Investigating the value of urinary biomarkers in relation to lupus nephritis histopathology: present insights and future prospects.

Lupus nephritis (LN), a leading cause of death in Systemic Lupus Erythematosus (SLE) patients, presents significant diagnostic and prognostic challenges. Although renal pathology offers critical insights regarding the diagnosis, classification, and therapy for LN, its clinical utility is constrained by the invasive nature and limited reproducibility of renal biopsies. Moreover, the continuous monitoring of renal pathological changes through repeated biopsies is impractical. Consequently, there is a growing interest in exploring urine as a non-invasive, easily accessible, and dynamic "liquid biopsy" alternative to guide clinical management. This paper examines novel urinary biomarkers from a renal pathology perspective, encompassing cellular components, cytokines, adhesion molecules, auto-antibodies, soluble leukocyte markers, light chain fragments, proteins, small-molecule peptides, metabolomics, urinary exosomes, and ribonucleic acids. We also discuss the application of combined models comprising multiple biomarkers in assessing lupus activity. These innovative biomarkers and models offer insights into LN disease activity, acute and chronic renal indices, fibrosis, thrombotic microangiopathy, podocyte injury, and other pathological changes, potentially improving the diagnosis, management, and prognosis of LN. These urinary biomarkers or combined models may serve as viable alternatives to traditional renal pathology, potentially revolutionizing the method for future LN diagnosis and observation.

Proteomic profiling of renal tissue of normo- and hypertensive rats with the renalase peptide RP220 as an affinity ligand.

Renalase (RNLS) is a recently discovered protein that plays an important role in the regulation of blood pressure by acting inside and outside cells. Intracellular RNLS is a FAD-dependent oxidoreductase that oxidizes isomeric forms of ß-NAD(P)H. Extracellular renalase lacking its N-terminal peptide and cofactor FAD exerts various protective effects via non-catalytic mechanisms. Certain experimental evidence exists in the literature that the RP220 peptide (a 20-mer peptide corresponding to the amino acid sequence RNLS 220-239) reproduces a number of non-catalytic effects of this protein, acting on receptor proteins of the plasma membrane. The possibility of interaction of this peptide with intracellular proteins has not been studied. Taking into consideration the known role of RNLS as a possible antihypertensive factor, the aim of this study was to perform proteomic profiling of the kidneys of normotensive and hypertensive rats using RP220 as an affinity ligand. Proteomic (semi-quantitative) identification revealed changes in the relative content of about 200 individual proteins in the kidneys of hypertensive rats bound to the affinity sorbent as compared to the kidneys of normotensive animals. Increased binding of SHR renal proteins to RP220 over the normotensive control was found for proteins involved in the development of cardiovascular pathology. Decreased binding of the kidney proteins from hypertensive animals to RP220 was noted for components of the ubiquitin-proteasome system, ribosomes, and cytoskeleton.

Augmentation of Nitric Oxide Deficient Hypertension by High Salt Diet Is Associated With Reduced TNF-α Receptor Type 1 Expression in the Kidneys.

BACKGROUND: High salt (HS) intake induces an augmented hypertensive response to nitric oxide (NO) inhibition, though it causes minimal changes in blood pressure (BP) in NO intact condition. The cause of such augmentation is not known. HS induces tumor necrosis factor-alpha (TNFα) production that causes natriuresis via activation of its receptor type 1 (TNFR1). We hypothesized that NO deficiency reduces renal TNFR1 activity, leading to enhanced sodium retention and hypertension. METHODS: We examined the changes in renal TNFR1 protein expression (Immunohistochemistry analyses) after HS (4% NaCl) intake in wild-type mice (WT, C57BL6) treated with a NO synthase (NOS) inhibitor, nitro-l-arginine methyl ester (L-NAME; 0.05 mg/min/g; osmotic mini-pump), as well as in endothelial NOS knockout mice (eNOSKO) and compared the responses in WT mice with normal salt (NS; 0.3% NaCl) intake. BP was measured with tail-cuff plethysmography and 24-hour urine collections were made using metabolic cages. RESULTS: HS alone did not alter mean BP in untreated mice (76 ±â€…3 to 77 ±â€…1 mm Hg) but induced an augmented response in L-NAME treated (106 ±â€…1 vs. 97 ±â€…2 mm Hg) and in eNOSKO (107 ±â€…2 vs. 89 ±â€…3 mm Hg) mice. The percentage area of TNFR1 expression in renal tissue was higher in WT + HS (4.1 + 0.5%) than in WT + NS mice (2.7 ±â€…0.6%). However, TNFR1 expression was significantly lower in L-NAME treated WT + NS (0.9 ±â€…0.1%) and in eNOSKO + NS (1.4 ±â€…0.2%) than in both WT + NS and WT + HS mice. CONCLUSIONS: These data indicate that TNFR1 activity is downregulated in NO deficient conditions, which facilitates salt retention leading to augmented hypertension during HS intake.

Comparative proteomic analysis of renal tissue of normotensive and hypertensive rats.

Comparative proteomic analysis of kidney tissue from normotensive (WKY) and spontaneously hypertensive (SHR) rats revealed quantitative and qualitative changes in renal proteins. The number of renal proteins specific for WKY rats (blood pressure 110-120 mm Hg) was 13-16. There were 20-24 renal proteins specific for SHR (blood pressure 180 mm Hg and more). The total number of identified renal proteins common for both rat strains included 972-975 proteins. A pairwise comparison of all possible (SHR-WKY) variants identified 8 proteins specific only for normotensive (WKY) animals, and 7 proteins specific only for hypertensive ones (SHR). Taking into consideration their biological roles, the lack of some enzyme proteins in hypertensive rats (for example, biliverdin reductase A) reduces the production of molecules exhibiting antihypertensive properties, while the appearance of others (e.g. betaine-homocysteine S-methyltransferase 2, septin 2, etc.) can be interpreted as a compensatory reaction. Renal proteins with altered relative content (with more than 2.5-fold change) accounted for no more than 5% of all identified proteins. Among the proteins with an increased relative content in hypertensive animals, the largest group consisted of proteins involved in the processes of energy generation and carbohydrate metabolism, as well as antioxidant and protective proteins. In the context of the development of hypertension, the identified relative changes can apparently be considered compensatory. Among the proteins with the most pronounced decrease in the relative content in hypertensive rats, the dramatic reduction in acyl-CoA medium-chain synthetase-3 (ACSM3) appears to make an important contribution to the development of renal pathology in these animals.

The relationship between trajectories of renal oxygen saturation and acute kidney injury: a prospective cohort study with a secondary analysis.

BACKGROUND: Acute kidney injury (AKI) is a major postoperative consequence, affecting prognosis of older patients. Effective prediction or intervention to predict or prevent the incidence of AKI is currently unavailable. AIMS: Dynamic changes of renal tissue oxygen saturation (RSO2) during surgery process are understudied and we intended to explore the distinct trajectories and associations with postoperative AKI. METHODS: This was a secondary analysis including data for older patients who underwent open hepatectomy surgery with informed consent. Latent class mixed models (LCMM) method was conducted to generate trajectories of intraoperative renal tissue RSO2 through different time points. The primary outcome was postoperative 7-day AKI. The univariate and multivariate regression analysis were performed to identify the relationship between distinct trajectories of renal tissue RSO2 and the risk of AKI. Meanwhile, the prediction efficacy of renal tissue RSO2 at different time points was compared to find potential intervention timing. RESULTS: Postoperative AKI occurred in 14 (15.2%) of 92 patients. There are two distinct renal tissue RSO2 trajectories, with 44.6% generating "high-downwards" trajectory and 55.4% generating "consistently-high" trajectory. Patients with "high-downwards" trajectory had significantly higher risk of postoperative AKI than another group (Unadjusted OR [Odds Ratio] = 3.790, 95% CI [Confidence Interval]: 1.091-13.164, p = 0.036; Adjusted OR = 3.973, 95% CI 1.020-15.478, p = 0.047, respectively). Predictive performance was 71.4% sensitivity and 60.3% specificity for "high-downwards" trajectory of renal tissue RSO2 to identify AKI. Furthermore, the renal tissue RSO2 exhibited the lowest level and the best results in terms of the sensitivity during the hepatic occlusion period, may be considered as a "time of concern". CONCLUSIONS: Older patients undergoing hepatectomy may show high-downwards trajectory of renal tissue RSO2, indicating a higher risk of AKI, and the lowest level was identified during the hepatic occlusion period. These findings may help to provide potential candidates for future early recognition of deterioration of kidney function and guide interventions.

3D hypoxia-mimicking and anti-synechia hydrogel enabling promoted neovascularization for renal injury repair and regeneration.

In-situ renal tissue engineering is promising yet challenging for renal injury repair and regeneration due to the highly vascularized structure of renal tissue and complex high-oxidative stress and ischemic microenvironment. Herein, a novel biocompatible 3D porous hydrogel (DFO-gel) with sustained release capacity of hypoxia mimicking micromolecule drug deferoxamine (DFO) was developed for in-situ renal injury repair. In vitro and in vivo experimental results demonstrated that the developed DFO-gels can exert the synchronous benefit of scavenging excess reactive oxygen species (ROS) regulating inflammatory microenvironment and promoting angiogenesis for effective renal injury repair by up-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). The in-situ neogenesis of neonatal glomerular- and tubular-like structures in the implanted areas in the partially nephrectomized rats also suggested the potential for promoting renal injury repair and regeneration. This multifunctional hydrogel can not only exhibit the sustained release and promoted bio-uptake capacity for DFO, but also improve the renal injured microenvironment by alleviating oxidative and inflammatory stress, accelerating neovascularization, and promoting efficient anti-synechia. We believe this work offers a promising strategy for renal injury repair and regeneration.

Stem Cells in Kidney Ischemia: From Inflammation and Fibrosis to Renal Tissue Regeneration.

Ischemic nephropathy consists of progressive renal function loss due to renal hypoxia, inflammation, microvascular rarefaction, and fibrosis. We provide a literature review focused on kidney hypoperfusion-dependent inflammation and its influence on renal tissue's ability to self-regenerate. Moreover, an overview of the advances in regenerative therapy with mesenchymal stem cell (MSC) infusion is provided. Based on our search, we can point out the following conclusions: 1. endovascular reperfusion is the gold-standard therapy for RAS, but its success mostly depends on treatment timeliness and a preserved downstream vascular bed; 2. anti-RAAS drugs, SGLT2 inhibitors, and/or anti-endothelin agents are especially recommended for patients with renal ischemia who are not eligible for endovascular reperfusion for slowing renal damage progression; 3. TGF-ß, MCP-1, VEGF, and NGAL assays, along with BOLD MRI, should be extended in clinical practice and applied to a pre- and post-revascularization protocols; 4. MSC infusion appears effective in renal regeneration and could represent a revolutionary treatment for patients with fibrotic evolution of renal ischemia.

Beyond conventional microscopy: Observing kidney tissues by means of fourier ptychography.

Kidney microscopy is a mainstay in studying the morphological structure, physiology and pathology of kidney tissues, as histology provides important results for a reliable diagnosis. A microscopy modality providing at same time high-resolution images and a wide field of view could be very useful for analyzing the whole architecture and the functioning of the renal tissue. Recently, Fourier Ptychography (FP) has been proofed to yield images of biology samples such as tissues and in vitro cells while providing high resolution and large field of view, thus making it a unique and attractive opportunity for histopathology. Moreover, FP offers tissue imaging with high contrast assuring visualization of small desirable features, although with a stain-free mode that avoids any chemical process in histopathology. Here we report an experimental measuring campaign for creating the first comprehensive and extensive collection of images of kidney tissues captured by this FP microscope. We show that FP microscopy unlocks a new opportunity for the physicians to observe and judge renal tissue slides through the novel FP quantitative phase-contrast microscopy. Phase-contrast images of kidney tissue are analyzed by comparing them with the corresponding renal images taken under a conventional bright-field microscope both for stained and unstained tissue samples of different thicknesses. In depth discussion on the advantages and limitations of this new stain-free microscopy modality is reported, showing its usefulness over the classical light microscopy and opening a potential route for using FP in clinical practice for histopathology of kidney.

Metabolomics study of corn silk on renal tissue and urine of diabetic nephropathy rats / 中国药理学通报

Aim To investigate the mechanism of corn silk decoction on diabetic nephropathy (DN) rats using metabolomics technology. Methods DN rat model was established by feeding with high-sugar and high-fat diet, combined with intraperitoneal injection of low dose streptozotocin. Renal organ index, fasting blood glucose, albumin creatinine ratio, serum creatinine, blood urea nitrogen, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol indexes were measured, and the pathological changes of renal tissues were also observed to evaluate the intervention effect of corn silk on DN model rats. Further, UPLC/Q-TOF-MS technology was used to screen potential biomarkers in renal tissues and urine, combined with principal component analysis (PC A) and orthogonal partial least squares discriminant analysis (OPLS-DA). After identification by HM-DB and KEGG database, the biomarkers were imported into MetaboAnalyst for metabolic pathway analysis. Results All indexes and pathological damage of kidneys were improved in groups with different doses of corn silk, indicating that corn silk had a good intervention effect on DN. Metabolomic analysis showed that 18 biomarkers could be significantly called back by corn silk, and it involved 18 metabolic pathways mainly including phenylalanine, tyrosine and tryptophan biosynthesis, riboflavin metabolism, arachidonic acid metabolism, and tyrosine metabolism. Conclusions The mechanism of corn silk decoction intervention on DN may be related to amino acid metabolism, riboflavin metabolism, and arachidonic acid metabolism.

Novel Expression of Thymine Dimers in Renal Cell Carcinoma, Demonstrated through Immunohistochemistry.

Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC.

Tunical Gliomatosis: An Uncommon Histological Entity.

Background Gliomatosis peritonei (GP) is characterized by widespread implants of mature glial tissue in the peritoneum. It is most often associated with immature or mature ovarian teratomas. Case Report: A 6-month old infant developed isolated gliomatosis involving the tunica vaginalis following excision of an immature sacrococcygeal teratoma in the neonatal period. Conclusion: Tunica vaginalis gliomatosis can occur in the setting of a retroperitoneal extragonadal congenital immature teratoma.

Renal tissue desaturation and acute kidney injury in infant cardiac surgery: a prospective propensity score-matched cohort study.

BACKGROUND: Previous studies on the association between renal tissue desaturation and acute kidney injury (AKI) in infant cardiac surgery are limited by small sample sizes and inconsistent results. This prospective study aimed to determine the association between renal desaturation and AKI in infants undergoing surgical repair of an isolated ventricular septal defect (VSD). METHODS: Infants undergoing VSD repair involving cardiopulmonary bypass participated in this prospective cohort study. The exposure of interest was renal tissue desaturation, defined as at least 20% decrease in saturation from baseline for at least 60 consecutive seconds. Intraoperative care was not guided by renal oxygenation, as the anaesthesiologists were blinded to the monitor. The outcome was AKI arising within postoperative Days 1-3. The primary analysis was based on propensity score-matched infants with and without intraoperative renal desaturation. RESULTS: Intraoperative renal desaturation was detected in 38 of 242 infants using near-infrared spectroscopy. This group of infants was matched with 114 infants without intraoperative renal saturation after propensity score matching. Acute kidney injury occurred in 47% (18/38) and 27% (31/114) of infants with or without renal desaturation, respectively. Infants with renal desaturation had higher odds of developing AKI than infants without renal desaturation based on conditional logistic regression (odds ratio 2.79; 95% confidence interval: 1.21-6.44; P=0.016). The cumulative time of renal desaturation correlated moderately with the ratio of postoperative peak creatinine to preoperative baseline creatinine (r=0.51; P<0.001). CONCLUSIONS: Intraoperative renal desaturation is associated with increased odds of developing AKI after surgical repair of an isolated VSD involving cardiopulmonary bypass in infants. CLINICAL TRIAL REGISTRATION: NCT03941015.

Enhancing Kidney Vasculature in Tissue Engineering-Current Trends and Approaches: A Review.

Chronic kidney diseases are a leading cause of fatalities around the world. As the most sought-after organ for transplantation, the kidney is of immense importance in the field of tissue engineering. The primary obstacle to the development of clinically relevant tissue engineered kidneys is precise vascularization due to the organ's large size and complexity. Current attempts at whole-kidney tissue engineering include the repopulation of decellularized kidney extracellular matrices or vascular corrosion casts, but these approaches do not eliminate the need for a donor organ. Stem cell-based approaches, such as kidney organoids vascularized in microphysiological systems, aim to construct a kidney without the need for organ donation. These organ-on-a-chip models show complex, functioning kidney structures, albeit at a small scale. Novel methodologies for developing engineered scaffolds will allow for improved differentiation of kidney stem cells and organoids into larger kidney grafts with clinical applications. While currently, kidney tissue engineering remains mostly limited to individual renal structures or small organoids, further developments in vascularization techniques, with technologies such as organoids in microfluidic systems, could potentially open doors for a large-scale growth of whole engineered kidneys for transplantation.

Role of Oxidative Stress and Reduced Endogenous Hydrogen Sulfide in Diabetic Nephropathy.

PURPOSE: Persistent hyperglycemia lead towards depletion of hydrogen sulfide (H2S) resulting in generation of oxidative stress and diabetic nephropathy. The aim of the current study was to explore the antioxidant potential of H2S and captopril, a -SH containing compound in streptozotocin (STZ)-induced diabetic nephropathy. METHODS: Fifty four Wistar-Kyoto (WKY) rats male (200-250g) were divided into nine groups (n=6) with each group injected once with STZ (60mg/kg i.p) except normal control. After 3 weeks of induction of diabetes, groups were assigned as normal control, diabetic control, diabetic-captopril, diabetic-NaHS, diabetic-captopril-NaHS, diabetic-spironolactone, diabetic-metformin, diabetic-metformin-NaHS and diabetic-vitamin-c. All the animals were served with normal saline (N/S 4mL/kg p.o), captopril (50mg/kg/day p.o), sodium hydrosulfide (NaHS) (56µmol/kg i.p), spironolactone (50mg/kg/day s.c), metformin (500mg/kg/day p.o) and vitamin-c (50mg/kg p.o) on daily basis for next 4 weeks, respectively. Metabolic studies, H2S levels, renal hemodynamics and oxidative stress markers were analyzed at 0, 14 and 28 days followed by histopathological analysis of renal tissues. RESULTS: The results showed decreased H2S levels, body weight, sodium to potassium ratio, glutathione (GSH), superoxide dismutase (SOD), total antioxidant assay (T-AOC) with malondialdehyde (MDA) and blood glucose levels significantly increased among diabetic rats. Treatment with captopril, NaHS, metformin, spironolactone and vitamin C showed significant improvement among renal hemodynamics and oxidative stress markers, respectively. But treatment groups like NaHS in combination with captopril and metformin showed more pronounced effects. CONCLUSION: The observations suggest that H2S mediated protective effects on STZ-induced diabetic nephropathy may be associated with reduced oxidative stress via augmenting the antioxidant effect.

Acardiac twin pregnancies part V: Why does an acardiac twin with renal tissue produce polyhydramnios?

BACKGROUND: Acardiac twinning is a complication of monochorionic twin pregnancies. From literature reports, 30 of 41 relatively large acardiac twins with renal tissue produced polyhydramnios within their amniotic compartment. We aim to investigate the underlying mechanisms that cause excess amniotic fluid using an established model of fetal fluid dynamics. METHODS: We assumed that acardiac onset is before 13 weeks, acardiacs with renal tissue have normal kidney function and produce urine flow from 11 weeks on, and acardiac urine production requires a pressure of half the pump twin's mean arterial pressure. We apply a resistance network with the pump twin's arterio-venous pressure as source, pump umbilical arteries, placenta, placental arterio-arterial (AA) anastomoses and acardiac resistances. Acardiac amniotic fluid dynamics excluded acardiac lung fluid secretion, swallowing and the relatively small intramembranous flow. RESULTS: In small acardiacs with sufficient urine production, polyhydramnios will occur due to the lack of amniotic fluid resorption. Urine production is dependent upon having sufficient mean arterial pressure, which requires nearly a two-fold larger resistance within the acardiac as compared to the placental AA resistance. Subphysiologic arterial pressure may result in renal dysgenesis. CONCLUSION: Our findings suggest the potential for prediction of which clinical acardiac cases may or may not develop polyhydramnios based upon noninvasive assessments of renal tissue, blood flow and urine production. This information would be of great value in determining early obstetric interventions as opposed to conservative management. These findings may also contribute to an improved knowledge of the fascinating pathophysiology that surrounds acardiac twinning.

Detection of microRNA-33a-5p in serum, urine and renal tissue of patients with IgA nephropathy.

The present study aimed to detect the levels of microRNA (miR)-33a-5p in the renal tissue, serum and urine of patients with primary IgA nephropathy (IgAN), thereby preliminarily exploring the association between the levels of miR-33a-5p and the condition of primary IgAN to provide evidence for the expression of miR-33a-5p in the serum and urine of IgAN patients as a clinical marker. Reverse-transcription quantitative PCR was performed to evaluate the level of miR-33a-5p in IgAN patients according to severity and pathological classification. The results suggested that the levels of miR-33a-5p in the serum, urine and kidney tissues of patients with IgAN were lower than those of the control tissues obtained from cancer patients (0.28±0.25 vs. 1.00±0.45, P<0.05; 0.34±0.28 vs. 1.00±0.53, P<0.05; 0.47±0.27 vs. 1.00±0.38, P<0.05, respectively). Receiver operating characteristic curve analysis suggested that the serum and urine levels of miR-33a-5p may be used as a marker to differentiate renal injury in IgAN patients from healthy individuals. At the same time, according to the estimated glomerular filtration rate (eGFR) and Lee classification of nephropathy, it was determined that with the progression of renal failure and the increase of the pathological grade of kidney tissue, the relative level of miR-33a-5p in kidney tissue also decreased (eGFR <50 ml/min vs. eGFR ≥50 ml/min/1.73 m2 group: 0.38±0.27 vs. 1.00±0.34, P<0.001; Lee grade ≤3 group vs. Lee grade >3: 1.00±0.48 vs. 0.38±0.45, P<0.05). This result suggested that the levels of miR-33a-5p in serum, urine and kidney tissues decreased with the severity of renal injury and the progression of renal failure in patients with IgAN. Hence, miR-33a-5p detected in the serum and urine may be used as a non-invasive biomarker to reflect the progression of renal injury and renal failure in patients with IgAN.

Effects of Modified Liuwei Dihuang Decoction on Kidney/Bone Injury of CKD-MBD Model Rats / 中国药房

OBJECTIVE：To study the effects of Modified liuwei dihuang decoction on kidney/bone injury of chronic kidney disease-mineral and bone disorder（CKD-MBD）model rats. METHODS ：The male SD rats were randomly divided into normal group（n＝10），high phosphorus group （n＝30），model group （n＝30），calcitriol group （positive control ，0.09 μg/kg，n＝30）， Modified liuwei dihuang decoction group （10 g/kg by crude drug ，n＝30）. CKD-MBD model was established by high phosphorus and adenine diet for 6 weeks. After modeling ，normal group and model group were given normal diet/high phosphorus diet and intragastric administration of water. Administration groups were fed with normal diet and given corresponding solution intragastrically（water as solvent ），0.1 mL/kg，once a day ，for consecutive 6 weeks. Blood sample of rats in the normal group were collected ，and they were sacrificed after the last administration. Blood sample of 10 rats in each other group were collected ， and they were sacrificed at 2，4 and 6 weeks after administration. The contents of blood urea nitrogen （BUN），serum creatinine （Scr），calcium，phosphorus，iPTH，FGF-23，RANKL and osteocalcin in serum were detected in each group. The bone mineral density（BMD）of femoral was measured ，the morphological changes of renal tissue and bone tissue were observed ，and the percentage of renal tubular injury and the score of renal interstitial fibrosis were calculated. RESULTS ：Compared with normal group，above indexes in high phosphorus group had no significant change at different time points （P＞0.05）. There was no abnormal change in renal/bone tissue. Compared with high phosphorus group at the same time point ，the contents of BUN ，Scr， phosphorus，iPTH，FGF-23，RANKL and osteocalcin in serum ，the percentage of renal tubular injury and the score of renal interstitial fibrosis in the model group were significantly increased ，while the contents of calcium in serum and the BMD of femoral were significantly decreased （P＜0.05 or P＜0.01）. The renal tissue showed diffuse fibrosis. The width of trabecular bone was increased and the number of osteoblasts was decreased. Compared with the model group at the same time point ，the contents of BUN（except for Modified liuwei dihuang decoction group after 2 weeks of administration ），Scr，serum phosphorus ，iPTH， FGF-23，RANKL and osteocalcin ，the percentage of renal tubular injury and the score of renal interstitial fibrosis in Modified liuwei dihuang decoction group and calcitriol group were decreased significantly at each time point ；serum calcium content and BMD（except for 2 weeks of administration ）were significantly increased （P＜0.05 or P＜0.01），and the pathological changes of renal/bone tissue were significantly improved ；there was no statistical significance in above indexes between Modified liuwei dihuang decoction group and calcitriol group （P＞0.05）. CONCLUSIONS ：Modified liuwei dihuang decoction can improve kidney/ bone injury of CKD-MBD model rats ，and improve BMD and regulate disorder of calcium and phosphorus metabolism.

Validation of phospholipase A2 receptor direct immunofluorescence staining in the diagnosis of primary membranous glomerulonephritis.

Distinguishing between primary and secondary subtypes of membranous glomerulonephritis (MGN) is critical for its clinical management. We prospectively compared direct immunofluorescence (DIF) staining for phospholipase A2 receptor (PLA2R) on frozen renal biopsy with the presence of detectable serum PLA2R antibody assessed by enzyme linked immunosorbent assay (ELISA) in the diagnosis of primary MGN. Forty-six patients with biopsy-proven MGN were enrolled from April 2017 to June 2019 with 31/46 (67.4%) being primary and 15/46 (32.6%) being secondary as determined by comprehensive clinical assessment. This is currently deemed to be the gold standard for distinguishing primary from secondary MGN. Amongst the 31 primary MGN patients, 24/31 were positive on PLA2R DIF staining compared to 18/31 being positive on the PLA2R ELISA (p=0.03). Amongst the 15 secondary MGN patients, 1/15 was positive on PLA2R DIF compared to 0/15 on PLA2R ELISA (p=1.0). In conclusion, the presence of PLA2R staining on DIF demonstrated superior sensitivity and similar specificity compared to the detection of circulating PLA2R antibodies by ELISA in the diagnosis of primary MGN in a cohort of 46 patients with biopsy-proven MGN. We suggest that DIF should be considered as part of routine work-up in all newly diagnosed cases of MGN.

Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury.

BACKGROUND: Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3-5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease. RESULTS: Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis. CONCLUSIONS: These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy.

Renal detection of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in malaria associated acute kidney injury: a retrospective case-control study.

OBJECTIVE: Acute kidney injury (AKI) is a frequent presentation in malaria infections. Several cases of AKI that are accompanied by clinical symptoms of malaria infection, such as fever, nausea, respiratory distress, and anemia remain undiagnosed due to challenges in accurate diagnosis using peripheral blood microscopy and rapid diagnostic tests that are currently used in clinical settings. This is particularly true for P. vivax and P. knowlesi infections. As a result, these patients are not able to receive anti-malarial therapy in a timely manner. The objective of the present study was to investigate if patients presenting with AKI harbored any of the five human Plasmodium species (P. falciparum, P. vivax, P. knowlesi, P. malariae, and P. ovale) within their renal tissues. RESULTS: We found that renal biopsies from malaria associated AKI patients harbor the human malaria parasites P. falciparum, P. vivax and P. knowlesi as mono- and mixed species infections. Presence of microvascular injury in a majority of the malaria associated AKI cases suggested vascular involvement of P. vivax and P. knowlesi. This research note also highlights P. knowlesi as an emerging pathogen in the Indian subcontinent.