Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials.

RATIONALE & OBJECTIVE: The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years. STUDY DESIGN: Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study. SETTING & STUDY POPULATIONS: Adult patients with CKD enrolled in the SoC arm of RCTs. SELECTION CRITERIA FOR STUDIES: Phase 3 RCTs evaluating GFR decline as an outcome in SoC arms. DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: The mean of GFR declines extracted in the SoC arm of selected RCTs were pooled by using a random effects model. Meta-regression analyses were performed to identify factors that may explain heterogeneity. RESULTS: The SoC arms from 92 RCTs were included in the meta-analysis with a total of 32,202 patients. The overall mean GFR decline was-4.00 (95% CI, -4.55 to-3.44) mL/min/1.73m2 per year in the SoC arms with a high level of heterogeneity (I2, 98.4% [95% CI, 98.2-98.5], P<0.001). Meta-regression analysis showed an association between publication year (ß estimate, 0.09 [95% CI, 0.032-0.148], P=0.003) and reduction in GFR over time. When evaluating publication decade categorically, GFR decline was-5.44 (95% CI, -7.15 to-3.73), -3.92 (95% CI, -4.82 to-3.02), and -3.20 (95% CI, -3.75 to -2.64) mL/min/1.73m2 per year during 1991-2000, 2001-2010, and 2011-2023, respectively. Using meta-regression, the heterogeneity of GFR decline was mainly explained by age and proteinuria. LIMITATIONS: Different methods assessing GFR in selected trials and observational design of the study. CONCLUSIONS: In the last 3 decades, GFR decline has decreased over time in patients enrolled in RCTs who received the standard of care. TRIAL REGISTRATION: Registered at PROSPERO with record number CRD42022357704. PLAIN-LANGUAGE SUMMARY: This study evaluated the secular trend in the change in glomerular filtration rate (GFR) decline in the placebo arms of randomized controlled trials (RCTs) that were studying approaches to protect the kidneys in the setting of chronic kidney disease. The placebo groups of RCTs are useful for examining whether the rate of progression of kidney disease has changed over time. We found an improvement in the slope of change in GFR over time. These findings suggest that adherence to standards of kidney care as implemented in clinical trials may be associated with improved clinical outcomes, and these data may inform the design of future RCTs in nephrology.

C-Phycoerythrin Prevents Chronic Kidney Disease-Induced Systemic Arterial Hypertension, Avoiding Oxidative Stress and Vascular Dysfunction in Remanent Functional Kidney.

Chronic kidney disease (CKD) is a burden in low- and middle-income countries, and a late diagnosis with systemic arterial hypertension (SAH) is the major complication of CKD. C-phycoerythrin (CPE) is a bioactive compound derived from Phormidium persicinum that presents anti-inflammatory and antioxidant effects in vitro and nephroprotective effects in vivo. In the current study, we determine the antihypertensive effect of CPE in a 5/6 nephrectomy-induced CKD model using twenty normotensives male Wistar rats, grouped into four groups (n = 5): sham; sham + CPE; 5/6 nephrectomy (NFx); and NFx + CPE. Treatment started a week post-surgery and continued for five weeks, with weekly hemodynamic evaluations. Following treatment, renal function, oxidative stress, and the expression of vascular dysfunction markers were assessed. The renal function analysis revealed CKD hyperfiltration, and the hemodynamic evaluation showed that SAH developed at the third week. AT1R upregulation and AT2R downregulation together with Mas1/p-Akt/p-eNOS axis were also observed. CPE treatment mitigated renal damage, preserved renal function, and prevented SAH with the modulation of the vasodilative AT1R, AT2R, and Mas1/pAKT/peNOS axis. This result reveals that CPE prevented CKD progression to SAH by avoiding oxidative stress and vascular dysfunction in the kidneys.

Protective effect of chicory and/or artichoke leaves extracts on carbon tetrachloride and gamma-irradiation-induced chronic nephrotoxicity in rats.

The prevalence of chronic kidney disease (CKD) is in progress that causes kidney failure, leading to global problems. This manuscript investigated the nephroprotective effects of chicory (CLE) and/or artichoke (ALE) leaves extracts on carbon tetrachloride (CCl4 ) and gamma-irradiation (Rad)-induced chronic nephrotoxicity in rats. Rats were divided into 10 groups (10 animals/group): group 1: control, groups 2-7 rats were treated with CLE, ALE, CLE/ALE, CCl4 , Rad, and CCl4 /Rad, respectively. Groups 8 to 10, rats were intoxicated with CCl4 /Rad, and treated with CLE, ALE, and CLE/ALE extracts, respectively, for 4 weeks. The data demonstrated that CCl4 administration or Rad exposure induced high levels of urea and creatinine, with low levels of total protein and albumin in the serum. However, high levels of malondialdehyde (MDA), nitric oxide (NO), hydrogen peroxide (H2 O2 ), some pro-inflammatory markers such as interleukins (IL-1ß, IL-2, IL-6), TNF-α, NF-κB, the fibrotic marker; TGF-ß1, calcium, and copper, low contents of reduced glutathione (GSH), iron, and zinc, and suppression of the antioxidant enzymes' activity, superoxide dismutase (SOD), and catalase (CAT) were observed. In addition, the Wnt and ß-catenin protein expression ratios were up-regulated in the kidney tissues of the CCl4 , and Rad intoxicated animals. However, the combined treatment CCl4 /Rad augmented these measurements. On the other hand, CLE, ALE, and CLE/ALE treatments demonstrated nephroprotection in the kidney tissues of CCl4 /Rad intoxicated animals, in the order of CLE/ALE>ALE>CLE by ameliorating the investigated parameters. Kidney tissues' histopathological examinations confirmed these results. In conclusion, CLE and/or ALE demonstrated nephroprotection against CCl4 /Rad co-toxicity mediated by down-regulation of renal Wnt/ß-catenin protein expressions.

Sodium glucose transporter 2 inhibitors: Will these drugs benefit non-diabetic veterinary patients with cardiac and kidney diseases?

Sodium glucose transporter type 2 (SGLT2) inhibitors have been introduced into human medicine where their beneficial effects go beyond the expected improvement in blood glucose control. These drugs appear to prevent progression of both cardiovascular and kidney diseases, not only in diabetic but also in non-diabetic human patients. As these drugs have received conditional approval for use in diabetic cats and are being used in other veterinary species, the intriguing question as to whether they will have similar cardioprotective and nephroprotective effects in dogs and cats is being asked. The primary mechanism(s) by which SGLT2 inhibitors are cardio- and nephroprotective remain to be fully characterized. This paper reviews these suggested mechanisms in the context of the pathophysiology of progressive cardiovascular and kidney diseases in dogs and cats with the goal of predicting which categories of non-diabetic veterinary patients these drugs might be of most benefit.

Sex-Specific Effects of Estradiol and Progesterone in Ischemic Kidney Injury.

The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of hormone action are poorly characterized. In this study, we investigated the influence of estradiol and progesterone on renal cells during ischemic injury. We performed both in vivo experiments on female and male rats and in vitro experiments on renal tubular cells (RTCs) obtained from the kidneys of intact animals of different sexes. Since mitochondria play an important role in the pathogenesis of AKI, we analyzed the properties of individual mitochondria in renal cells, including the area, roundness, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening time. We found that pre-treatment with progesterone or estradiol attenuated the severity of ischemia/reperfusion (I/R)-induced AKI in female rats, whereas in male rats, these hormones exacerbated renal dysfunction. We demonstrated that the mPTP opening time was higher in RTCs from female rats than that in those from male rats, which may be one of the reasons for the higher tolerance of females to ischemic injury. In RTCs from the kidneys of male rats, progesterone caused mitochondrial fragmentation, which can be associated with reduced cell viability. Thus, therapy with progesterone or estradiol displays quite different effects depending on sex, and could be only effective against ischemic AKI in females.

Anti-Inflammatory Effect of Synaptamide in Ischemic Acute Kidney Injury and the Role of G-Protein-Coupled Receptor 110.

The development of drugs for the treatment of acute kidney injury (AKI) that could suppress the excessive inflammatory response in damaged kidneys is an important clinical challenge. Recently, synaptamide (N-docosahexaenoylethanolamine) has been shown to exert anti-inflammatory and neurogenic properties. The aim of this study was to investigate the anti-inflammatory effect of synaptamide in ischemic AKI. For this purpose, we analyzed the expression of inflammatory mediators and the infiltration of different leukocyte populations into the kidney after injury, evaluated the expression of the putative synaptamide receptor G-protein-coupled receptor 110 (GPR110), and isolated a population of CD11b/c+ cells mainly representing neutrophils and macrophages using cell sorting. We also evaluated the severity of AKI during synaptamide therapy and the serum metabolic profile. We demonstrated that synaptamide reduced the level of pro-inflammatory interleukins and the expression of integrin CD11a in kidney tissue after injury. We found that the administration of synaptamide increased the expression of its receptor GPR110 in both total kidney tissue and renal CD11b/c+ cells that was associated with the reduced production of pro-inflammatory interleukins in these cells. Thus, we demonstrated that synaptamide therapy mitigates the inflammatory response in kidney tissue during ischemic AKI, which can be achieved through GPR110 signaling in neutrophils and a reduction in these cells' pro-inflammatory interleukin production.

SGLT2 Inhibitors in Kidney Diseases-A Narrative Review.

Some of the most common conditions affecting people are kidney diseases. Among them, we distinguish chronic kidney disease and acute kidney injury. Both entities pose serious health risks, so new drugs are still being sought to treat and prevent them. In recent years, such a role has begun to be assigned to sodium-glucose cotransporter-2 (SGLT2) inhibitors. They increase the amount of glucose excreted in the urine. For this reason, they are currently used as a first-line drug in type 2 diabetes mellitus. Due to their demonstrated cardioprotective effect, they are also used in heart failure treatment. As for the renal effects of SGLT2 inhibitors, they reduce intraglomerular pressure and decrease albuminuria. This results in a slower decline in glomelular filtration rate (GFR) in patients with kidney disease. In addition, these drugs have anti-inflammatory and antifibrotic effects. In the following article, we review the evidence for the effectiveness of this group of drugs in kidney disease and their nephroprotective effect. Further research is still needed, but meta-analyses indicate SGLT2 inhibitors' efficacy in kidney disease, especially the one caused by diabetes. Development of new drugs and clinical trials on specific patient subgroups will further refine their nephroprotective effects.

[Non-pharmacological prevention of chronic kidney disease]. / Prévention non médicamenteuse de la maladie rénale chronique.

Preventing chronic kidney disease (CKD) is a major public health objective. CKD leads to significant cardiovascular morbidity and mortality, with a negative impact on quality of life and significant societal repercussions. Several drugs are effective in preventing and curbing CKD, including blockers of the renin/angiotensin/aldosterone system and inhibitors of the SGLT2 co-transporter. New molecules are currently in clinical trials focusing on the nephro-protection, such as non-steroidal mineralocorticoid receptor antagonists and GPL-1 receptor agonists. In addition to this drug arsenal, CKD prevention also relies on non-pharmacological optimization of hygienic-dietary measures, including smoking avoidance, physical activity and dietetics. The aim of this article is to detail this non-medicinal approach to the prevention and slow down of CKD.

La prévention de la maladie rénale chronique (MRC) est un objectif majeur de santé publique. La MRC engendre, en effet, une morbi-mortalité cardiovasculaire importante, avec un impact négatif sur la qualité de vie et des répercussions sociétales non négligeables. Plusieurs piliers médicamenteux sont efficaces dans la prévention et la freination de la MRC, tels que les bloqueurs du système rénine/angiotensine/aldostérone et les inhibiteurs du co-transporteur SGLT2. De nouvelles molécules sont en cours d'essais cliniques visant la néphro-protection, comme les antagonistes non stéroïdiens du récepteur aux minéralocorticoïdes et les agonistes du récepteur au GPL-1. Outre cet arsenal médicamenteux, la prévention de la MRC repose également sur une optimisation non pharmacologique des mesures hygiéno-diététiques, comprenant l'éviction tabagique, l'activité physique et la diététique. L'objectif de cet article est de détailler cette approche non médicamenteuse dans la prévention et la freination de la MRC.

[Chronic kidney disease in geriatrics]. / La maladie rénale chronique en gériatrie.

Chronic kidney disease (CKD) affects almost 10% of the world's population, and over 30% of people aged over 70 [1,2]. The overall incidence of treated CKD is stable in France, but continues to rise sharply in people aged over 85 [3]. In its advanced stages, CKD is associated with numerous complications linked to disturbances in water, acid-base and phosphocalcium balance, as well as anemia and increased cardiovascular risk. A better understanding of risk factors, improved practices to promote nephroprotection, and progress in therapeutic education and preparation for suppletive techniques would help reduce this risk.

Localization of natriuretic peptide receptors A, B, and C in healthy and diseased mouse kidneys.

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection. Since neither the NP-mediated renal functions nor the renal target cells of renoprotection are completely understood, we performed systematic localization studies of NP receptors using in situ hybridization (RNAscope) in mouse kidneys. NPR-A mRNA is highly expressed in glomeruli (mainly podocytes), renal arterioles, endothelial cells of peritubular capillaries, and PDGFR-receptor ß positive (PDGFR-ß) interstitial cells. No NPR-A mRNA was detected by RNAscope in the tubular system. In contrast, NPR-B expression is highest in proximal tubules. NPR-C is located in glomeruli (mainly podocytes), in endothelial cells and PDGFR-ß positive cells. To test for a possible regulation of NPRs in kidney diseases, their distribution was studied in adenine nephropathy. Signal intensity of NPR-A and NPR-B mRNA was reduced while their spatial distribution was unaltered compared with healthy kidneys. In contrast, NPR-C mRNA signal was markedly enhanced in cell clusters of myofibroblasts in fibrotic areas of adenine kidneys. In conclusion, the primary renal targets of ANP and BNP are glomerular, vascular, and interstitial cells but not the tubular compartment, while the CNP receptor NPR-B is highly expressed in proximal tubules. Further studies are needed to clarify the function and interplay of this specific receptor expression pattern.

Renal denervation in patients with chronic kidney disease: current evidence and future perspectives.

Supported by several high-quality randomized controlled trials and registry analyses, catheter-based renal denervation is becoming an important adjunctive treatment modality for the safe and efficacious treatment of hypertension besides lifestyle modifications and antihypertensive medication. Renal denervation is of particular interest to nephrologists as the intervention may provide additional benefits to hypertensive people with chronic kidney disease (CKD), a condition typically characterized by sympathetic hyperactivity. A growing body of clinical evidence supports the safety and efficacy of renal denervation in this difficult-to-control population. In addition, preclinical and clinical research works indicate potential nephroprotective effects in CKD patients. The current review examines recent research on renal denervation with a focus on renal disease and assesses the latest findings and their implications from a nephrologist's perspective.

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease.

Diabetic kidney disease (DKD) develops in ∼40% of patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Patients with CKD, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular (CV) death. The use of renin-angiotensin system (RAS) blockers to reduce the incidence of kidney failure in patients with DKD dates back to studies that are now ≥20 years old. During the last few years, sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with RAS blockers and SGLT2is, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of CV death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists (MRAs) reduce albuminuria and surrogate markers of CV disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in DKD (FIDELIO-DKD) study comparing the actions of the non-steroidal MRA finerenone with placebo, finerenone reduced the progression of DKD and the incidence of CV events, with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of MRAs, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic CKD.

Deacetyl epoxyazadiradione protects aminoglycoside antibiotic-induced renal cell apoptosis, in vitro.

Aminoglycoside antibiotics such as gentamicin are used frequently to treat bacterial infections in humans. Excessive consumption of these antibiotics lead to renal dysfunction. One of the factors contributing to renal dysfunction is oxidative damage, which causes apoptosis. Hence, this study investigates the effect of the antioxidant compound deacetyl epoxyazadiradione (DEA) in reducing cell death induced by gentamicin treatment in kidney cells (Madin-Darby canine kidney cells). The antioxidant experiments showed that reactive oxygen species level is decreased up to 27.06 ± 0.18% in 150 µM of DEA treatment. At this concentration, the activity of antioxidant enzymes such as superoxide dismutase increased from 0.4 ± 0.04 to 1.46 ± 0.05 µmol/min/L and catalase increased from 7.48 ± 0.39 to 17.6 ± 0.74 U/mg. The relative folds of gene expression of mitochondrial enzymes such as GST, GPx and GR restored from 0.596 ± 0.019, 0.521 ± 0.013 and 0.775 ± 0.014 to 0.866 ± 0.013, 0.669 ± 0.015 and 0.8615 ± 0.028, respectively. Consequently, the percentage of cell viability increases upto 91.8 ± 2.01 from 61.93 ± 1.63 with much less fragmentation in genomic DNA. Additionally, molecular docking results showed that DEA could bind to Bax, Bcl- 2, Caspase- 3 and Caspase- 9 proteins. These results indicate that DEA could reduce cell apoptosis by reducing oxidative stress due to antibiotics and interrupting the apoptotic signal pathway in kidney cells.

Phytocompounds from Amazonian Plant Species against Acute Kidney Injury: Potential Nephroprotective Effects.

There are several Amazonian plant species with potential pharmacological validation for the treatment of acute kidney injury, a condition in which the kidneys are unable to adequately filter the blood, resulting in the accumulation of toxins and waste in the body. Scientific production on plant compounds capable of preventing or attenuating acute kidney injury-caused by several factors, including ischemia, toxins, and inflammation-has shown promising results in animal models of acute kidney injury and some preliminary studies in humans. Despite the popular use of Amazonian plant species for kidney disorders, further pharmacological studies are needed to identify active compounds and subsequently conduct more complex preclinical trials. This article is a brief review of phytocompounds with potential nephroprotective effects against acute kidney injury (AKI). The classes of Amazonian plant compounds with significant biological activity most evident in the consulted literature were alkaloids, flavonoids, tannins, steroids, and terpenoids. An expressive phytochemical and pharmacological relevance of the studied species was identified, although with insufficiently explored potential, mainly in the face of AKI, a clinical condition with high morbidity and mortality.

[Finerenone (Kerendia®), a new weapon against the chronic kidney disease of a patient with type 2 diabetes]. / Le médicament du mois. La finérénone (Kerendia®), une nouvelle arme contre la maladie rénale chronique du patient avec diabète de type 2.

Finerenone, a new nonsteroidal mineralocorticoid receptor antagonist, showed a significant reduction in a primary composite renal outcome in FIDELIO-DKD and a significant reduction in a primary composite cardiovascular outcome in FIGARO-DKD in patients with type 2 diabetes (T2D) and a chronic kidney disease (CKD). In a subsequent analysis that combined these two clinical trials (FIDELITY), the reduction becomes statistically significant when compared to placebo for both outcomes, with a hazard ratio of 0.86 (95 % confidence interval 0.78-0.95; P = 0.0018) for the cardiovascular outcome and 0.77 (0.67-0.88; P = 0.0002) for the renal outcome. Furthermore, all renal events occurred less frequently with finerenone than with placebo, including the progression to end-stage CKD independently of the baseline levels of glomerular filtration rate and albuminuria and regardless of associated medications (including gliflozins). The safety profile was excellent. However, a significant increase in serum potassium level was observed. Even if it is less pronounced than the increase usually seen with spironolactone, the risk of hyperkalemia requires some caution regarding both patient selection and monitoring. Finerenone (Kerendia®) is indicated in the treatment of CKD with albuminuria in adult patients with T2D. In Belgium, it is reimbursed with conditions in combination with a renin-angiotensin blocker.

La finérénone, un nouvel antagoniste non stéroïdien du récepteur des minéralocorticoïdes, a montré, dans deux grandes études réalisées chez des patients avec un diabète de type 2 (DT2) et une maladie rénale chronique (MRC), une réduction significative du critère composite rénal dans FIDELIO-DKD et du critère composite cardiovasculaire dans FIGARO-DKD. Dans une analyse combinant les deux études (FIDELITY), la réduction est statistiquement significative dans le groupe finérénone par rapport au groupe placebo pour les deux critères, avec un hasard ratio de 0,86 (intervalle de confiance à 95 % 0,78-0,95; P = 0,0018) pour le critère cardiovasculaire et de 0,77 (0,67-0,88; P = 0,0002) pour le critère rénal. De plus, tous les événements rénaux surviennent moins fréquemment sous finérénone que sous placebo, y compris la progression vers l'insuffisance rénale terminale et ce, indépendamment du niveau du débit de filtration glomérulaire et de l'albuminurie à l'inclusion dans les essais ou des traitements associés (y compris les gliflozines). Le profil de sécurité est excellent, avec cependant une élévation de la kaliémie. Si elle est moindre que celle observée avec la spironolactone, elle nécessite néanmoins des précautions d'usage en termes de sélection des patients et de leur surveillance. La finérénone (Kerendia®) est indiquée dans le traitement de la MRC avec albuminurie chez le patient adulte avec DT2 et est remboursée en Belgique, sous conditions, en association avec un bloqueur du système rénine-angiotensine.

[State-of-the-art trends in the treatment of immune-mediated inflammatory kidney diseases: Translation of the fundamental science into clinical practice. A review].

Immune-mediated kidney diseases like glomerulonephritis and tubulointerstitial nephritis are not the most common cause of chronic kidney disease in the population, however the difficulties in their management, as well as a more rapid deterioration of kidney function, compared to diabetes mellitus and hypertension, justify the importance of this problem for internal medicine. Due to the fundamental discoveries in pathology and to the introduction of various methods of laboratory and instrumental investigation in the second half of the XX century substantial progress was made in the diagnostic approaches and treatment of these conditions. State-of-the-art diagnostic approach requires complex evaluation of the clinical, laboratory and morphological data to identify the nosological form of the disease. The accumulation of knowledge in the field of diseases' pathogenesis led to the revision of the current classification of glomerulonephritis that should be based on the immunopathogenesis of these conditions. The following phenotypes were suggested: autoimmunity-related, autoinflammation-related, alloimmunity-related, infections-related, and monoclonal gammopathy-related. The assessment of disease activity and chronicity in the kidney tissue should be mandatory. Personalized selection of the optimal treatment modality on the basis of the diagnosis, severity, and individual features of the patient is currently possible. The leading trends include rational prescription of glucocorticoids (steroid-sparing regimens) and cytotoxic agents, e.g. cyclophosphamide, as well as the introduction of multitarget regimens that include biologic agents or small molecules selectively suppressing B-cells or various complement pathways. Another mandatory component of treatment on par with immune suppression is nephroprotective therapy, which currently comprises not only traditional renin-angiotensin-aldosterone antagonists, but also endothelin receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Current guidelines emphasize the importance of the non-pharmacological interventions for the implementation of the nephroprotective strategy. Rational combination of the aforementioned approaches allows for the optimization of the management of patients with immune-mediated kidney diseases, although it requires high competencies and strict adherence to the principles of the evidence-based medicine from the healthcare providers.

Ellagic acid ameliorates hexavalent chromium-induced renal toxicity by attenuating oxidative stress, suppressing TNF-α and protecting mitochondria.

Nephrotoxicity is an important adverse effect of oxidative stress induced by hexavalent chromium [Cr(VI)]. The effect of ellagic acid, a dietary polyphenolic compound with potent antioxidant activity, was investigated in Cr(VI)-induced kidney injury. Six groups of male Wistar rats were treated intragastrically with vehicle or ellagic acid (15 and 30 mg/kg) for 10 days. On day 10, rats received saline or Cr(VI) (K2Cr2O7 15 mg/kg) subcutaneously. Cr(VI) significantly increased kidney weight, affected kidney function assessed by biomarkers in blood and urine (protein, creatinine and urea nitrogen), caused histological changes (tubular injury and glomerular capillary tuft damage), increased markers of oxidative stress and reduced the activity of antioxidant enzymes. In addition, Cr(VI) altered mitochondrial ultrastructure, impaired mitochondrial respiration, increased lipid peroxidation, and inhibited the function of mitochondrial enzymes. Pretreatment with ellagic acid (30 mg/kg) attenuated all the aforementioned alterations. Furthermore, we explored whether ellagic acid might regulate the tumor necrosis factor-alpha (TNF-α)/receptor-interacting protein kinase 3 (RIPK3) pathway, reducing Cr(VI)-induced tubular necrosis. Cr(VI) upregulated both TNF-α and RIPK3, but ellagic acid only decreased TNF-α levels, having no effect on RIPK3 content. Therefore, understanding the mechanisms through which Cr(VI) promotes necroptosis is crucial for future studies, in order to design strategies to mitigate kidney damage. In conclusion, ellagic acid attenuated Cr(VI)-induced renal alterations by preventing oxidative stress, supporting enzymatic activities, suppressing TNF-α, and preserving mitochondrial ultrastructure and function, most likely due to its antioxidant properties.

Renal denervation: where do we stand and what is the relevance to the nephrologist?

Catheter-based renal denervation to reduce high blood pressure (BP) has received well-deserved attention after a recent series of sham-controlled trials reported significant antihypertensive efficacy and very favourable tolerability and safety of the intervention. This emerging treatment option is of high relevance to nephrologists. Patients with chronic kidney disease (CKD) are at elevated risk of cardiovascular adverse events and often present with hypertension, which is very difficult to control with medication. Renal denervation promises a new tool to reduce BP and to prevent loss of renal function in this population. The current review considers the role of the kidney and neurohormonal activation in the development of hypertension and the rationale for renal denervation. The current state of the evidence for the effectiveness and tolerability of the procedure is considered from the nephrologists' perspective, with a focus on the potential future role of renal denervation in the management of CKD patients with hypertension.

Dissecting the genotype-phenotype correlation of COL4A5 gene mutation and its response to renin-angiotensin-aldosterone system blockers in Chinese male patients with Alport syndrome.

BACKGROUND: Alport syndrome (AS) is an inherited type IV collagen-related disorder with an irreversible tendency to progress to end-stage renal disease (ESRD). X-linked AS (XLAS) is caused by mutations in the COL4A5 gene. The aim of this study was to investigate the effects of underlying mutations on clinical manifestations and the response to therapy in XLAS. METHODS: We conducted a retrospective cohort study of 187 Chinese male patients with XLAS confirmed by pathological examination and genetic analysis. The Kaplan-Meier method and Cox proportional hazards model were used to assess the age and risk of progression to ESRD under different genotypes and treatment conditions. RESULTS: A strong relationship between transcript type and renal outcome was observed, with the median age of ESRD onset being 22 years for truncating mutations and 39 years for non-truncating mutations. The response of affected patients to renin-angiotensin-aldosterone system (RAAS) blockers was genotype-associated. This therapy delayed the onset of ESRD by 16 years in patients with non-truncating mutations and 3 years in patients with truncating mutations. The efficacy of RAAS blockers functioned in a time-dependent manner, with a 7% reduction in the risk of progression to ESRD per each 6-month increase in treatment duration [hazard ratio 0.93 (95% confidence interval 0.89-0.96); P < 0.001]. CONCLUSIONS: Clinical features and response to RAAS blockers were observed to be strongly correlated with the genotypes of male XLAS patients. Genotyping of COL4A5 gene mutations is essential and is a useful tool to assess the prognosis of AS patients.

Protective effect of rutin and ß-cyclodextrin against hepatotoxicity and nephrotoxicity induced by lambda-cyhalothrin in Wistar rats: biochemical, pathological indices and molecular analysis.

BACKGROUND: This study aimed to assess hepatotoxicity and nephrotoxicity of Lambda-cyhalothrin (LCT) and the protective effect of rutin alone and in combination with ß-cyclodextrin (ß-CD). MATERIALS AND METHODS: Male Wistar rats were divided into five groups: Group 1: was used as a control and received a standard diet and water. Group 2, 3, 4 and 5 were orally administered with LCT (7.6 mg/kg body weight), rutin (200 mg/kg body weight) LCT and rutin (at the same doses as in Group 2 and Group 3), and LCT and a mixture of rutin with ß-CD (400 mg/kg body weight), respectively. All experimental animals were orally gavaged 5 days/week for 60 days. RESULTS: Our data revealed that LCT-induced liver and kidney injuries were related to the up-regulated expression of TNF-α and down-regulated expression of NRF-2 genes mRNA, whereas these effects were reversed with rutin treatment. LCT-induced oxidative stress altered the histological picture, and the hematological and biochemical parameters. CONCLUSION: Treatment with a rutin-ß-CD complex had preventive potential against LCT via suppression of oxidative stress and augmentation of the antioxidant defense system.