.5%, 5%, 10% SQP-containing  serum. In in vivo assays, serum creatinine (SCr) and blood urea  nitrogen (BUN) content were measured, kidney histopathology  was evaluated., and α-smooth muscle actin (α-SMA) expression  was detected by immunohistochemistry. Interleukin-1ß (IL-1ß),  interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) content,  inhibitor of kappa B alpha (IKBα) and P65 phosphorylation were  assessed. Meanwhile, cell viability, inflammatory cytokines content,  α-SMA expression, IKBα and P65 phosphorylation were detected  in vitro experiment.  Results. SQP exhibited reno-protective effect by decreasing SCr  and BUN content, improving renal interstitial damage, blunting  fibronectin (FN) and α-SMA expression in RIF rats. Similarly, after  the treatment with SQP-containing serum, viability and α-SMA  expression were remarkably decreased in TGFß1-stimulated HK-2  cell. Furthermore, SQP markedly down-regulated IL-1ß, IL-6, and  TNF-α content, IKBα and RelA (P65) phosphorylation both in vivo and in vitro.  Conclusion. SQP has a reno-protective effect against RIF in vivo and in vitro, and the effect is partly linked to nuclear factor-kappa  B (NF-κB) pathway related inflammatory response, which indicates  that SQP may be a candidate drug for RIF. DOI: 10.52547/ijkd.7546.

Icariin alleviates renal inflammation and tubulointerstitial fibrosis via Nrf2-mediated attenuation of mitochondrial damage.

Tubulointerstitial fibrosis is an inevitable consequence of all progressive chronic kidney disease (CKD) and contributes to a substantial health burden worldwide. Icariin, an active flavonoid glycoside obtained from Epimedium species, exerts potential antifibrotic effect. The study aimed to explore the protective effects of icariin against tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-induced CKD mice and TGF-ß1-treated HK-2 cells, and furthermore, to elucidate the underlying mechanisms. The results demonstrated that icariin significantly improved renal function, alleviated tubular injuries, and reduced fibrotic lesions in UUO mice. Furthermore, icariin suppressed renal inflammation, reduced oxidative stress as evidenced by elevated superoxide dismutase activity and decreased malondialdehyde level. Additionally, TOMM20 immunofluorescence staining and transmission electron microscope revealed that mitochondrial mass and morphology of tubular epithelial cells in UUO mice was restored by icariin. In HK-2 cells treated with TGF-ß1, icariin markedly decreased profibrotic proteins expression, inhibited inflammatory factors, and protected mitochondria along with preserving mitochondrial morphology, reducing reactive oxygen species (ROS) and mitochondrial ROS (mtROS) overproduction, and preserving membrane potential. Further investigations demonstrated that icariin could activate nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway both in vivo and in vitro, whereas inhibition of Nrf2 by ML385 counteracted the protective effects of icariin on TGF-ß1-induced HK-2 cells. In conclusion, icariin protects against renal inflammation and tubulointerstitial fibrosis at least partly through Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests that icariin could be developed as a promising therapeutic candidate for the treatment of CKD.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway / Losartán mejora la fibrosis renal al inhibir la vía de señalización del factor de necrosis tumoral

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.(AU)

El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.(AU)

Estrategias de prevención y tratamiento de la infección por SARS-CoV-2 (Severe Acute Respiratory Coronavirus 2) en pacientes con enfermedad renal crónica: revisión de la literatura / Strategies for prevention and treatment of SARS-CoV-2 infection in patients with chronic kidney disease: Literature review

La COVID-19 ha demostrado ser especialmente agresiva con los pacientes con enfermedad renal crónica (ERC). La menor tasa de respuesta inmunológica y la mayor facilidad para la progresión a formas graves de enfermedad ha propiciado este hecho, que se ha mantenido en la era posvacunal de la pandemia. Paradójicamente, la ERC ha sido excluida de la mayoría de los ensayos clínicos de las principales herramientas terapéuticas desarrolladas frente a SARS-CoV-2. Sin embargo, se ha ido reuniendo experiencia de uso de estos fármacos en distintos estadios de la ERC que avala su uso con garantías de eficacia y seguridad. El objetivo de esta revisión es reunir todas las indicaciones de tratamiento frente a la COVID-19 en los distintos estadios de la enfermedad adaptadas a la ERC en sus distintas fases, incluyendo el tratamiento sustitutivo renal.(AU)

COVID-19 has proven to be particularly aggressive in patients with chronic kidney disease (CKD). The lower immune response rate and the greater susceptibility to progress to severe forms of the disease have contributed to this phenomenon, which has persisted in the post-vaccination era of the pandemic. Paradoxically, CKD has been excluded from most clinical trials of the main therapeutic tools developed against SARS-CoV-2. However, experience in the use of these drugs has been accumulating in different stages of CKD, supporting their use with guarantees of efficacy and safety. The objective of this review is to gather all treatment indications for COVID-19 in the different phases of the disease, tailored to CKD in its various stages, including renal replacement therapy.(AU)

Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Association of anti-diabetic drugs and covid-19 outcomes in patients with diabetes mellitus type 2 and chronic kidney disease: Nationwide registry analysis.

INTRODUCTION: Patients with diabetes mellitus type 2 and chronic kidney disease (T2DM-CKD) have a 5 times higher risk of developing severe SARS-CoV-2 infection than those without these 2 diseases. The goal of this study is to provide information on T2DM-CKD and COVID-19 outcomes, with an emphasis on the association with anti-diabetic medications. METHODOLOGY: Study is designed as a retrospective cohort analysis covering the years 2020 and 2021. Data from the National Diabetes Registry (CroDiab) were linked to hospital data, primary healthcare data, Causes of Death Registry data, the SARS-CoV-2 vaccination database, and the SARS-CoV-2 test results database. Study outcomes were cumulative incidence of SARS-CoV-2 positivity, COVID-19 hospitalizations, and COVID-19 deaths. For outcome predictors, logistic regression models were developed. RESULTS: Of 231 796 patients with diabetes mellitus type 2 in the database, 7 539 were T2DM-CKD (3.25%). The 2-year cumulative incidences of all three studies' outcomes were higher in T2DM-CKD than in diabetes patients without CKD (positivity 18.1% vs. 14.4%; hospitalization 9.7% vs. 4.2%; death 3.3% vs. 1.1%, all p<0.001). For COVID-19 hospitalization, protective factors were SGLT-2 inhibitors use (OR 0.430; 95%CI 0.257-0.719) and metformin use (OR 0.769; 95% CI 0.643-0.920), risk factors were insulin use (1.411; 95%CI 1.167-1.706) and sulfonylureas use (OR 1.226; 95% CI 1.027-1.464). For SARS-CoV-2 positivity protective factors were SGLT-2 inhibitors (0.607; 95% CI 0.448-0.823), repaglinide use (OR 0.765; 95% CI 0.593-0.986) and metformin use (OR 0.857; 95% CI 0.770-0.994). DPP-4 inhibitors showed a non-significant decrease in risk for COVID-19 death (OR 0.761; 95% CI 0.568-1.019). CONCLUSION: T2DM-CKD are heavily burdened by COVID-19 disease. Our results suggest no association between antidiabetic drugs and COVID-19 death outcome while SGLT-2 and metformin show to be protective against COVID-19 hospitalization and infection, repaglinide against infection, and insulin and sulfonylureas show to be risk factors for COVID-19 hospitalization and infection. Further research in T2DM-CKD is needed.

Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications: A Systematic Review.

Importance: Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM). Objective: To evaluate the underrepresentation of patients with CKD in cardiovascular RCTs, and to highlight evidence gaps in CVRM medications in this population. Evidence Review: A systematic search was conducted in ClinicalTrials.gov from February 2000 through October 2021 for RCTs with full-text publications. If no full-text publications were found in ClinicalTrials.gov, MEDLINE, Embase, and Google Scholar were also searched. Eligible RCTs were those evaluating the effectiveness of antiplatelets, anticoagulants, blood pressure-lowering drugs, glucose-lowering drugs, or cholesterol-lowering drugs in adults with cardiovascular disease or cardiovascular risk factors. Trials with a sample size of fewer than 100 patients were excluded. Findings: In total, 1194 RCTs involving 2 207 677 participants (mean [SD] age, 63 [6] years; 1 343 970 males [64%]) were included. Since 2000, the percentage of cardiovascular RCTs excluding patients with CKD has increased from 66% to 79% (74% overall [884 RCTs]). In 864 RCTs (72%), more patients were excluded than anticipated on safety grounds (63% [306] of trials required no dose adjustment, and 79% [561] required dose adjustment). In total, 158 RCTs (13%) reported results for patients with CKD separately (eg, in subgroup analyses). Significant evidence gaps exist in most CVRM interventions for patients with CKD, particularly for those with CKD stages 4 to 5. Twenty-three RCTs (2%) reported results for patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2, 15 RCTs (1%) reported for patients receiving dialysis, and 1 RCT (0.1%) reported for recipients of kidney transplant. Conclusions and Relevance: Results of this systematic review suggest that representation of patients with CKD in cardiovascular RCTs has not improved in the past 2 decades and that these RCTs excluded more patients with CKD than expected on safety grounds. Lack of reporting or underreporting of results for this patient population is associated with evidence gaps in the effectiveness of most CVRM medications in patients with all stages of CKD, particularly CKD stages 4 to 5.

Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression.

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-ß1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.

Risk factors for mortality in Stenotrophomonas maltophilia bacteremia - a meta-analysis.

BACKGROUND: Stenotrophomonas maltophilia (S. maltophilia) is a nosocomial pathogen causing life-threatening invasive infections with a high mortality rate in some patient populations, especially those who are severely ill or immunocompromised. There is a need for data on mortality in patients with S. maltophilia bacteremia. OBJECTIVE: In this meta-analysis, we aimed to investigate risk factors for mortality in S. maltophilia bacteremia. METHODS: Studies comparing patients who died from S. maltophilia bacteremia with patients who survived were considered for inclusion. Studies were included if they reported one or more risk factors for mortality. Mortality risk factors included clinical predisposing factors, predisposing comorbidities and appropriateness of antibiotic therapy. RESULTS: Nineteen studies with 1248 patients were included in the meta-analysis. Five hundred and six (40.5%) patients died. The following risk factors for mortality were identified: ICU admission, septic shock, need for mechanical ventilation, indwelling central venous catheter, neutropenia, comorbid hematological malignancies, chronic kidney disease, inappropriate antimicrobial therapy and prior antibiotic use. CONCLUSIONS: Appropriate antimicrobial therapy had a protective effect against mortality in S. maltophilia bacteremia. Indwelling central venous catheter, neutropenia, hematological malignancies and chronic kidney disease were also risk factors for mortality.

A Nuphar lutea plant active ingredient, 6,6'-dihydroxythiobinupharidine, ameliorates kidney damage and inflammation in a mouse model of chronic kidney disease.

Chronic Kidney Disease (CKD) associated complications are associated with increased inflammation through the innate immune response, which can be modulated with anti-inflammatory agents. An active ingredient derived from the Nuphar lutea aquatic plant, 6,6'-dihydroxythiobinupharidine (DTBN) has anti-inflammatory properties, mainly through the inhibition of NF-κB. We tested the effects of DTBN on mice with CKD. After preliminary safety and dosing experiments, we exposed 8 weeks old male C57BL/6J mice to adenine diet to induce CKD. Control and CKD animals were treated with IP injections of DTBN (25 µg QOD) or saline and sacrificed after 8 weeks. Serum urea and creatinine were significantly decreased in CKD-DTBN Vs CKD mice. Kidney histology showed a decrease in F4/80 positive macrophage infiltration, damaged renal area, as well as decreased kidney TGF-ß in CKD-DTBN Vs CKD mice. Kidney inflammation indices (IL-1ß, IL-6 and P-STAT3) were significantly decreased in CKD-DTBN as compared to CKD mice. DTBN treatment showed no apparent damage to tissues in control mice, besides a decrease in weight gain and mild hypoalbuminemia without proteinuria. Thus, DTBN significantly improved renal failure and inflammation indices in CKD mice. Therefore, this and similar substances may be considered as an additional treatment in CKD patients.

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to be required to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.