Search Results (98)

Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension. By 2040, CKD is predicted to be the fifth-leading cause of years of life lost. Developing strategies to prevent CKD and to reduce its progression to kidney failure is thus of great public health significance. Hypertension is known to be both a cause and a consequence of kidney damage and an eminently modifiable risk factor. An increased risk of hypertension, especially among women, has been linked to chronic exposure to the ubiquitous food contaminant cadmium (Cd). The mechanism is unclear but is likely to involve its action on the proximal tubular cells (PTCs) of the kidney, where Cd accumulates. Here, it leads to chronic tubular injury and a sustained drop in the estimated glomerular filtration rate (eGFR), a common sequela of ischemic acute tubular necrosis and acute and chronic tubulointerstitial inflammation, all of which hinder glomerular filtration. The present review discusses exposure levels of Cd that have been associated with an increased risk of hypertension, albuminuria, and eGFR ≤ 60 mL/min/1.73 m² (low eGFR) in environmentally exposed people. It highlights the potential role of 20-hydroxyeicosatetraenoic acid (20-HETE), the second messenger produced in the kidneys, as the contributing factor to gender-differentiated effects of Cd-induced hypertension. Use of GFR loss and albumin excretion in toxicological risk calculation, and derivation of Cd exposure limits, instead of β₂-microglobulin (β₂M) excretion at a rate of 300 µg/g creatinine, are recommended. Full article

Background and Clinical Significance: Although dietary supplements have often been deemed safe, some have been linked to drug-induced nephropathy due to their diverse ingredients. The aim of this report is to enhance clinical awareness of a novel and emerging cause of Fanconi syndrome due to red yeast rice supplements and to contribute new histopathological and clinical data. Case Presentation: We report two cases of renal dysfunction and Fanconi syndrome associated with the use of red yeast rice supplements. Both patients presented with renal impairment accompanied by elevated markers of tubular injury, hypouricemia, hypokalemia, and glucosuria, consistent with Fanconi syndrome. Following the discontinuation of the red yeast rice supplement and initiation of steroid therapy, Fanconi syndrome resolved, however, moderate renal dysfunction persisted. Urinary NGAL levels improved after treatment in both cases. KIM-1 normalized in one case but remained elevated in the other. Uromodulin recovery was complete in one case and partial in the other. Renal biopsy revealed mild tubulointerstitial nephritis, with notable shedding of proximal tubular epithelial cells. Immunohistochemical analysis demonstrated reduced expression of URAT-1, Na-K ATPase, and Na-Pi IIa in some tubules. Conclusions: These findings suggest that renal injury induced by red yeast rice supplements is mediated by direct proximal tubular necrosis caused by a harmful substance in the supplement, resulting in persistence of tubular dysfunction. Full article

Background: Acute phosphate nephropathy (APN) is an underrecognized cause of acute kidney injury (AKI), typically associated with the use of oral sodium phosphate (OSP)-based bowel preparations. It is characterized by calcium phosphate crystal deposition within the renal tubules and may result in permanent renal impairment. Despite known risks, phosphate-containing solutions are still widely used without sufficient risk stratification. Methods: We retrospectively evaluated 517 native kidney biopsies performed in our nephrology clinic between 2017 and 2022. Among these, 12 patients with unexplained AKI and recent colonoscopy history were identified. In nine cases, non-specific tubular deposits on routine staining prompted further histochemical analysis. All had a history of recent OSP-based bowel cleansing. The use of von Kossa staining confirmed calcium phosphate deposition, consistent with APN. Results: Out of 517 kidney biopsies performed during the study period, 9 patients were diagnosed with APN based on histopathological findings following recent colonoscopy and OSP-based bowel cleansing. The mean age was 58.7 years, and three were female. Hypertension was present in seven patients, diabetes mellitus in three, and epilepsy in two; one patient had no comorbidities. Baseline renal function was normal (mean serum creatinine 0.86 mg/dL) and increased to 1.76 mg/dL at three months post-exposure. All biopsies revealed tubulointerstitial calcium phosphate deposits and interstitial inflammation; mesangial hypercellularity was observed in five cases, tubular atrophy in three, and acute tubular necrosis in one. All samples stained positive with von Kossa staining. Over time, all patients developed chronic kidney disease, and one progressed to end-stage renal disease requiring dialysis. Conclusions: In patients presenting with unexplained AKI and recent OSP-based bowel preparation, APN should be considered in the differential diagnosis. When routine histology is inconclusive, definitive diagnosis may require special histochemical staining. Risk-based restrictions on phosphate-containing agents are warranted to reduce preventable kidney injury. Full article

Prolonged exposure to fine particulate matter (PM_2.5) has been implicated in accelerated aging, including organ fibrosis. This study aimed to investigate whether prenatal and postnatal PM_2.5 exposure promotes renal fibrogenesis in adulthood and whether long-term vitamin D supplementation alleviates associated renal injury. Pregnant Sprague-Dawley rats were randomly assigned to three groups: control (normal saline, NS), PM_2.5 exposure, and PM_2.5 exposure with vitamin D supplementation during gestation and lactation (n = 3/group). Male offspring were subsequently exposed to the same conditions from postnatal weeks 3 to 8 (n = 7/group). On postnatal day 56, PM_2.5-exposed rats showed lower body weight and more severe glomerular and tubulointerstitial damage compared to controls. Serum calcium levels were elevated in the PM_2.5 group. The expression of intrarenal renin, transforming growth factor-β1, α-smooth muscle actin, and vimentin was upregulated, accompanied by increased collagen deposition. Long-term vitamin D supplementation reversed most of these changes, except for intrarenal vimentin expression and serum calcium levels. These findings indicate that prenatal and postnatal PM_2.5 exposure can activate intrarenal renin signaling and fibrogenic pathways, contributing to renal fibrosis later in life. Long-term vitamin D supplementation may provide partial protective effects against PM_2.5-induced renal fibrogenesis. Full article

Hypertension and diabetes are two common causes of chronic kidney disease. Hypertension can induce renal vascular injury, glomerular damage, podocyte loss, and tubular injury, leading to tubulointerstitial fibrosis. A number of factors influence the regulation of hypertension, among which G-protein-coupled receptors (GPCRs) have been studied extensively because they are desirable targets for drug development. Compared to hypertension, the regulatory effects of GPCRs on hypertensive kidney disease (HKD) are less generalized. In this review, we discussed the GPCRs involved in hypertensive kidney disease, such as angiotensin II receptors (AT1R and AT2R), Mas receptor (MasR), Mas-related G-protein-coupled receptor member D (MrgD), relaxin family receptor 1 (RXFP1), adenosine receptors (A₁, A_2A, A_2B, and A₃), purinergic P2Y receptors, and endothelin receptors (ET_A and ET_B). The progression of HKD is rarely reversed but can be retarded by ameliorating the hypertensive microenvironment in the kidneys. However, simply reducing blood pressure cannot stop the progression of HKD. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD), which is a major cause of morbidity and mortality in diabetes. Many GPCRs are involved in DN. Here, we select some well-studied GPCRs that are directly associated with the pathogenesis of DN to illustrate their mechanisms. The main purpose of this review is to provide an overview of the GPCRs involved in the occurrence and progression of HKD and DN and their probable pathophysiological mechanisms, which we hope will help in developing new therapeutic strategies. Full article

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression. Full article

Primary membranous nephropathy is a leading cause of nephrotic syndrome in adults, characterized by immune complex deposition in the glomerular basement membrane. Predicting proteinuria remission is essential for guiding treatment decisions, optimizing immunosuppressive therapy, and improving renal outcomes. Traditional prognostic markers, such as anti-PLA2R antibody status and baseline proteinuria levels, offer valuable insights into disease progression. However, recent research has identified additional biomarkers that may enhance risk stratification and refine individualized treatment strategies. Serum-based markers, such as uric acid and inflammatory indices, may indicate systemic changes that impact disease progression. Urinary biomarkers, including microhematuria, α1-microglobulin, and CXCL13, have been proposed as potential predictors of disease activity and remission likelihood. Furthermore, histopathological features, such as glomerular basement membrane thickness, tubulointerstitial injury, and acute kidney injury, provide structural correlates that may inform prognosis. This review explores both established and emerging prognostic indicators across various biological domains. Understanding these predictors can aid in developing personalized therapeutic strategies, optimizing disease management, and improving patient outcomes in primary membranous nephropathy. Full article

Background/Objectives: Anethole, a terpenoid with several pharmacologic effects, is the major constituent of the essential oil of Croton zehntneri (EOCz), Pax & K. Hoffm, Euphorbiaceae. Due to the mild renal toxicity associated with high doses of EOCz, its potential therapeutic effects on several diseases, and the fact that its chemical composition consists of 80% anethole, the renal effects of anethole in mice were investigated. Methods: Mice were randomly divided into eight groups, dosed daily as follows: Group 1—CTRL (control; vehicle only); Groups 2—A100, 3—A125_2x, and 4—A250 (dosed with 100, 125 twice daily, and 250 mg/kg, per os anethole); Group 5—_SUBAKI (i.p. albumin to induce hyperproteinemia and proteinuria; subclinical acute kidney injury); and Groups 6—_SUBAKI+A100, 7—_SUBAKI+A125_2x, and 8—_SUBAKI+A250 (per os anethole + i.p. albumin). Results: The A125_2x and A250 groups significantly increased urinary proteinuria and interstitial inflammation (p < 0.001, for these groups). _SUBAKI+A100, _SUBAKI+A125_2x, and _SUBAKI+A250 showed a neither protective nor additive effect in the proteinuria induced by anethole and by administered albumin. The anethole-induced proteinuria was spontaneously reversible in approximately 4 weeks. In vitro experiments showed that anethole (300 µg/mL) inhibits albumin uptake from the culture medium by tubular cells. Conclusions: Anethole at high doses bears renal acute toxicity that, although mild and spontaneously fully reversible, must be taken into consideration in a cost–benefit analysis. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have generated a revolutionary approach in the treatment of cancer, but their effectiveness has been compromised by immune-related adverse events, including renal damage. Although rare, these effects are relevant because they have been related to poor patient prognoses. The objective of this review was to estimate the current incidence of nephrotoxicity in patients treated with single and double ICI therapies. Methods: A total of 1283 potential articles were identified, which were reduced to 50 after applying the exclusion and inclusion criteria. Results: This study reveals the increase in acute kidney injury associated with these drugs in the last decade and shows that, interestingly, combined therapies with ICIs does not lead to an increase in kidney damage compared with anti-CTLA-4. It also suggests that kidney damage could be underdiagnosed when it comes to interstitial nephritis, because definitive evidence requires a renal biopsy. Conclusions: In perspective, these conclusions could guide clinicians in making decisions for therapy personalization and highlight the need to search for new diagnostic systems that are more sensitive and specific to the type of damage and could replace the biopsy. Full article

Background: Tubulointerstitial hypoxia is a key factor for lupus nephritis progression to end-stage renal disease. Numerous aquaporins (AQPs) are expressed by renal tubules and are essential for their proper functioning. The aim of this study is to characterize the tubular expression of AQP1, AQP2 and AQP3, which could provide a better understanding of tubulointerstitial stress during lupus nephritis. Methods: This retrospective monocentric study was conducted at Erasme-HUB Hospital. We included 37 lupus nephritis samples and 9 healthy samples collected between 2000 and 2020, obtained from the pathology department. Immunohistochemistry was performed to target AQP1, AQP2 and AQP3 and followed by digital analysis. Results: No difference in AQP1, AQP2 and AQP3 staining location was found between healthy and lupus nephritis samples. However, we observed significant differences between these two groups, with a decrease in AQP1 expression in the renal cortex and in AQP3 expression in the cortex and medulla. In the subgroup of proliferative glomerulonephritis (class III/IV), this decrease in AQPs expression was more pronounced, particularly for AQP3. In addition, within this subgroup, we detected lower AQP2 expression in patients with higher interstitial inflammation score and lower AQP3 expression when higher interstitial fibrosis and tubular atrophy were present. Conclusions: We identified significant differences in the expression of aquaporins 1, 2, and 3 in patients with lupus nephritis. These findings strongly suggest that decreased AQP expression could serve as an indicator of tubular injury. Further research is warranted to evaluate AQP1, AQP2, and AQP3 as prognostic markers in both urinary and histological assessments of lupus nephritis. Full article

The ubiquitin–proteasome system (UPS) and autophagy maintain protein homeostasis, which is critical to cellular function and survival. The dysregulation of these pathways has been recognized as a hallmark of acute kidney injury and chronic kidney disease. This review elucidates the role of the UPS and autophagy in kidney disease, namely through inflammation, oxidative stress, fibrosis and apoptosis. The pathways of NF-κB, TGF-β and mitochondrial failure result in glomerular injury and tubulointerstitial fibrosis due to impaired proteostasis in podocytes and tubular epithelial cells. Recent studies have revealed a connection between the autophagic process and the UPS, wherein compensatory mechanisms aim to spike down proteotoxic stress but eventually seem inadequate in cases of chronic derangement. Low-dose pharmacological inhibitors, autophagy modulators, and new gene and nanotechnology-based treatments may all help to restore the protein balance and reduce kidney injury. A more thorough understanding of these pathways is needed to develop kidney-protective and disease-modifying therapeutic interventions. Full article

Background: Diabetic nephropathy (DN) is a serious condition that can result in end-stage renal failure. Recent evidence has focused on the dietary effects of polyphenols on blood glucose levels and the complications of diabetes. Objectives: In this study, we investigated the protective effect of glucosyl hesperidin (G-Hes), composed of glucose and hesperidin, against streptozotocin (STZ)-induced nephropathy in mice. Methods: We used an STZ-induced diabetic mouse model to investigate the preventive effect of G-Hes on renal pathology. After G-Hes supplementation for 4 weeks, we investigated the renal gene expression profiles using DNA microarray analysis and renal histology to examine the underlying molecular mechanism. Results: G-Hes suppressed the increase in kidney weight without any change in the blood glucose levels. This study identified 511 genes whose expression levels were substantially increased during DN development but were downregulated by G-Hes supplementation. G-Hes prevented mRNA expression associated with renal tubule injury, fibrosis, and immune responses. Notably, G-Hes supplementation considerably decreased the complement component C3 at the mRNA and protein levels in the glomeruli and ameliorated glomerular and mesangial matrix expansion in diabetic nephropathy. Conclusions: G-Hes supplementation is useful in preventing tubulointerstitial fibrosis and inflammation in a mouse model of DN, without exhibiting a hypoglycemic effect. Full article

Acute kidney injury (AKI) is a major but often underestimated risk factor for the development of chronic kidney disease (CKD). Exploring innovative approaches to prevent this progression is critical. Intermittent fasting (IF), recognized for its metabolic and anti-inflammatory benefits, may offer protective effects in this context. Using a unilateral ischemia-reperfusion injury (UIRI) model in male C57BL/6 mice, we evaluated the impact of IF on tubulointerstitial fibrosis and tubular epithelial–mesenchymal transition (EMT) over 8 weeks. Mice in the IF group followed a 5:2 regimen, fasting for 24 h twice weekly. Four groups were studied: control, IF, UIRI, and IF + UIRI. The UIRI group exhibited increased fibrosis and EMT, both of which were significantly attenuated in the IF + UIRI group. IF also reduced levels of TGF-β1, phosphorylated NF-κB p65, inflammatory cytokines, and F4/80-positive macrophages, along with markers of oxidative stress. These findings highlight IF’s ability to mitigate fibrosis and EMT through reductions in inflammation and oxidative stress during AKI-to-CKD progression. Our study suggests that IF may serve as a promising dietary strategy to prevent AKI from advancing into CKD. Full article

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR. Full article

Primary aldosteronism (PA) is a major cause of hypertension, especially in younger patients. Early diagnosis and treatment are crucial to prevent damage to vital organs, including the heart and kidneys. Independent of blood pressure, aldosterone excess has direct deleterious effects on the kidneys, leading to tubulointerstitial fibrosis, glomerular hypertrophy, and glomerulosclerosis. Emerging biomarkers such as albuminuria and liver fatty acid-binding protein may have the potential to detect renal injury in PA, particularly in the setting of glomerular hyperfiltration. Comprehensive risk assessment of long-term renal dysfunction, based on both modifiable and non-modifiable risk factors, would aid clinicians in prediction and would even, in some cases, allow them to mitigate the risk of patients developing CKD in the setting of PA. Full article