Peritubular capillary (PTC) rarefaction is a common pathological feature of chronic kidney disease (CKD). The critical function of PTCs in maintaining blood supply for tubular epithelial cells renders PTCs a promising therapeutic target. However, the role of PTC rarefaction in the progression of kidney fibrosis remains elusive. In this study, we first characterized mice with altered PTC density. CD31 staining, together with microvascular network perfusion with FITC-labelled albumin and laser speckle contrast imaging, revealed a significant increase in PTC density in Flt1 heterozygous-deficient mice, whereas homozygous disruption of the plasminogen activator, urokinase receptor gene (Plaur/uPAR), led to a notable decrease in PTC density. Using these genetically distinct mice, we showed that preexisting higher PTC density protected against tubular injury and attenuated the progression of tubulointerstitial fibrosis in two distinct kidney injury models, namely, ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO). By contrast, Plaur-deficient mice with established lower PTC density displayed exacerbated tubular injury and renal fibrosis when subjected to IRI or UUO. The pathophysiological significance of PTC density was associated with protective effects on tubular cell apoptosis and concomitant regeneration. Finally, vasodilation of the renal capillary with minoxidil, a clinically available drug, effectively prevented UUO-induced tubular injury and renal fibrosis. Moreover, minoxidil treatment abolished the detrimental effect of Plaur deficiency on the UUO-treated kidney, thus suggesting a causative role of PTC density in the susceptibility of Plaur knockout mice to tubular injury following fibrosis. Our results provide an overview of the pathologic significance of PTC density alterations in the progression of CKD, and show that improving peritubular microcirculation is effective in preventing tubular injury and the subsequent renal fibrosis. © 2025 The Pathological Society of Great Britain and Ireland.

This study investigated how changes in metabolic phenotype, defined by obesity and metabolic health, impact chronic kidney disease (CKD) development in a large cohort.

A retrospective cohort study analyzed health data collected between 2011 and 2021 from 84,729 Panasonic Holdings Corporation (formerly Panasonic Corporation) employees aged ≥40 years. Metabolic phenotypes were classified as metabolically healthy with no obesity (MHNO), metabolically healthy with obesity (MHO), metabolic abnormalities with no obesity (MANO), and metabolic abnormalities with obesity (MAO). Changes in metabolic phenotype over 3 years and their association with CKD development were assessed using Cox proportional hazards models adjusted for confounding variables.

During a mean follow-up of 5.1 years, a total of 12,172 of participants (14.4%) developed CKD. Transitioning from MHO to MHNO and from MAO to MANO did not reduce CKD risk compared to each stable group. In contrast, participants in the MANO-to-MHNO and MAO-to-MHO groups significantly lowered CKD risk relative to each stable group, with hazard ratios of 0.86 (95% CI: 0.77-0.96) and 0.83 (95% CI: 0.67-1.02), respectively. The same results were observed when a rapid decline in renal function was used as the outcome.

The improvement of metabolic profile might outweigh weight reduction in CKD risk.

Renal hypoxia has a key role in the pathophysiology of many kidney diseases. MRI provides surrogate markers of oxygenation, offering a critical opportunity to detect renal hypoxia. However, studies that have assessed the diagnostic performance of oxygenation MRI for kidney disorders have provided inconsistent results because MRI metrics do not fully capture the complexity of renal oxygenation. Most oxygenation MRI studies are descriptive in nature and fail to detail the pathophysiological importance of the imaging findings. These limitations have restricted the clinical application of oxygenation MRI and the full potential of this technology to facilitate early diagnosis, risk prediction and treatment monitoring of kidney disease has not yet been realized. Understanding of the relationship between renal tissue oxygenation and MRI metrics, which is affected by kidney size, tubular volume fraction and renal blood volume fraction, and measurement of these factors using novel MR methods is imperative for correct physiological interpretation of renal MR oximetry findings. Next steps to enable the clinical adoption of MR oximetry should involve multidisciplinary collaboration to address standardization of acquisition and data analysis protocols and establish reference values of MRI metrics.

Even after recovery of kidney function following AKI, progression to CKD may still occur, characterized by a reduction in peritubular capillaries (PTC) and subsequent kidney fibrosis. Reactive oxygen species (ROS) from uncoupled eNOS are suspected to damage endothelial cells and cause PTC rarefaction observed in AKI-CKD. Intermedin (IMD) inhibits eNOS uncoupling by activating AMPK, but its impact on AKI-CKD transition remains unclear.

We utilized IMD-deficient (IMD-/-) mice to explore its effects on AKI-CKD transition, PTC density, endothelial damage, and kidney ROS in a kidney ischemia/reperfusion injury (IRI) model. To elucidate its protective mechanism for PTCs, we subsequently investigated the effects of IMD on endothelial cells and ROS using a hypoxia/reoxygenation (HR) model with human umbilical vein endothelial cells (HUVECs). Finally, we investigated the influence of IMD on AMPK/GTPCH-I/BH4/eNOS to explore its mechanism in alleviating oxidative stress.

Compared with IMD+/+ littermate sham controls, PTC density was significantly reduced in IMD-/- sham mice, with significantly increased oxidative stress. Post-AKI, both IMD+/+ and IMD-/- mice demonstrated substantial declines in kidney function and histology, along with significant fibrosis, PTC reduction, and heightened oxidative stress. Moreover, the severity of kidney damage in IMD-/- mice following AKI was considerably more pronounced than in IMD+/+ mice. HR significantly induced eNOS uncoupling and oxidative stress in HUVECs. Treatment with IMD effectively inhibited eNOS uncoupling and ROS production, achieving levels comparable to the antioxidant N-acetylcysteine. The inhibitory effect of IMD on eNOS uncoupling was abrogated when L-NAME was introduced after HR. HR significantly impaired AMPK activation, which could be reversed by IMD. Additional experiments with inhibitors of GTPCH-I and AMPK, and exogenous BH4, confirmed that IMD protects endothelial cells by activating AMPK/GTPCH-I/BH4, thereby inhibiting eNOS uncoupling and ROS production.

We concluded that IMD inhibits AKI-CKD transition by protecting endothelial cells of PTC via AMPK/GTPCH-I/BH4/eNOS pathway.

Renal fibrosis represents the final common pathological manifestation of chronic kidney disease (CKD), yet the underlying mechanism remains elusive, and there is still a lack of effective targeted therapeutic strategy. Although previous research indicated that repressor element 1-silencing transcription factor (REST) contributed to acute kidney injury (AKI) in renal tubular epithelial cells (RTECs), its specific contribution to renal fibrosis and associated mechanisms remains largely unexplored.

Renal biopsies from CKD patients were collected to evaluate the expression of REST. Kidney-specific Rest conditional knockout (Cdh16-Cre/Restflox/flox) mice were generated and employed unilateral ureter obstruction (UUO) models to investigate the role of REST in renal fibrosis. RNA sequencing was performed to elucidate the mechanism. Mitochondrial function was evaluated by transmission electron microscopy (TEM), reactive oxygen species (ROS), oxygen consumption rates (OCR), extracellular acidifcation rate (ECAR) and adenosine triphosphate (ATP). The severity of renal fibrosis was assessed through Western blot, immunofluorescent staining and immumohistochemical staining. Bioinformatic prediction, dual luciferase reporter gene assay, point mutation and chromatin immunoprecipitation (ChIP) assay were utilized to clarify the molecular mechanism.

REST was significantly up-regulated in the kidney tissues from CKD patients, UUO-induced fibrotic mouse models and TGF-β1-incubated RTECs. Notably, kidney-specific knockout of Rest prominently alleviated renal fibrosis by improving mitochondrial energy metabolism and restoring fatty acid oxidation. Mechanically, REST disturbed mitochondrial energy metabolism through repressing the transcription of oxoglutarate dehydrogenase-like (OGDHL) via directly binding to its promotor region. Further, pharmacological inhibition of REST using the specific REST inhibitor, X5050, significantly ameliorated the progression of renal fibrosis both in vitro and in vivo.

Our explorations revealed the upregulation of REST in renal fibrosis disrupts mitochondrial energy metabolism through transcriptionally suppressing OGDHL, which may act as a promising therapeutic target for renal fibrosis.

Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, are influenced by environmental factors and play a central role in the progression and therapeutic targeting of kidney diseases, such as diabetic kidney disease (DKD), chronic kidney disease (CKD), and hypertension. These epigenetic changes are also preserved as cellular memory, with this "epigenetic memory" known to have long-term effects on such chronic diseases. Histone modifications are readily reversible epigenetic changes that regulate gene expression by altering chromatin structure or providing docking sites for transcriptional regulators. From a disease perspective, the involvement of epigenetics and "epigenetic memory" in DKD, CKD, senescence, and hypertension has been increasingly studied in recent years. Targeting epigenetic mechanisms is, thus, expected to offer novel therapeutic strategies for these diseases. Advances in treatment include histone deacetylase inhibitors and methyltransferase inhibitors, their applications of which have expanded from oncology to nephrology. However, challenges such as long-term toxicity and off-target effects remain significant. Further elucidation of kidney-specific epigenetic pathways and memory mechanisms may pave the way for precision epigenetic therapies, enabling the reversal of pathological epigenetic signatures and the mitigation of disease progression.

This review integrates recent advancements, highlighting functional evidence that histone modifications, particularly histone tail methylation, are involved in the pathogenesis of kidney diseases. It also emphasizes the translational significance of these findings, underlining the potential of epigenetics-based therapies to transform the management of kidney diseases.

Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.

Previous observational studies have shown that obstructive sleep apnea (OSA) was associated with chronic kidney disease(CKD). Early diagnosis of OSA usually helps better prevent the occurrence of CKD. This cross-sectional investigation was conducted using data from the National Health and Nutrition Examination Survey, which was carried out between 2007 to 2008 and 2015 to 2016. Logistic regression model was employed to assess the impact of OSA on CKD. We did a mediation analysis to assess how much of the effect of OSA on CKD was mediated through mediators. Additionally, Mendelian randomization (MR) analysis assessed the causal link between OSA and various measures of renal impairment and possible mediators: obesity, hypertension and type 2 diabetes mellitus. In the cross-sectional study, the results of unadjusted model showed that participants with OSA had a higher risk of CKD compared to non-OSA (OR = 1.14, 95% confidence intervals [CI]: 1.01-1.28, P < .05). In mediation analysis, the proportion of hypertension and obesity mediating the effect of OSA on CKD was 41.83% and 30.74%, respectively. Univariate MR analysis results showed that: genetically predicted OSA was associated with decreased estimated glomerular filtration ratecystatin c (eGFRcystatin c) level (OR = 0.997, 95% CI: 0.995-0.999, P < .05), increased blood urea nitrogen (BUN) levels (OR = 1.023, 95% CI: 1.008-1.038, P < .05), increased serum creatinine levels (OR = 1.010, 95% CI: 1.002-1.018, P < .05), increased serum cystatin C levels (OR = 1.015, 95% CI: 1.005-1.026, P < .05). Multivariable MR results showed that obesity mediated the causal effect of OSA on eGFRcystatin c, BUN levels and serum cystatin C levels. The cross-sectional study revealed a positive relationship between OSA and CKD, which was mediated by hypertension and obesity. The MR analysis suggest that OSA was associated with several measures of renal impairment, which was mediated by obesity. These findings may inform prevention and intervention strategies against CKD.

Severely hypoxic environments with oxygen concentrations around 1% are often found in serious diseases such as ischemia and cancer. However, existing near-infrared (NIR) fluorescent probes that can visualize hypoxia are also activated in mildly hypoxic environments (around 5% oxygen). Here, in order to selectively detect severe hypoxia, we used julolidine-based SiR (JSiR) as a NIR fluorophore and developed T-azoJSiR640 as a fluorescent probe. T-azoJSiR640 was able to detect severe hypoxia (around 1% oxygen concentration or less) in live cell imaging. Furthermore, the ischemic liver in a portal-vein-ligated mouse model was successfully visualized in vivo.

Many genetic and environmental factors are involved in the development and progression of diabetic kidney disease (DKD), and its pathology shows various characteristics. Animal models of DKD play an important role in elucidating its pathogenesis and developing new therapies. In this study, we investigated the pathophysiological features of two DKD animal models: db/db mice (background of hyperglycemia) and KK-Ay mice (background of hyperinsulinemia). Male and female mice were fed a high-fat/high-sucrose (HFS) diet for eight weeks. Two mouse models fed the HFS diet showed increases in urinary protein, kidney weight, and glomerular size, but these changes were pronounced in KK-Ay mice. Pathological examination revealed tubulointerstitial fibrosis in KK-Ay mice fed the HFS diet, but not in db/db mice. In addition, fat accumulation was observed in the macula densa of db/db mice and in the glomeruli of KK-Ay mice fed with the HFS diet. In conclusion, an HFS diet exacerbates renal lesions with tubulointerstitial fibrosis in KK-Ay mice, and KK-Ay mice fed an HFS diet are expected to be useful as a DKD model.

Postoperative acute kidney injury (AKI) is associated with poor clinical outcomes. Identification of risk factors for postoperative AKI is clinically important. Serum lactate can increase in situations of inadequate oxygen delivery and is widely used to assess a patient's clinical course. We investigated the association between intraoperative serum lactate levels and AKI after brain tumor resection.

Demographics, medical and surgical history, tumor characteristics, surgery, anesthesia, preoperative and intraoperative blood test results, and postoperative clinical outcomes were retrospectively collected from 4131 patients who had undergone brain tumor resection. Patients were divided into high (n=1078) and low (n=3053) lactate groups based on an intraoperative maximum serum lactate level of 3.35 mmol/L. After propensity score matching, 1005 patients were included per group. AKI was diagnosed using the Kidney Disease Improving Global Outcomes criteria, based on serum creatinine levels within 7 days after surgery.

Postoperative AKI was observed in 53 (1.3%) patients and was more frequent in those with high lactate both before (3.2% [n=35] vs. 0.6% [n=18]; P < 0.001) and after (3.3% [n=33] vs. 0.6% [n=6]; P < 0.001) propensity score matching. Intraoperative predictors of postoperative AKI were maximum serum lactate levels > 3.35 mmol/L (odds ratio [95% confidence interval], 3.57 [1.45-8.74], P = 0.005), minimum blood pH (odds ratio per 1 unit, 0.01 [0.00-0.24], P = 0.004), minimum hematocrit (odds ratio per 1%, 0.91 [0.84-1.00], P = 0.037), and mean serum glucose levels > 200 mg/dL (odds ratio, 6.22 [1.75-22.16], P = 0.005).

High intraoperative serum lactate levels were associated with AKI after brain tumor resection.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current treatments for DKD do not halt renal injury progression, highlighting an urgent need for therapies targeting key disease mechanisms. Our previous studies demonstrated that activating the Sigma-1 receptor (S1R) with fluvoxamine (FLU) protects against acute kidney injury by inhibiting inflammation and ameliorating the effect of hypoxia. Based on these, we hypothesized that FLU might exert a similar protective effect in DKD. Diabetes was induced in male Wistar rats using streptozotocin, followed by a seven-week FLU treatment. Metabolic and renal parameters were assessed along with a histological analysis of glomerular damage and fibrosis. The effects of FLU on inflammation, hypoxia, and fibrosis were tested in human proximal tubular cells and normal rat kidney fibroblasts. FLU improved renal function and reduced glomerular damage and tubulointerstitial fibrosis. It also mitigated inflammation by reducing TLR4, IL6, and NFKB1 expressions and moderated the cellular response to tubular hypoxia. Additionally, FLU suppressed TGF-β1-induced fibrotic processes and fibroblast transformation. These findings suggest that S1R activation can slow DKD progression and protect renal function by modulating critical inflammatory, hypoxic, and fibrotic pathways; therefore, it might serve as a promising novel drug target for preventing DKD.

Diabetes mellitus (DM) is a huge global health issue and one of the most studied diseases, with a large global prevalence. Oxidative stress is a cytotoxic consequence of the excessive development of ROS and suppression of the antioxidant defense system for ROS elimination, which accelerates the progression of diabetes complications such as diabetic neuropathy, retinopathy, and nephropathy. Hyperglycaemia induced oxidative stress causes the activation of seven major pathways implicated in the pathogenesis of diabetic complications. These pathways increase the production of ROS and RNS, which contributes to dysregulated autophagy, gene expression changes, and the development of numerous pro-inflammatory mediators which may eventually lead to diabetic complications. This review will illustrate that oxidative stress plays a vital role in the pathogenesis of diabetic complications, and the use of antioxidants will help to reduce oxidative stress and thus may alleviate diabetic complications.

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin-angiotensin system inhibitors (RASis) and sodium-glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage.

Background: Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Methods: Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Results: Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). Conclusion: The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.

This study was performed to investigate the relationship between hemoglobin, albumin, lymphocyte and platelet (HALP) score and Oxford classification severe tubular atrophy/interstitial fibrosis (T2) in IgA nephropathy (IgAN).

The clinical data and pathological findings of patients with IgA nephropathy diagnosed through renal biopsy at Hangzhou Hospital of Traditional Chinese Medicine between June 1, 2019 and May 31, 2022 were retrospectively collected and analyzed. The HALP score was calculated as hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/ platelets (/L). According to the quartile of HALP scores in the study population, the subjects were divided into four groups: Quartile 1 (< 30.72), Quartile 2 (30.72-39.97), Quartile 3 (39.97-53.25) and Quartile 4(> 53.25). According to the extent of tubular atrophy/interstitial fibrosis, patients were categorized into mild to moderate injury (T0 + T1, ≤ 50%) and severe injury (T2, > 50%). The relationship between HALP score and severe tubular atrophy/interstitial fibrosis was investigated using Spearman's rank correlation coefficient, logistic regression analysis, restricted cubic splines (RCS), and receiver operating characteristic (ROC) curve analysis.

A total of 895 patients diagnosed with IgAN were included in this study, with an average age of 40.97 ± 12.261 years. Among them, 384 (42.9%) were male and 61 (6.8%) exhibited severe tubular atrophy/interstitial fibrosis. Multifactorial logistic regression analysis revealed that HALP independently influenced T2 (OR = 0.952, 95% CI 0.923-0.982, P = 0.002). Compared to Quartile 1, patients in Quartile 4 exhibited a significantly reduced risk of T2 (OR = 0.205, 95% CI 0.058-0.722, P = 0.014). Restricted cubic splines analysis revealed a linear inverse association between HALP and T2 risk (nonlinear P = 0.896). Furthermore, the receiver operating characteristic curve demonstrated that HALP possessed predictive value for T2 (AUC = 0.693, Jorden index = 0.324), and the cutoff value of HALP score is 36.54.

The risk of severe renal tubular atrophy/interstitial fibrosis is higher in IgAN patients with low HALP. HALP greater than 36.54 May reduce the risk of severe tubular atrophy/interstitial fibrosis.

This study aims to explore the correlation between renal blood perfusion (RBP) and diabetic nephropathy (DN).

A total of 72 mice included db/db and db/m mice at the ages of 6, 14, and 22 weeks, forming six groups. RBP was assessed using Laser Speckle Contrast Imaging (LSCI). Kidney function markers and the extent of pathological damage were evaluated. Pearson correlation analysis was employed to predict the relationship between RBP and various indicators of kidney damage.

Compared to db/m mice of all ages, 6-week-old db/db mice showed no significant difference in kidney function markers and had no apparent pathological damage. However, db/db mice at other ages showed deteriorating kidney functions and evident pathological damage, which worsened with age. The RBP in db/m mice of all ages and 6-week-old db/db mice showed no significant difference; however, RBP in db/db mice demonstrated a significant declining trend with age. The correlation between RBP and kidney damage indicators was as follows: 24 h urinary microalbumin (r=-0.728), urinary transferrin (r=-0.834), urinary beta2-microglobulin (r=-0.755), urinary monocyte chemoattractant protein-1 (r=-0.786), Masson's trichrome staining (r=-0.872), and Periodic Acid-Schiff staining (r=-0.908).

RBP is strongly correlated with the extent of diabetic kidney damage.

The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular pattern altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to recovery from a model of bilateral ischemic injury and measured vascular dynamics in aged mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared to control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with aging compared to a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function; thus, modulating renal vascular patterning may represent an effective therapeutic strategy. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury or aging has important implications for enhancing kidney regeneration and tissue engineering strategies.

Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis - including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis - have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD.

Renal tubular dysfunction is common in transfusion-dependent β thalassemia (β-TM). Iron overload, chronic anemia, and hypoxia are precipitating factors for renal insult. However, gut microbiota engagement in the renal insult has not been explored. Our work aimed to assess the potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in these children.

We enrolled 40 children with β-TM and 40 healthy controls. Gut leakage/dysbiosis biomarkers (trimethylamine-N-oxide [TMAO] and fecal short-chain fatty acids [SCFAs]), oxidative stress and inflammatory biomarkers, TMAO-regulated proteins such as serum sirtuin 1 (S.SIRT1) and serum high mobility box group-1 (S.HMGB1), and tubular dysfunction biomarkers were assessed. Correlations and regression analysis were performed to assess the relation between different parameters.

Iron overload, redox imbalance, and generalized inflammation were evident in children with β-TM. Renal tubular dysfunction biomarkers and S.TMAO were significantly elevated in the patient group. Furthermore, fecal SCFAs were significantly lower with upregulation of the investigated genes in the patient group. The correlation studies affirmed the close relationship between circulating ferritin, TMAO, and renal dysfunction and strongly implicated SIRT1/HMGB1 axis in TMAO action.

Gut dysbiosis may have a role in the pathogenesis of renal injury in children with β-TM.

Renal tubular dysfunction is a prominent health issue in β thalassemia major (β-TM). Iron overload, chronic anemia, and hypoxia are known precipitating factors. However, gut microbiota engagement in renal insult in these patients has not yet been explored. We aimed to assess potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in β-TM children and to highlight the SIRT1/HMGB1 axis, a signal motivated by the gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO), involvement in such insults. We found that gut leakage/dysbiosis may have a role in kidney dysfunction in β-TM children by exacerbating the iron-motivated oxidative stress, inflammation, ferroptosis, and modulating SIRT1/HMGB1 axis.

We evaluated the efficacy of different immunosuppressive regimens in patients with primary membranous nephropathy in a large national cohort.

In this registry study, 558 patients from 47 centers who were treated with at least one immunosuppressive agent and had adequate follow-up data were included. Primary outcome was defined as complete (CR) or partial remission (PR). Secondary composite outcome was at least a 50% reduction in estimated glomerular filtration (eGFR), initiation of kidney replacement therapies, development of stage 5 chronic kidney disease, or death.

Median age at diagnosis was 48 (IQR: 37-57) years, and 358 (64.2%) were male. Patients were followed for a median of 24 (IQR: 12-60) months. Calcineurin inhibitors (CNIs) with or without glucocorticoids were the most commonly used regimen (43.4%), followed by glucocorticoids and cyclophosphamide (GC-CYC) (39.6%), glucocorticoid monotherapy (25.8%), and rituximab (RTX) (9.1%). Overall remission rate was 66.1% (CR 26.7%, PR 39.4%), and 59 (10.6%) patients reached secondary composite outcome. Multivariate logistic regression showed that baseline eGFR (OR 1.011, 95% CI: 1.003-1.019, p = 0.007), serum albumin (OR 1.682, 95% CI: 1.269-2.231, p < 0.001), and use of RTX (OR 0.296, 95% CI: 0.157-0.557, p < 0.001) were associated with remission rates; whereas only lower baseline hemoglobin was significantly associated with secondary composite outcome (OR: 0.843, 95% CI: 0.715-0.993, p = 0.041). CYC use was significantly associated with higher remission (OR 1.534, 95% CI: 1.027-2.290, p = 0.036).

Higher baseline eGFR and serum albumin levels correlated with increased remission rates. Remission rates were lower in patients treated with RTX, while those on GC-CYC showed higher rates of remission. Due to the study's retrospective nature and multiple treatments used, caution is warranted in interpreting these findings.

To investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study.

14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83-0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82-0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79-0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39-0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28-0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases.

There was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

Renin-expressing cells are myoendocrine cells crucial for the maintenance of homeostasis. Renin is regulated by cAMP, p300 (histone acetyltransferase p300)/CBP (CREB-binding protein), and Brd4 (bromodomain-containing protein 4) proteins and associated pathways. However, the specific regulatory changes that occur following inhibition of these pathways are not clear.

We treated As4.1 cells (tumoral cells derived from mouse juxtaglomerular cells that constitutively express renin) with 3 inhibitors that target different factors required for renin transcription: H-89-dihydrochloride, PKA (protein kinase A) inhibitor; JQ1, Brd4 bromodomain inhibitor; and A-485, p300/CBP inhibitor. We performed assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA sequencing, cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation sequencing for H3K27ac (acetylation of lysine 27 of the histone H3 protein) and p300 binding on biological replicates of treated and control As4.1 cells.

In response to each inhibitor, Ren1 expression was significantly reduced and reversible upon washout. Chromatin accessibility at the Ren1 locus did not markedly change but was globally reduced at distal elements. Inhibition of PKA led to significant reductions in H3K27ac and p300 binding specifically within the Ren1 super-enhancer region. Further, we identified enriched TF (transcription factor) motifs shared across each inhibitory treatment. Finally, we identified a set of 9 genes with putative roles across each of the 3 renin regulatory pathways and observed that each displayed differentially accessible chromatin, gene expression, H3K27ac, and p300 binding at their respective loci.

Inhibition of renin expression in cells that constitutively synthesize and release renin is regulated by an epigenetic switch from an active to poised state associated with decreased cell-cell communication and an epithelial-mesenchymal transition. This work highlights and helps define the factors necessary for renin cells to alternate between myoendocrine and contractile phenotypes.

The kidney is a metabolically active organ that requires energy to drive processes such as tubular reabsorption and secretion, and shows a decline in function with advancing age. Various molecular mechanisms, including genomic instability, telomere attrition, inflammation, autophagy, mitochondrial function, and changes to the sirtuin and Klotho signalling pathways, are recognized regulators of individual lifespan and pivotal factors that govern kidney ageing. Thus, mechanisms that contribute to ageing not only dictate renal outcomes but also exert a substantial influence over life expectancy. Conversely, kidney dysfunction, in the context of chronic kidney disease (CKD), precipitates an expedited ageing trajectory in individuals, leading to premature ageing and a disconnect between biological and chronological age. As CKD advances, age-related manifestations such as frailty become increasingly conspicuous. Hence, the pursuit of healthy ageing necessitates not only the management of age-related complications but also a comprehensive understanding of the processes and markers that underlie systemic ageing. Here, we examine the hallmarks of ageing, focusing on the mechanisms by which they affect kidney health and contribute to premature organ ageing. We also review diagnostic methodologies and interventions for premature ageing, with special consideration given to the potential of emerging therapeutic avenues to target age-related kidney diseases.

Chronic kidney disease (CKD) represents a significant and escalating global health challenge, with morbidity and mortality rates rising steadily. Evidence increasingly implicates perirenal adipose tissue (PRAT) deposition as a contributing factor in the pathogenesis of CKD. This review explores how PRAT deposition may exert deleterious effects on renal structure and function. The anatomical proximity of PRAT to the kidneys not only potentially causes mechanical compression but also leads to the dysregulated secretion of adipokines and inflammatory mediators, such as adiponectin, leptin, visfatin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and exosomes. Additionally, PRAT deposition may contribute to renal lipotoxicity through elevated levels of free fatty acids (FFA), triglycerides (TAG), diacylglycerol (DAG), and ceramides (Cer). PRAT deposition is also linked to the hyperactivation of the renin-angiotensin-aldosterone system (RAAS), which further exacerbates CKD progression. Recognizing PRAT deposition as an independent risk factor for CKD underscores the potential of targeting PRAT as a novel strategy for the prevention and management of CKD. This review further discusses interventions that could include measuring PRAT thickness to establish a baseline, managing metabolic risk factors that promote its deposition, and inhibiting key PRAT-induced signaling pathways.

Recent clinical studies suggest protective effects of SGLT2 inhibitors on kidney disease outcome. Chronic hypoxia has a critical role in kidney disease development, thus we speculated that canagliflozin, an SGLT2 inhibitor, can improve kidney oxygenation.

A single-arm study was conducted to investigate the effects of canagliflozin on T2* value, which reflects oxygenation level, in patients with type 2 diabetes (T2D) using repeated blood oxygenation level-dependent MRI (BOLD MRI) examinations. Changes in cortical T2* from before (Day 0) to after single-dose treatment (Day 1) and after five consecutive treatments (Day 5) were evaluated using 12-layer concentric objects (TLCO) and region of interest (ROI) methods.

In the full analysis set (n=14 patients), the TLCO method showed no change of T2* with canagliflozin treatment, whereas the ROI method found that cortical T2* was significantly increased on Day 1 but not on Day 5. Sensitivity analysis using TLCO in 13 well-measured patients showed that canagliflozin significantly increased T2* on Day 1 with no change on Day 5, whereas a significant improvement in cortical T2* following canagliflozin treatment was found on both Day 1 and 5 using ROI.

Short-term canagliflozin treatment may improve cortical oxygenation and lead to better kidney outcomes in patients with T2D.

Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear.

We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure.

In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis.

Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

Data on the prognostic factors for C3 glomerulopathy (C3G) are limited, and validation of the new C3G histologic index (C3G-HI) in different settings is still needed. We aimed to evaluate the chronicity score of C3G-HI and probable prognostic factors in our population.

In this registry study, 74 patients from 20 centers with adequate follow-up data were included. Total chronicity score (TCS) was calculated according to percentages of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and presence of arterio- and arteriolosclerosis. Primary composite outcome was defined as doubling of serum creatinine from baseline, undergoing dialysis or transplantation, development of stage 5 chronic kidney disease, or death.

Median age was 34 [interquartile range (IQR) 24-46] years, and 39 patients (52.7%) were male. Median follow-up duration was 36 (IQR 12-60) months, and median TCS was 3 (IQR 1-5). Overall, 19 patients (25.7%) experienced primary composite outcome. Multivariate Cox regression model showed that only hemoglobin [adjusted HR (aHR) 0.67, 95% confidence interval 0.46-0.97, P = .035] predicted primary composite outcome, and TCS fell short of the statistical significance (aHR 1.26, 0.97-1.64, P = .08). Receiver operating characteristic analysis demonstrated that TCS showed an area under the curve value of 0.68 (0.56-0.78, P = .028) in discriminating primary composite outcome at 3 years, and 3-year kidney survival was lower in patients with TCS ≥4 (72.4%) compared with TCS <4 (91.1%) in Kaplan-Meier analysis (P = .036).

Low hemoglobin levels predicted dismal outcomes in patients with C3G. TCS ≥4 was associated with a worse 3-year kidney survival, which validated the 3-year prognostic value of the TCS of C3G-HI in our population.

Renal dysfunction in patients with chronic heart failure predicts a poor prognosis. Tolvaptan has a diuretic effect in patients with chronic kidney disease and heart failure without adverse effects on renal function. We aimed to determine the effects of tolvaptan and predictors of worsening renal function in patients with heart failure.

This post hoc analysis was a sub-analysis of a single-centre prospectively randomized trial on the early and short-term tolvaptan administration. We enrolled 201 participants with decompensated heart failure between January 2014 and March 2019 (early group, n = 104; age: 79.0 ± 12.8 years; late group, n = 97; age: 80.3 ± 10.8 years). Renal ultrasonography was performed before and after the administration of tolvaptan. Urine output and oral water intake significantly increased during tolvaptan administration. The difference between water intake and urine volume increased during tolvaptan administration. Changes in body weight, blood pressure, heart rate, and estimated glomerular filtration rate (eGFR) in both groups were comparable. The changes in peak-systolic velocity (PSV), acceleration time (AT) of the renal arteries, and resistance index were comparable. The changes in PSV and end-diastolic velocity (EDV) of the interlobar arteries increased following tolvaptan administration (Δmax PSV: 0.0 ± 14.8 cm/s before tolvaptan vs. 5.6 ± 15.7 cm/s after tolvaptan, P = 0.002; Δmean PSV: 0.4 ± 12.3 vs. 4.9 ± 12.7 cm/s, P = 0.002; Δmax EDV: -0.2 ± 3.5 vs. 1.4 ± 4.0 cm/s, P = 0.001; Δmean EDV: -0.0 ± 3.1 vs. 1.1 ± 3.4 cm/s, P = 0.003). The renal artery AT was negatively correlated with the eGFR (Δmax AT: beta = -0.2354, P = 0.044; Δmean AT: beta = -0.2477, P = 0.035).

Tolvaptan increased the PSV and EDV of the interlobar artery, which may mean tolvaptan increased renal blood flow. The renal artery AT may be a surrogate for worsening renal function.

To quantitatively evaluate chronic kidney disease (CKD), a deep convolutional neural network-based segmentation model was applied to renal enhanced computed tomography (CT) images. A retrospective analysis was conducted on a cohort of 100 individuals diagnosed with CKD and 90 individuals with healthy kidneys, who underwent contrast-enhanced CT scans of the kidneys or abdomen. Demographic and clinical data were collected from all participants. The study consisted of two distinct stages: firstly, the development and validation of a three-dimensional (3D) nnU-Net model for segmenting the arterial phase of renal enhanced CT scans; secondly, the utilization of the 3D nnU-Net model for quantitative evaluation of CKD. The 3D nnU-Net model achieved a mean Dice Similarity Coefficient (DSC) of 93.53% for renal parenchyma and 81.48% for renal cortex. Statistically significant differences were observed among different stages of renal function for renal parenchyma volume (VRP), renal cortex volume (VRC), renal medulla volume (VRM), the CT values of renal parenchyma (HuRP), the CT values of renal cortex (HuRC), and the CT values of renal medulla (HuRM) (F = 93.476, 144.918, 9.637, 170.533, 216.616, and 94.283; p < 0.001). Pearson correlation analysis revealed significant positive associations between glomerular filtration rate (eGFR) and VRP, VRC, VRM, HuRP, HuRC, and HuRM (r = 0.749, 0.818, 0.321, 0.819, 0.820, and 0.747, respectively, all p < 0.001). Similarly, a negative correlation was observed between serum creatinine (Scr) levels and VRP, VRC, VRM, HuRP, HuRC, and HuRM (r = - 0.759, - 0.777, - 0.420, - 0.762, - 0.771, and - 0.726, respectively, all p < 0.001). For predicting CKD in males, VRP had an area under the curve (AUC) of 0.726, p < 0.001; VRC, AUC 0.765, p < 0.001; VRM, AUC 0.578, p = 0.018; HuRP, AUC 0.912, p < 0.001; HuRC, AUC 0.952, p < 0.001; and HuRM, AUC 0.772, p < 0.001 in males. In females, VRP had an AUC of 0.813, p < 0.001; VRC, AUC 0.851, p < 0.001; VRM, AUC 0.623, p = 0.060; HuRP, AUC 0.904, p < 0.001; HuRC, AUC 0.934, p < 0.001; and HuRM, AUC 0.840, p < 0.001. The optimal cutoff values for predicting CKD in HuRP are 99.9 Hu for males and 98.4 Hu for females, while in HuRC are 120.1 Hu for males and 111.8 Hu for females. The kidney was effectively segmented by our AI-based 3D nnU-Net model for enhanced renal CT images. In terms of mild kidney injury, the CT values exhibited higher sensitivity compared to kidney volume. The correlation analysis revealed a stronger association between VRC, HuRP, and HuRC with renal function, while the association between VRP and HuRM was weaker, and the association between VRM was the weakest. Particularly, HuRP and HuRC demonstrated significant potential in predicting renal function. For diagnosing CKD, it is recommended to set the threshold values as follows: HuRP < 99.9 Hu and HuRC < 120.1 Hu in males, and HuRP < 98.4 Hu and HuRC < 111.8 Hu in females.

Renal fibrosis is a common pathway of chronic kidney disease (CKD) progression involving primary kidney injury and kidney diseases. Group 2 innate lymphoid cells (ILC2s) mediate type 2 immune responses irrespective of antigen presentation and play a reno-protective role in kidney injury and disease. In the present study, we observed a decrease in kidney-resident ILC2s in CKD and found that enrichment of ILC2s in the kidney ameliorates renal fibrosis. In CKD kidney, ILC2s preferentially produced IL-13 over IL-5 in response to IL-33 stimulation, regardless of ST2L expression. Moreover, GATA3 expression was decreased in ILC2s, and T-bet+ ILC1s and RORγt+ ILC3s were increased in CKD kidney. Adoptive transfer of kidney ILC2s into adenine-induced CKD model mouse improved renal function and fibrosis. Renal fibroblasts cultured with IL33-activated kidney ILC2s suppressed myofibroblast trans-differentiation through Acta2 and Fn-1 regulation. These results suggest that kidney ILC2s prevent CKD progression via improvement of renal fibrosis. Our findings also suggest that ILC2s may contribute to the development of new therapeutic agents and strategies for tissue fibroses.

Hypoxia-induced inflammation and apoptosis are important pathophysiological features of heat stroke-induced acute kidney injury (HS-AKI). Hypoxia-inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF-PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF-PHI could alleviate HS-induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi-1, 3-MA, and Baf-A1 reversed the renoprotective effects of HIF-PHI. Mechanistically, HIF-PHI protects RTECs from inflammation and apoptosis by enhancing Bcl-2 adenovirus E18 19-kDa-interacting protein 3 (BNIP3)-mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF-PHI-induced mitophagy and abolished HIF-PHI-mediated renal protection. Thus, our results indicated that HIF-PHI protects renal function by upregulating BNIP3-mediated mitophagy to improve HS-induced inflammation and apoptosis of RTECs, suggesting HIF-PHI as a promising therapeutic agent to treat HS-AKI.

To assess renal interstitial fibrosis (IF) using diffusion MRI approaches, and explore whether corticomedullary difference (CMD) of diffusion parameters, combination among MRI parameters, or combination with estimated glomerular filtration rate (eGFR) benefit IF evaluation.

Forty-two patients with chronic kidney disease were included, undergoing MRI examinations. MRI parameters from apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), and diffusion-relaxation correlated spectrum imaging (DR-CSI) were obtained both for renal cortex and medulla. CMD of these parameters was calculated. Pathological IF scores (1-3) were obtained by biopsy. Patients were divided into mild (IF = 1, n = 23) and moderate-severe fibrosis (IF = 2-3, n = 19) groups. Group comparisons for MRI parameters were performed. Diagnostic performances were assessed by the receiver operator's curve analysis for discriminating mild from moderate-severe IF patients.

Significant inter-group differences existed for cortical ADC, IVIM-D, IVIM-f, DKI-MD, DR-CSI VB, and DR-CSI VC. Significant inter-group differences existed in ΔADC, ΔMD, ΔVB, ΔVC, ΔQB, and ΔQC. Among the cortical MRI parameters, VB displayed the highest AUC = 0.849, while ADC, f, and MD also showed AUC > 0.8. After combining cortical value and CMD, the diagnostic performances of the MRI parameters were slightly improved except for IVIM-D. Combining VB with f brings the best performance (AUC = 0.903) among MRI bi-variant models. A combination of cortical VB, ΔADC, and eGFR brought obvious improvement in diagnostic performance (AUC 0.963 vs 0.879, specificity 0.826 vs 0.896, and sensitivity 1.000 vs 0.842) than eGFR alone.

Our study shows promising results for the assessment of renal IF using diffusion MRI approaches.

Our study explores the non-invasive assessment of renal IF, an independent and effective predictor of renal outcomes, by comparing and combining diffusion MRI approaches including compartmental, non-compartmental, and model-free approaches.

Significant difference exists for diffusion parameters between mild and moderate-severe IF. Generally, cortical parameters show better performance than corresponding CMD. Bi-variant model lifts the diagnostic performance for assessing IF.