Renal Pathology Research Articles

Protective effects of Notoginsenoside R2 on reducing lipid accumulation and mitochondrial dysfunction in diabetic nephropathy through regulation of c-Src

BackgroundThe treatment options to delay the progression of diabetic nephropathy (DN), a key contributor to chronic kidney disease (CKD), are urgently needed. Previous studies reported that traditional Chinese medicine Panax notoginseng (PNG) exerted beneficial effects on DN. However, the renoprotective effects of Notoginsenoside R2 (NR2), an active component of PNG, on DN have not been investigated. This study aimed to assess the therapeutic potential of NR2 in DN and explore its underlying mechanisms.MethodsIn vivo models were developed using db/db mice, while in vitro models utilized HK-2 cells exposed to high glucose and palmitic acid (HGPA). Online databases and Cytoscape software were employed to predict the potential targets of NR2. The expression of associated proteins was measured using immunohistochemistry and western blot. Lipid accumulation, oxidative stress levels, mitochondrial function and cell apoptosis were also assessed. Small interfering RNA was used in in vitro experiments to examine the effect of c-Src.ResultsNR2 ameliorated albuminuria, renal function and renal pathology in db/db mice. The activation of c-Src was suppressed in db/db mice and in HK-2 cells exposed to HGPA. NR2 inhibited JNK/STAT1 phosphorylation and CD36 overexpression. NR2 also ameliorated lipid accumulation, oxidative stress, mitochondrial dysfunction and cell apoptosis in vivo and in vitro. By inhibiting c-Src, HK-2 cells exposed to HGPA experienced less lipid deposition and mitochondrial damage, indicating the renoprotective effects of NR2 were correlated with the inhibition of c-Src.ConclusionNR2 ameliorated mitochondrial dysfunction and delayed the progression of DN partly through suppression of c-Src. The protective effects of NR2 might be related to a reduction in lipid accumulation.Graphical

Mechanosensitive Ca2+ channel TRPV1 activated by low-intensity pulsed ultrasound ameliorates acute kidney injury through Notch1-Akt-eNOS signaling.

Acute Kidney Injury (AKI) is a significant medical condition characterized by the abrupt decline in kidney function.Low-intensity pulsed ultrasound (LIPUS), a non-invasive therapeutic technique employing low-intensity acoustic wave pulses, has shown promise in promoting tissue repair and regeneration. A novel LIPUS system was developed and evaluated in rat AKI models, focusing on its effects on glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine (SCr), and the Notch1-Akt-eNOS signaling pathway. The results demonstrated that LIPUS treatment improved GFR, BUN, SCr levels, and renal pathology in AKI rats. Invitro experiments using HUVEC cells revealed that LIPUS stimulation promoted angiogenesis, cell migration mechanically-dependent calcium ion influx, which was partially attenuated by TRPV1 knockdown. RNA sequencing analysis indicated LIPUS-induced activation of the Notch pathway, phosphorylation of Akt and eNOS. Furthermore, inhibition or genetic silencing of Notch1 abolished the beneficial effects of LIPUS on angiogenesis, renal function, and Akt-eNOS phosphorylation in both cells and AKI rats. These findings suggest that LIPUS-induced calcium influx promotes Akt-eNOS phosphorylation, nitric oxide (NO) production, angiogenesis, and improved renal function in AKI via Notch1-Akt-eNOS signaling, positioning LIPUS as a promising therapeutic strategy for AKI by targeting vascular regeneration.

A case of Sjögren's syndrome with selective anion exchanger 1 defect causing distal renal tubular acidosis.

Distal renal tubular acidosis (dRTA) is a significant clinical expression of Sjögren's syndrome (SS). While SS-related dRTA is traditionally linked to impaired H+-ATPase, we report a unique case demonstrating selectively decreased anion exchanger 1 (AE1) expression with preserved H+-ATPase expression. A 16-year-old girl with SS presented with muscle weakness, difficulty in ambulation, and severe hypokalemia. Laboratory studies revealed non-anion gap metabolic acidosis, elevated urinary potassium excretion, and overt proteinuria. Renal histology identified a notably reduced expression of AE1 but normal H+-ATPase in intercalated cells, a previously undescribed finding. Despite high-dose potassium and bicarbonate supplementation, her hypokalemia and metabolic acidosis showed inadequate response; however, the clinical condition improved dramatically following corticosteroid therapy. This case sheds light on an atypical SS-associated dRTA mechanism characterized by selective AE1 impairment, presumed to be mediated by autoantibodies. The discovery accentuates AE1's critical role in SS-induced renal pathology and underscores the efficacy of steroids in the management of SS-related dRTA.

Effects of higher dietary acid load: a narrative review with special emphasis in children.

Metabolic effects of high diet acid load (DAL) have been studied for years in adults, although only recently in children. Contemporary diets, especially those of Western societies, owe their acidogenic effect to high animal-origin protein content and low contribution of base-forming elements, such as fruits and vegetables. This imbalance, where dietary acid precursors exceed the body's buffering capacity, results in an acid-retaining state known by terms such as "eubicarbonatemic metabolic acidosis," "low-grade metabolic acidosis," "subclinical acidosis," or "acid stress". Its consequences have been linked to chronic systemic inflammation, contributing to various noncommunicable diseases traditionally considered more common in adulthood, but now have been recognized to originate at much earlier ages. In children, effects of high DAL are not limited to growth impairment caused by alterations of bone and muscle metabolism, but also represent a risk factor for conditions such as obesity, insulin resistance, diabetes, hypertension, urolithiasis, and chronic kidney disease (CKD). The possibility that high DAL may be a cause of chronic acid-retaining states in children with growth impairment should alert pediatricians and pediatric nephrologists, since its causes have been attributed traditionally to inborn errors of metabolism and renal pathologies such as CKD and renal tubular acidosis. The interplay between DAL, overall diet quality, and its cascading effects on children's health necessitates comprehensive nutritional assessments and interventions. This narrative review explores the clinical relevance of diet-induced acid retention in children and highlights the potential for prevention through dietary modifications, particularly by increasing fruit and vegetable intake alongside appropriate protein consumption.

Characterizing the urobiome and associated metabolic profiles during acute rejection in renal transplant patients: A pilot study.

Characteristic alterations in the urinary microbiome, or urobiome, are associated with renal transplant pathology. To date, there has been no direct study of the urobiome during acute allograft rejection. The goal of this study was to determine if unique urobiome alterations are present during acute rejection in renal transplant recipients. We performed shotgun metagenomic sequencing of 32 mid-stream urine samples obtained from 15 transplant recipients pre-transplant, 1- and 3-months post-transplant, and at time of rejection discovered with for-cause biopsy. Within individuals, there was a 40-60 % difference in urobiome composition from pre-to-post-transplant in both rejectors and non-rejectors. The taxa Ureaplasma was enriched in rejectors compared to non-rejectors. However, a greater number of microbial genes were enriched in non-rejectors compared to rejectors, except for genes associated with tetracycline resistance, the lysophosphatidic acid synthesis pathway, and tryptophanyl-tRNA synthetase. Together, our findings suggest that the urobiome is significantly altered post-transplant with certain taxa and/or microbial genes potentially associated with acute allograft rejection/inflammation.

Evaluation of the effect of Ela tablets in the treatment of diabetic nephropathy based on rat experiments and screening strategy for quality markers of Ela tablets targeting aldose reductase.

Ela tablets (ALP) is a traditional Uyghur medicinal formulation comprising 9 herbs. Clinical applications have demonstrated its potential in treating diabetic nephropathy (DN). However, its specific medicinal effects and pharmacodynamic components have not been elucidated. This research aims to investigate the efficacy of ALP in treating DN and to explore the quality markers (Q-markers) for its exertion of efficacy. Using the UHPLC-Q-Orbitrap HRMS technique, a total of 60 compounds were identified within ALP. Animal experiments were conducted to investigate the effect of ALP intervention at doses of 80, 160, and 320mg/kg in Sprague-Dawley rats. Then, fingerprints of ten batches of ALP extracts were established using UPLC-DAD. Spectrum-effect relationship analysis of these fingerprints and aldose reductase (AR) activity was conducted by chemometric analysis methods. The results were further validated by molecular docking and cellular experiments. The animal experiments indicated that ALP had a therapeutic effect on DN. Specifically, ALP reduced biochemical indexes such as serum creatinine (SCr), 24-hour urinary total protein (24h UTP), uric acid (UA), blood urea nitrogen (BUN), triglycerides (TG), and total cholesterol (TC). ALP stabilized body weight and fasting blood glucose, enhanced the antioxidant capacity of kidneys, and improved renal pathology. Comprehensive analysis indicated that crocin-I and gallic acid may be used as Q-markers for ALP. In summary, ALP has been identified as a treatment for DN, and gallic acid and crocin-I can be used as its Q-markers.

The impact of donor diabetes on recipient postoperative complications, renal function, and survival rate in deceased donor kidney transplantation: a single-center analysis

As the global incidence of diabetes rises and diagnoses among younger patients increase, transplant centers worldwide are encountering more organ donors with diabetes. This study examined 80 donors and 160 recipients, including 30 donors with diabetes (DD) and their 60 recipients (DDR). The control group comprised 50 non-diabetic donors (ND) and 100 recipients (NDR). We analyzed clinical, biochemical, and pathological data for both diabetic and control groups, using logistic regression to identify risk factors for delayed graft function (DGF) after kidney transplantation. Results showed that pre-procurement blood urea nitrogen levels were significantly higher in DD [18.20 ± 10.63 vs. 10.86 ± 6.92, p = 0.002] compared to ND. Renal pathological damage in DD was notably more severe, likely contributing to the higher DGF incidence in DDR compared to NDR. Although DDR had poorer renal function during the first three months post-transplant, both groups showed similar renal function thereafter. No significant differences were observed in 1-year or 3-year mortality rates or graft failure rates between DDR and NDR. Notably, according to the Renal Pathology Society (RPS) grading system, kidneys from diabetic donors with a grade > IIb are associated with significantly lower postoperative survival rates. Recipient gender [OR: 5.452 (1.330–22.353), p = 0.013] and pre-transplant PRA positivity [OR: 34.879 (7.698–158.030), p < 0.001] were identified as independent predictors of DGF in DDR. In conclusion, transplant centers may consider utilizing kidneys from diabetic donors, provided they are evaluated pathologically, without adversely impacting recipient survival and graft failure rates.

Glucocorticoid does not improve the renal prognosis of patients with diabetic nephropathy combined with acute tubulointerstitial nephritis: a retrospective analysis

Background and objectives In clinical practice, some patients are diagnosed with diabetic nephropathy (DN) combined with acute tubulointerstitial nephritis (ATIN) through renal biopsy. There is relatively little research on the treatment and prognosis of such patients, and no consensus exists on the use of glucocorticoid for treatment. Therefore, our study explores the progression of DN combined with ATIN and the renal outcomes after treatment with glucocorticoid. Methods This study retrospectively analyzed patients diagnosed with DN combined with ATIN through renal biopsy at our center from January 1, 2015, to December 31, 2021. We collected general patient information, laboratory indicators, renal pathology indicators, and the glucocorticoid usage after kidney biopsy. Follow-up data were collected from medical records. Statistical analysis methods included t-tests, non-parametric tests, and chi-square tests. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for renal endpoint events in patients. Statistical significance was defined as p-values < 0.05. Results In this study, a total of 67 patients were included. The subjects were divided into two groups based on whether they received glucocorticoid treatment: 33 patients in the steroid group and 34 in the non-steroid group. In the steroid group, 19 patients reached the renal endpoint event, which was significantly higher than in the non-steroid group (57.58% vs. 29.41%, p = 0.038). Univariate Cox regression analysis showed that serum creatinine (HR = 1.008, p < 0.001), albumin (HR = 0.919, p < 0.001), 24-h urinary protein (HR = 1.093, p = 0.002), hemoglobin (HR = 0.964, p = 0.001), triglycerides (HR = 1.12, p = 0.04), and the use of glucocorticoid (HR = 2.507, p = 0.019) were influencing factors for renal endpoint events in patients with DN combined with ATIN. Multivariate Cox regression analysis showed that albumin (HR = 0.863, p = 0.003) was an independent risk factor for renal endpoint events in patients with DN combined with ATIN. Conclusions The use of glucocorticoid in treatment does not improve renal prognosis in patients with DN combined with ATIN. Lower levels of albumin are associated with a worse renal prognosis.

Klotho enhances stability of chronic kidney disease atherosclerotic plaques by inhibiting GRK2/PLC-β-mediated endoplasmic reticulum stress in macrophages via modulation of the ROS/SHP1 pathway

Klotho has been importantly linked to atherosclerosis, but little is known about its specific role. This study investigates the mechanism by which Klotho enhances the stability of atherosclerotic plaques in chronic kidney disease. apoE-/- knockout mice and C57BL/6 mice underwent 5/6 nephrectomy and then klotho-NC and klotho-mimic groups were set up to be fed a high-fat chow diet and a dummy group was created to be fed a normal chow diet. qPCR detected relative mRNA expression of klotho. Oil Red O and HE staining assessed lipid proportion in the aorta. Masson staining evaluated renal failure pathology in mice. Immunohistochemistry measured MAC-2 and α-SMA expression in the aorta. ELISA quantified urea, cholesterol, calcium ions, and triglycerides in mouse plasma. Western blotting detected associated protein expression, followed by cell-based experiments for validation. Compared with the Klotho-NC group, the plaque area and aortic lipid and renal fibrosis area were reduced in the Klotho-mimic group. Klotho-mimic reduced macrophage area, plasma urea, cholesterol, calcium ions, and triglyceride levels, and decreased the expression of p-PERK, NOX2, NOX4, Caspase-3, Caspase-9, Bax, p-GRK2, p-PLCβ, p-Src, and p-IP3R. Without ox-LDL stimulation, Klotho expression increased in the Klotho-mimic group, with no significant differences in NOX2, p-SHP1, p-Src, p-PERK, p-GRK2, and p-PLCβ. With ox-LDL in high-calcium medium, Klotho and p-SHP1 increased, while NOX2, p-Src, p-PERK, p-GRK2, and p-PLCβ decreased in the Klotho-mimic group. After ox-LDL and TPI-1 treatment, Klotho increased, NOX2 decreased, and other proteins showed no significant changes. Adding shRNA-GRK2 reduced NOX2, p-Src, and p-PERK, increased p-SHP1, with no changes in p-GRK2 and p-PLCβ. Differences in NOX2, p-GRK2, p-PLCβ, and p-PERK between groups were reduced in high-calcium medium, while p-SHP1 differences increased. Klotho enhances chronic kidney disease atherosclerotic plaque stability by inhibiting GRK2/PLC-β-mediated endoplasmic reticulum stress in macrophages via the ROS/SHP1 pathway.

Lyophilized powder of calf bone marrow hydrolysate liposomes improved renal anemia: In vitro and in vivo evaluation.

This study aimed to find whether oral administration of calf bone marrow hydrolysate liposomes (CBMHL) can improve renal anemia. Calf bone marrow was defatted, papain hydrolyzed, liposomalized and lyophilized. Its hematopoietic ability was proved by the colony formation experiment of umbilical cord blood hematopoietic stem cells in vitro. The rat model of renal anemia was established by adenine intragastric administration, and different concentrations of CBMHL were intragastricly administrated. Blood routine and serological indexes, transcription levels of hematopoietic factors and renal pathology were detected. From the appearance, redispersability, water content, liposome indexes and stability of Lyophilized powder of CBMHL, it could be concluded that the quality of freeze-dried CBMHL powder under this freeze-drying process was good. Compared with the control group, the burst forming unit-erythroid (BFU-E) in the CBMHL group was larger and the number of colonies increased significantly in the colony formation experiment (P < 0.05). The results of lyophilized powder of CBMHL co-culture with human adipose mesenchymal stem cells (MSCs) and human cytokine-induced killer (CIK) cells showed that the lyophilized powder of CBMHL had no potential toxicity and allergic reaction in vitro. Compared with the Model Group, the red blood cell (RBC) count, hemoglobin (HB) content and hematokrit (HCT) of rats blood routine in the Model+high doses of CBMHL Group (Model+H-CBMHL Group) increased significantly (P < 0.05). Serum erythropoietin (EPO) and glutathione (GSH) levels increased significantly (P < 0.05), while serum creatinine (Cr) levels decreased significantly(P < 0.05). The transcription level of Epo in kidney increased significantly (P < 0.05), the transcription levels of erythropoietin receptor (Epor) in bone marrow and interleukin 6 (Il6) in spleen were significantly increased (P < 0.01). The fragility of red blood cells decreased significantly, and the pathological structure of kidney improved significantly. It was proved that lyophilized powder of CBMHL could effectively enhance the hematopoietic ability of rats with renal anemia and protect the kidney structure and function.

Research progress on the molecular mechanisms of Saikosaponin D in various diseases (Review).

Bupleurum, a Traditional Chinese Medicine (TCM) herb, is widely used in China and other Asian countries to manage chronic liver inflammation and viral hepatitis. Saikosaponin D (SSD), a triterpenoid saponin extracted from Bupleurum, exhibits extensive pharmacological properties, including anti‑inflammatory, antioxidant, anti‑apoptotic, anti‑fibrotic and anti‑cancer effects, making it a therapeutic candidate for numerous diseases. Clarifying the targets and molecular mechanisms underlying TCM compounds is essential for scientifically validating TCM's therapeutic roles in disease prevention and treatment, as well as for identifying novel therapeutic targets and lead compounds. This analysis comprehensively examines SSD's mechanisms across various conditions, such as myocardial injury, pulmonary diseases, hepatic disorders, renal pathologies, neurological disorders, diabetes and cancer. In addition, challenges and potential solutions encountered in SSD research are addressed. SSD is posited as a promising monomer for multifaceted therapeutic applications and this article aims to enhance researchers' understanding of the current landscape of SSD studies, offering strategic insights to guide future investigations.

Monoclonal gammopathy is present in one fourth of patients undergoing renal biopsy but is pathogenic only in half of them.

About 4-7% of renal biopsies show a monoclonal gammopathy-related nephropathy, such as AL amyloidosis, cast nephropathy, or light chain deposition disease. Both a high prevalence and a causal role of monoclonal gammopathy have been observed in patients with C3 glomerulopathy or thrombotic microangiopathy, although a definitive causative role cannot be established in most cases (potentially monoclonal gammopathy-related nephropathies). A coexisting monoclonal gammopathy has been identified in many cases of nephropathy without a defined causative role (monoclonal gammopathy-unrelated nephropathies). The aim of this study was to investigate the prevalence and distribution of monoclonal gammopathy in patients who underwent arenal biopsy and assess its possible causal role in nephropathies not ordinarily related to monoclonal gammopathy. In our single-center retrospective observational study, we considered patients who underwent native kidney biopsy from 2009 to 2023 at the Nephrology Unit, Careggi University Hospital, Florence (Italy)and for whom a complete monoclonal gammopathy workup (serum electrophoresis, serum and urinary immunofixation, serum free light chains) was available. Overall, 827 patients were included: 208 (25%) had a monoclonal gammopathy: in104 cases the monoclonal gammopathywasunrelated tothekidney disease; 87 subjects showed renal pathology related to monoclonal gammopathy (monoclonal gammopathy-related nephropathies). Patients with thrombotic microangiopathy and C3 glomerulopathy (potentially monoclonal gammopathy-related nephropathies) exhibited a prevalence of monoclonal gammopathy > 30%. In a subgroup of diagnoses (e.g. tubulointerstitial nephritis, membranoproliferative glomerulonephritis) a possible causal and/or prognostic role of a concomitant monoclonal gammopathy may be hypothesized. In our cohort, one fourth of patients undergoing arenal biopsy had a monoclonal gammopathy, although in half of them the monoclonal gammopathy did not have a causative rolein the kidney disease.Hence, it is impossible to conclude that a monoclonal gammopathy in the context of renal disease equates to a causal association without performing a renal biopsy because of the high frequency of monoclonal gammopathy in patients undergoing a kidney biopsy.

A case of a young man with secondary hypertension

Background: Secondary hypertension is characterized by an elevated blood pressure greater than 140/90 mmHg, which occurs as a consequence of other diseases. The common etiologies of secondary hypertension include renal parenchymal causes, endocrine disorders, and vascular pathologies like coarctation of the aorta (CoA). Case presentation: A 20-year-old patient was admitted to our hospital as he complained of headache and palpitations since one week. On examination, the blood pressure in his right upper limb was 180/100 mmHg. The volume of the femoral and the dorsalis pedis pulses was found to be reduced bilaterally. The patient was started on antihypertensive medication labetalol 10 mg injection intravenously immediately. After clinical suspicion and a series of investigations, the patient was diagnosed with severe CoA, distal to the origin of the left subclavian artery via computed tomography (CT) aortogram. The patient was managed by coarctoplasty with stenting. Discussion: The most striking examination findings indicative of CoA include decreased lower limb pulses and a blood pressure difference of &gt;20 mmHg across both the lower and upper extremities. It is important to evaluate the blood pressure in both upper and lower limbs to diagnose obstructive vascular diseases. Conclusion: The presence of multiple well-developed collaterals can often mask symptoms and delay the detection of hypertension in patients with CoA. Patients with CoA require regular follow-up to monitor left ventricular outflow tract obstruction, and patients with severe CoA should be treated interventionally to prevent complications including aortic aneurysm and dissection. The patient was managed by coarctoplasty with stenting and recovered well post-surgery.

Novel NUP160 mutations related to simultaneous congenital nephropathy and ovarian insufficiency

Abstract Nucleoporins, as major components of nuclear pore complex, have been recently discovered to participate in organ development. Here, we report a young female patient with nephrotic proteinuria resistant to immune suppressant treatment and congenital ovarian insufficiency. Renal pathology confirmed focal segmental glomerulosclerosis (FSGS) and whole exome sequencing revealed compound heterozygous mutations in Nucleoporin 160 (NUP160), NM_015231.2 c.4154C &amp;gt; T(p.Pro1385Leu) and c.1102–9T &amp;gt; G. Notably, NUP160 mutations have been associated with congenital nephropathy in four families. We also ruled out competing genetic variants implicated in FSGS and ovarian dysgenesis. Our identification of two novel NUP160 mutations associated with congenital nephropathy and ovarian insufficiency simultaneously contributes to a deeper understanding of nuclear pore complex function in the urogenital system.

Interobserver agreement analysis among renal pathologists in classification of lupus nephritis using a digital pathology image dataset: after a third evaluation.

Lupus nephritis is well-known for low concordance in classification. Furthermore, there has been no agreement analysis among Korean renal pathologists regarding lupus nephritis. Inconsistent diagnosis leads to confusion and increases medical costs, as well as failure of appropriate therapeutic interventions. This study aimed to assess the level of agreement among Korean renal pathologists regarding classification. Representative glomerular images from patients diagnosed with lupus nephritis were obtained from five hospitals. Twenty-five questions were formulated, and multiple-choice questions with 14 options, consisting of characteristic histopathological findings of lupus nephritis were provided. Three rounds of surveys were conducted and educational sessions were conducted before the second and third surveys. The agreement was calculated using Fleiss' κ and the means for each round of questions were as follows: Survey 1, 0.42 (range, 0.18-0.61), Survey 2, 0.42 (range, 0.19-0.64), and Survey 3, 0.47 (range, 0.23-0.65). Although κ after the first education session showed no significant difference compared to the initial κ (p = 0.95), after the second education session, κ increased significantly compared to the initial κ (p < 0.001). The κ for each item generally increased with each education session, but they were not statistically significant (p = 0.46, p = 0.17). Additionally, the rankings of agreement, for each item, were relatively consistent. This study conducted an interobserver agreement analysis of Korean pathologists for lupus nephritis, with the goal of increasing agreement through education. Although the education increased overall agreement, items like "mesangial hypercellularity," "endocapillary hypercellularity," and "neutrophils and/or karyorrhexis" remained inconsistent attributable to innate subjectivity and ineffective education.

Autosomal recessive renal tubular dysgenesis: antenatal ultrasound scanning and molecular investigations.

This study aimed to elucidate the fetal ultrasound characteristics, pathology, and molecular genetic etiology of autosomal recessive tubular dysplasia. This retrospective study examined four fetuses with autosomal recessive tubular dysplasia (ARRTD) from two pregnancies, utilizing ultrasound evaluations and fetal renal pathology. Whole-exome sequencing-copy number variation analysis was employed to identify gene mutations. We present for the first time renal vascular resistance in fetuses with ARRTD, characterized by increased renal blood flow resistance and reversed diastolic blood flow, indicating fetal renal insufficiency. This is the first report of a nonsense mutation (C.571C>T) found in the angiotensinogen gene. ARRTD disease should be strongly suspected when ultrasound examinations reveal increased renal blood flow resistance, oligohydramnios, and inadequate bladder filling, regardless of the presence of renal abnormalities.

Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus.

We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. We first induced lupus-like disease in T cell specific Rictor, a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients' PBMCs using an in vitro T-B coculture assay. T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4+ T cells accompanied by restored CD4+ T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor-ASO treatment improves renal function and pathology in MRL/lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR-ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05). Targeting mTORC2 could be a promising therapeutic for SLE.

Prognosis and risk factors of IgA vasculitis nephritis in children

Objective: To investigate the prognosis and risk factors of IgA vasculitis nephritis (IgAVN) in children. Methods: A retrospective cohort study was conducted. Clinical data were collected from 264 children who were pathologically diagnosed with IgAVN at Department of Pediatric Nephrology, Tongji Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, between January 2011 and December 2017. All patients had a follow-up period of more than 3 years. Clinical characteristics, renal pathology, 3-year and 5-year prognosis were analyzed. The patients were grouped based on gender, age of onset (≤6 years, >6-9 years, and >9 years), pathological classification (≤Ⅲ and>Ⅲ),whether the prognosis was complete remission at 3 and 5 years. Independent sample t-tests, ANOVA or chi-squared test were used for intergroup comparisons. Spearman correlation analysis was applied for ordinal data, and multivariate Logistic regression was used to analyze factors affecting the prognosis. Receiver operating characteristic (ROC) curve was utilized to evaluate the predictive value of these factors. Results: Of the 264 children with IgAVN, 153 were male and 111 were female, the age of onset was 8.3 (6.7, 10.3) years, 118 patients (45%) with onset age >6-9 years accounted for the highest proportion. All patients presented with skin purpura and renal involvement, primarily manifesting as hematuria and/or proteinuria. Microscopic hematuria was observed in 253 patients (95.8%), while 246 patients (93.2%) showed proteinuria. In 256 patients (97.0%), hematuria or proteinuria urinalysis was detected within 6 months of skin purpura onset, and 243 patients (92.0%) underwent renal biopsy within 6 months of renal involvement. The most common clinical subtype in 264 IgAVN children was hematuria and proteinuria (204 cases, 77.3%), with grade Ⅲ being the predominant pathological classification (181 cases, 68.6%). Among children ≤6 years old, the 3-year complete remission rate was higher in males than in females (83.9% (26/31) vs. 7/16, χ²=8.12, P=0.012). Factors independently associated with poor 5-year prognosis included time from hematuria or proteinuria urinalysis to renal biopsy >6 months, elevated serum cholesterol levels, and incomplete remission 3 years post-biopsy (OR=5.41, 1.39, 6.02, 95%CI 1.40-20.86, 1.04-1.84, 2.61-13.88, all P<0.05). The serum cholesterol has a predictive value for 5-year prognosis (P=0.020, AUC=0.62, 95%CI 0.52-0.71, Youden index=0.27, cutoff=4.37). Conclusions: For children with IgAVN aged≤6 years, the 3-year prognosis is better in males than in females. Time from hematuria or proteinuria urinalysis to renal biopsy >6 months, elevated serum cholesterol levels, and incomplete remission at 3 years post-biopsy may be independent risk factors for poor 5-year prognosis in children with IgAVN.

An Experimental Insight Into the Role of Agomelatine in Renal Ischemia/Reperfusion Injury.

Acute kidney injury (AKI) is one of the leading causes of chronic kidney disease and accounts for 50%-75% of mortality following renal pathologies or organ transplantation. Ischemia‒reperfusion injury (IRI) involves an interrupted blood supply to organs and the kidney; IRI exacerbates AKI development. Owing to several pharmacological treatment methods, AKI still has a poor prognosis, and novel therapeutic options are needed. Agomelatine (AGM) is a melatonin receptor agonist (MT1 and MT2) with increased bioavailability and lipophilicity. In this study, we aimed to investigate the antioxidant and anti-inflammatory effects of AGM in experimental renal IRI via long-term and short-term applications. Sixty male Sprague-Dawley rats were randomly divided into six groups (n = 10): the control, I/R, AGM20S, AGM40S, AGM20L, and AGM40L groups. Following the establishment of the renal IRI model, the rats received agomelatine at 20 and 40 mg/kg orally, and agomelatine solvent (hydroxyethylcellulose) was used as a vehicle. At the end of the experiment, blood samples and renal tissues were harvested for histopathological and biochemical analysis. Urea, creatinine, tumor necrosis factor (TNF-α), and interleukin-1 beta (IL-1β) levels were measured in blood serum samples. Malondialdehyde (MDA) levels and increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), and total glutathione (GSH) levels were measured in renal tissue supernatants. Our biochemical results indicated that AGM reduced creatinine, TNF-α, IL-1β, and malondialdehyde levels and increased SOD, CAT, GSHPx, and total GSH levels. Agolematine reduced infiltration, intratubular hemorrhage, and intratubular cast formation histopathologically. Our results suggest that AGM could be a potential therapeutic adjuvant agent for ischemia‒reperfusion injury in the kidney and several other organs.

Pediatric Acute Lobar Nephronia: A Case Series and Literature Review.

Acute lobar nephronia (ALN) is a focal renal infection without liquefaction, historically regarded as rare in the pediatric population, yet recent literature suggests it may be under-diagnosed, which may result in the formation of renal abscess and future renal scarring. The clinical presentation, investigations, treatment and long-term outcomes of 5 patients diagnosed with ALN was described and literature review was conducted by reviewing publications in PubMed using the keywords "acute lobar nephronia" and "pediatric". Three patients were males, aged 1 to 11 years. The primary complaint in all cases was fever, accompanied by significantly elevated inflammatory markers. Upon presentation, none of the patients exhibited pyuria on urinalysis, and all had sterile blood and urine cultures. Diagnosis was based on CT scans for three patients and renal sonography for two. Main findings included hyperechogenic renal parenchyma, and hypodense localized parenchyma. Treatment consisted of broad-spectrum intravenous antibiotics, administered for 7 to 12 days and additional 1week course with amoxicillin-clavulanate, resulting in similar defervescence times across all patients. None of the patients demonstrated recurrence and none had renal pathology upon repeated renal sonography and upon DMSA scintigraphy. Clinical suspicion for ALN should arise in cases of abdominal pain and markedly increased inflammatory markers. It"s crucial to note that the absence of pyuria and negative culture results should not exclude ALN diagnosis, underscoring the need for a high index of suspicion in the pediatric population.