Renal Tubulointerstitial Lesions Research Articles

The role of interleukin-36 in health and disease states.

The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.

Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy

Collagen 17A1 (COL17A1), an epidermal hemidesmosome component, is ectopically induced in the urothelium of mouse and human renal pelvis (RP) in parallel with urinary tract-associated lymphoid structure development. Here, we found that COL17A1 was induced in obstructive uropathy-prone ureter of humans and cats. To ascertain its function, murine urinary organs with unilateral ureteral obstruction (UUO) were analyzed during 1 week after surgery. One day after UUO, COL17A1 expression increased in urothelial cells of RP and ureter, and was positively correlated with renal tubulointerstitial lesions. A portion of RP where the smooth muscle layer from the ureter was interrupted was sensitive to urothelium deciduation and COL17A1 induction, showing urine leaked from the RP lumen into the parenchyma. After urine stimulation, cultured immune cells expressed Cxcl2, also up-regulated in CD11b+ cells following COL17A1 stimulation. One day after UUO, CXCL2+ CD11b+ cells infiltrated the urothelium-disrupted area; however, these numbers were significantly lower in Col17a1-deficient mice. COL17A1+ urothelial cells partially co-expressed cytokeratin-14, a progenitor cell marker for urothelium, whereas Col17a1-deficient mice had lower numbers of cytokeratin-14+ cells. Gene Ontology analysis revealed that expression of epithelial- and immune-associated genes was up-regulated and down-regulated, respectively, in the ureter of Col17a1-deficient mice 4 days after UUO. Thus, COL17A1 maintains urothelium integrity by regulating urothelial cell adhesion, proliferation, and differentiation, and activates local immune responses during obstructive uropathy in mammals.

Clinical presentation and prognosis in children over 10-year-old with primary nephrotic syndrome

Objective: To summary the clinical presentation and prognosis of primary nephrotic syndrome (PNS) in teenagers. Methods: The clinical data, renal pathological types and prognosis of 118 children over 10-year-old with PNS treated in the Department of Nephrology of the Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2010 to December 2020 were retrospectively analyzed, with 408 children ≤10-year-old as control group synchronously. Chi-square test was used to compare the difference of clinical types, pathologic types, response to steroids and tubulointerstitial changes between the groups. The teenagers with steroid resistant nephrotic syndrome (SRNS) were divided into initial non-responder group and late non-responder group. Kaplan-Meier method was used to compare the difference of persistent proteinuria, and Fisher's exact test for the histological types. Results: There were 118 children >10-year-old, including 74 males and 44 females, with the onset age of 12.1 (10.8, 13.4) years; and 408 children ≤10-year-old with the onset age of 4.5 (3.2, 6.8) years. The proportion of SRNS was significantly higher in patients >10-year-old than those ≤10-year-old (24.6% (29/118) vs. 15.9% (65/408), χ2=4.66, P=0.031). There was no statistical difference in the pathological types between >10-year-old and ≤10-year-old (P>0.05), with minimal change disease the most common type (56.0% (14/25) vs. 60.5% (26/43)). The percentage of cases with renal tubulointerstitial lesions was significantly higher in children >10-year-old compared to those ≤10-year-old (60.0% (15/25) vs. 23.3% (10/43), χ2=9.18, P=0.002). There were 29 cases presented with SRNS in PNS over 10-year-old, including 19 initial non-responders and 10 late non-responders. Analyzed by Kaplan-Meier curve, it was shown that the percentage of persistent proteinuria after 6 months of immunosuppressive treatments was significantly higher in initial non-responders than those of the late non-responders ((22±10)% vs. 0, χ2=14.68, P<0.001); the percentage of minimal change disease was significantly higher in patients of late non-responders than those of the initial non-responders (5/6 vs. 3/13, P=0.041). Of the 63 >10-year-old with steroid-sensitive nephrotic syndrome followed up more than one year, 38 cases (60.3%) had relapse, and 14 cases (22.2%) were frequent relapse nephrotic syndrome and steroid dependent nephrotic syndrome. Among the 45 patients followed up over 18-year-old, 22 cases (48.9%) had recurrent proteinuria continued to adulthood, 3 cases of SRNS progressed to kidney insufficiency, and one of them developed into end stage kidney disease and was administrated with hemodialysis. Conclusions: Cases over 10-year-old with PNS tend to present with SRNS and renal tubulointerstitial lesions. They have a favorable prognosis, but are liable to relapse in adulthood.

TNFR2 as a Potential Biomarker for Early Detection and Progression of CKD

The inflammatory pathway driven by TNF-α, through its receptors TNFR1 and TNFR2, is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the initial disease cause. Evidence correlates the chronic inflammatory status with decreased renal function. Our aim was to evaluate the potential of TNF receptors as biomarkers for CKD diagnosis and staging, as well as their association with the progression of renal lesions, in rat models of early and moderate CKD. We analyzed the circulating levels of inflammatory molecules-tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) and tissue inhibitor of metalloproteinase-1 (TIMP-1)-and studied their associations with TNFR1 and TNFR2 renal expression, glomerular and tubulointerstitial lesions, and with biomarkers of renal (dys)function. An increase in all inflammatory markers was observed in moderate CKD, as compared to controls, but only circulating levels of both TNFR1 and TNFR2 were significantly increased in the early disease; TNFR2 serum levels were negatively correlated with eGFR. However, only TNFR2 renal expression increased with CKD severity and showed correlations with the score of mild and advanced tubular lesions. Our findings suggest that renal TNFR2 plays a role in CKD development, and has potential to be used as a biomarker for the early detection and progression of the disease. Still, the potential value of this biomarker in disease progression warrants further investigation.

Cellular senescence of renal tubular epithelial cells in renal fibrosis.

Renal fibrosis (RF) is the common pathological manifestation of virtually all chronic kidney diseases (CKD) and one of the major causes of end-stage renal disease (ESRD), but the pathogenesis of which is still unclear. Renal tubulointerstitial lesions have been identified as a key pathological hallmark of RF pathology. Renal tubular epithelial cells are the resident cells of the tubulointerstitium and play an important role in kidney recovery versus renal fibrosis following injury. Studies in recent years have shown that senescence of renal tubular epithelial cells can accelerate the progression of renal fibrosis. Oxidative stress(OS), telomere attrition and DNA damage are the major causes of renal tubular epithelial cell senescence. Current interventions and therapeutic strategies for cellular senescence include calorie restriction and routine exercise, Klotho, senolytics, senostatics, and other related drugs. This paper provides an overview of the mechanisms and the key signaling pathways including Wnt/β-catenin/RAS, Nrf2/ARE and STAT-3/NF-κB pathway involved in renal tubular epithelial cell senescence in RF and therapies targeting renal tubular epithelial cell senescence future therapeutic potential for RF patients. These findings may offer promise for the further treatment of RF and CKD.

S-40-6: ACTIVATION OF CATHEPSIN S/CXCL1 AXIS-MEDIATED MACROPHAGE AND TUBULAR CELL CROSSTALK LEADS TO RENAL INFLAMMATION AND FIBROSIS

Chronic kidney disease (CKD) is a progressive and irreversible pathological feature with no effective therapies in clinic. Persistent inflammation is a key characteristic of CKD that leads to progressive renal fibrosis. Cathepsin S (Cat S) is a cysteine protease contributing to the progression of multiple diseases through modulating inflammation, but its role in the pathogenesis of CKD remains unknown. Here, we found that Cat S was significantly upregulated in renal macrophage during unilateral ureteral obstruction (UUO). Knockout of Cat S attenuated, whereas AAV (adeno-associated virus)-mediated macrophage-specific overexpression of Cat S exacerbated macrophage recruitment, inflammatory factors expression, renal injury and epithelial mesenchymal transition (EMT). Using macrophage depletion, bone marrow transplantation, protein chip and luciferase reporter assays, we determined that macrophage-derived Cat S induced CXCL1 secretion from tubular cells which mediated macrophage recruitment. Immunoprecipitation combined with mass spectrometry identified that Cat S directly bind with Rack1, which disrupted the Rack1-IKK-alpha complex to activate NF-kappaB signaling. Knockdown of CXCL1 attenuated aggravating pathological changes in macrophage-specific overexpression of Cat S mice. Furthermore, therapeutic administration of Cat S inhibitor significantly reversed renal injury in UUO mice. In patients with renal tubulointerstitial lesions, increase expression of plasma and renal Cat S was associated with renal function impairment and fibrosis severity. Our study demonstrated that Cathepsin S/CXCL1 axis mediated interaction between macrophage and tubular cell that contributed to CKD, with translational implications in humans.

Long-term prognosis of primary focal segmental glomerulosclerosis in children

Objective: To investigate risk factors for the long-term prognosis of primary focal segmental glomerulosclerosis (FSGS) and associated with renal prognosis in children. Methods: A retrospective study was conducted by collecting clinical data including general information, clinical features and renal pathological findings of 124 children with primary FSGS in Department of Pediatrics of Jinling Hospital from January 2003 to December 2019. The cumulative renal survival rate was calculated by Kaplan-Meier survival analysis. The risk factors related to renal prognosis were identified by Cox regression risk model analysis and receiver operating characteristic (ROC) curve. Results: Among 124 children, 94 were males (75.8%) and 30 were females (24.2%). The children were 16 (14, 17) years of age at the time of kidney biopsies. There were 102 cases (82.3%) aged from 13 to 18 years. The period of follow-up was 64.8 (32.1, 86.0) months. There were 49 cases (39.5%) with nonspecific variant, 33 cases (26.6%) with tip variant, 22 cases (17.7%) with collapsing variant, 14 cases (11.3%) with cellular variant and 6 cases (4.8%) with periportal variant. The data of Kaplan-Meier survival analysis showed that cumulative renal survival rates of end-stage kidney disease (ESKD) or ≥50% decline in estimated glomerular filtration rate (eGFR) from baseline at the year of 5, 10 and 15 after renal biopsies were 66.9%, 51.4% and 21.0% respectively. Multivariate Cox regression analysis showed that hypertension, glomerular segmental sclerosis ratio, moderate to severe chronic tubulointerstitial lesions were independent risk factors for progressing to ESKD or ≥50% reduction in eGFR from baseline in pediatric FSGS (HR=5.28, 1.03, 7.81, 95%CI 2.77-10.05, 1.01-1.04, 4.08-14.98, all P<0.01). ROC curve analysis showed glomerular segmental sclerosis ratio (AUC=0.734, P<0.05, optimal cut-off value=25.4%, sensitivity=50.0%, specificity=88.6%), moderate and severe chronic renal tubulointerstitial lesions (AUC=0.724, P<0.05, sensitivity=46.3%, specificity=98.6%) had good efficacy in evaluating renal outcomes of FSGS. Conclusions: The long-term prognosis of FSGS in children is poor. The risk factors of poor prognosis in children with FSGS are hypertension, moderate to severe chronic renal tubulointerstitial lesions and glomerular segmental sclerosis (≥25.4%).

Identification of Hub Genes Involved in Tubulointerstitial Injury in Diabetic Nephropathy by Bioinformatics Analysis and Experiment Verification.

Diabetic nephropathy (DN) is the most important cause of end-stage renal disease with a poorer prognosis and high economic burdens of medical treatments. It is of great research value and clinical significance to explore potential gene targets of renal tubulointerstitial lesions in DN. To properly identify key genes associated with tubulointerstitial injury of DN, we initially performed a weighted gene coexpression network analysis of the dataset to screen out two nonconserved gene modules (dark orange and dark red). The regulation of oxidative stress-induced intrinsic apoptotic signaling pathway, PI3K-Akt signaling pathway, p38MAPK cascade, and Th1 and Th2 cell differentiation were primarily included in Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of these two modules. Next, 199 differentially expressed genes (DEGs) were identified via the limma package. Then, the GO annotation and KEGG pathways of the DEGs were primarily enriched in extracellular matrix (ECM) organization, epithelial cell migration, cell adhesion molecules (CAMs), NF-kappa B signaling pathway, and ECM-receptor interaction. Gene set enrichment analysis showed that in the DN group, the interaction of ECM-receptor, CAMs, the interaction of cytokine-cytokine receptor, and complement and coagulation cascade pathways were significantly activated. Eleven key genes, including ALB, ANXA1, ANXA2, C3, CCL2, CLU, EGF, FOS, PLG, TIMP1, and VCAM1, were selected by constructing a protein-protein interaction network, and expression validation, ECM-related pathways, and glomerular filtration rate correlation analysis were performed in the validated dataset. The upregulated expression of hub genes ANXA2 and FOS was verified by real-time quantitative PCR in HK-2 cells treated with high glucose. This study revealed potential regulatory mechanisms of renal tubulointerstitial damage and highlighted the crucial role of extracellular matrix in DN, which may promote the identification of new biomarkers and therapeutic targets.

Efficacy of novel agents in patients with nephropathy associated with POEMS syndrome

ObjectiveTo evaluate the clinical characteristics and outcomes of patients with nephropathy associated with POEMS syndrome who received novel agents in combination with dexamethasone therapy, and renal pathological changes based on repeat biopsy in some patients after these novel-agent-based therapies.MethodsThe records of patients with nephropathy associated with POEMS syndrome in a single hospital from May 2017 to February 2021 were retrieved and studied in detail. All the patients received four cycles of initial novel-agent-based regimens such as bortezomib and dexamethasone (BD) or thalidomide plus dexamethasone (TD) or lenalidomide plus dexamethasone (RD) treatment. We further evaluated the pathological efficacy of these novel agents by repeat renal biopsy.ResultsTwelve patients with an average age of 48.6 ± 8.3 years diagnosed with nephropathy associated with POEMS syndrome were enrolled in this study. The duration from disease onset to renal biopsy was 28(8.3 ~ 54.5) months. All patients achieved good clinical responses in different degree after four cycles of initial novel agents in combination with dexamethasone therapy. After the treatment with novel-agent-based regimens, the levels of proteinuria decreased in most patients and were negative in five patients. The levels of serum creatinine (SCr) decreased in ten patients. Serum M protein was negative in four patients and still positive in the other eight patients. The levels of serum vascular endothelial growth factor (VEGF) were detected in seven patients, which were all decreased. The levels of interleukin-6 (IL-6) were detected in eight patients, which were also decreased. Repeat biopsies were performed after four cycles of novel-agent-based therapies in four patients who were all treated with BD treatment. Mesangiolysis, mesangial cells proliferation, endothelial cells proliferation, subendothelial space widening and acute renal tubulointerstitial lesions improved, the chronic renal tubulointerstitial lesions were stable.ConclusionsNovel agents improved clinical manifestations in patients with nephropathy associated with POEMS syndrome. In addition, novel-agent-based regimens such as BD treatment improved renal pathological manifestations, which suggested that novel agents could improve renal prognosis of the patients from the perspective of renal pathology.

NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice.

Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC50, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.

AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice

Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

Application of Diffusion Tensor Imaging in Obstructive Nephropathy

Background: Obstructive nephropathy is a common clinical disease. Objectives: To explore the value of diffusion tensor imaging (DTI) in obstructive nephropathy. Materials and Methods: Forty healthy Sprague-Dawley (SD) rats were examined in this study. Thirty-two animals underwent complete obstruction of the left ureter, while eight animals underwent a sham surgery. Magnetic resonance imaging (MRI) was performed before surgery and within different intervals after surgery. Eight rats from the experimental group and two rats from the sham group were used in each interval. Following MRI, the animals were sacrificed and sent for medical examinations. The scanning sequences included positioning, transverse T2-weighted (T2W), coronal, and coronal DTI sequences. Image postprocessing was performed after DTI to measure DTI parameters, including apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and to reconstruct DTI fiber traces. One-way analysis of variance was used to compare the parameters between the cortex and medulla and between different intervals. Results: The fiber tracing showed that the obstructed renal fiber bundles were sparse and disordered. The ADC and FA values of the renal cortex, extrarenal medulla, and inner medulla decreased with prolonged hydrops and were negatively correlated with the expression of alpha-smooth muscle actin (α-SMA) and the renal tubulointerstitial lesion grade (r &lt; 0, P &lt; 0.001). Comparison of the cortex, extrarenal medulla, and inner medulla showed the following trends for the ADC and FA values: cortex &gt; extrarenal medulla &gt; inner medulla and cortex &lt; extrarenal medulla &lt; inner medulla, respectively. Conclusions: DTI in obstructive nephropathy not only can reflect the degree of renal interstitial fibrosis and accurately indicate the renal function, but also can provide information regarding renal blood perfusion, water metabolism, and ultrastructural changes.

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

BackgroundProgression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy.MethodsA total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality.ResultsAt baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality.ConclusionsImpacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Relationship between Renal Damage and Serum Complement C3 in Children with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Background: Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) disease is a well-known antibody-induced autoimmune disease. The pathogenesis of AAV has not yet been completely clarified, but may be related to heredity, infection, environmental factors, cellular immunity, etc. In recent years, complement in AAV pathogenesis has become the latest research hotspot, and the decrease of serum complement C3 is associated with poor prognosis of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. In the current study, we investigated the associations between serum complement C3 and kidney injury in AAV children. Methods: Twenty-four children with AAV admitted to our hospital from June 2014 to June 2019 were divided into the low C3 group and the normal C3 group. All the children have undergone renal biopsy. The clinical manifestations, laboratory tests, renal pathology, treatment, and prognosis of the 2 groups were observed. The primary end point was end-stage renal disease (ESRD). Results: It was shown that kidney injury was more obvious in patients with low C3 than in patients with normal C3 serum. The values of ESR, Scr, and UA before treatment in the low C3 group were higher than those in the normal C3 group (p < 0.01); the values of RBC, Hb, PLT, ALB, LDH, and eGFR in the normal C3 group were higher than those in the low C3 group (p < 0.01). The values of urinary protein and NAG enzyme in the low C3 group were higher than those in the normal C3 group (p < 0.01). The area of glomerular abandonment, sclerosis, segmental sclerosis, crescent, cellular crescent, cellular fibrous crescent, fibrous crescent, segmental loop necrosis, and the number of cases with acute renal tubulointerstitial lesions in the low C3 group were bigger than those in the normal C3 group (p < 0.05 and < 0.01). The number of cases with C3 deposition in the low C3 group was higher than that in the normal C3 group (p < 0.05). The number of patients receiving CRRT and PE in the low C3 group was higher than that in the normal C3 group (p < 0.05 and < 0.01). In this study, 3 children entered the stage of ESRD and 1 died in the low C3 group. Conclusion: The kidney injury of AAV children with low complement C3 is serious, and the prognosis is poor. We should pay attention to the influence of decreased complement C3 on the condition and prognosis of AAV children.

Four cases of acute renal injury caused by acute dimethyl oxalate poisoning

Objective: To investigate the clinical features, non-dialysis treatment and prognosis of acute renal injury caused by acute dimethyl oxalate (DMO) poisoning. Methods: Retrospective analysis was performed on the occupational data, clinical manifestation, laboratory examination, treatment methods and prognosis of 4 patients with acute DMO poisoning in July 2020. Results: A large number of white DMO crystals were observed in the workplace. Four patients had acute onset, presenting symptoms such as fatigue, abdominal distension, abdominal cramps and nocturia to varying degrees. Laboratory tests all showed acute kidney injury. Serum creatinine of patients at the onset were 119-835 μmol/L. Patients were given early treatment including rest, protection of renal function, hydration and alkalization of urine, Bailing capsule. Renal function of 4 patients returned to normal, and clinical prognosis was good. Conclusion: Acute DMO poisoning leads to acute renal injury, mainly with renal tubulointerstitial lesions such as hypogravity uria and aseptic leucuria. Active treatment in the early stage has a good short-term clinical prognosis.

Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto's Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations.

Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.

Diagnostic roles of urinary kidney microvesicles in diabetic nephropathy.

BackgroundThe pathology of diabetic nephropathy (DN) broadly involves the injury of glomeruli, tubulointerstitium and endothelium. Cells from these compartments can release increased numbers of microvesicles (MVs) into urine when stressed or damaged. Currently whether urinary MVs from these three parts can help diagnose DN and reflect pathological features remain unclear.MethodsForty-nine patients with histologically proven DN and 29 proteinuric controls with membranous nephropathy or minimal change disease were enrolled. Urinary podocyte, proximal tubular and endothelial cell-derived MVs were quantified by flow cytometry. Renal glomerular, tubulointerstitial and vascular lesions were semi-quantitatively scored and their relevance to urinary MVs were analyzed.ResultsDN patients had greater numbers of urinary MVs from podocytes, proximal tubular and endothelial cells compared with proteinuric controls. The combination of podocyte nephrin+ MVs and diabetic retinopathy optimally diagnose DN with 89.7% specificity and 88.9% sensitivity. Moreover, positive correlations were observed between urinary levels of proximal tubular MVs and the severity of tubular injury and between urinary levels of endothelial MVs and the degree of vascular injury. Using urinary proximal tubular MVs as the indicators for tubular injury, the differences between DN patients and proteinuric controls diminished after matching the degree of renal vascular injury or when proteinuria >8 g/24 h.ConclusionsUrinary kidney-specific cell-derived MVs might serve as noninvasive biomarkers for the diagnosis of DN in diabetic proteinuric patients. Their elevated levels could reflect corresponding renal pathological lesions, helping physicians look into the heterogeneity of DN.

Total Flavones of Abelmoschus manihot Remodels Gut Microbiota and Inhibits Microinflammation in Chronic Renal Failure Progression by Targeting Autophagy-Mediated Macrophage Polarization.

BackgroundRecently, progression of chronic renal failure (CRF) has been closely associated with gut microbiota dysbiosis and intestinal metabolite-derived microinflammation. In China, total flavones of Abelmoschus manihot (TFA), a component of Abelmoschus manihot, has been widely used to delay CRF progression in clinics for the past two decades. However, the overall therapeutic mechanisms remain obscure. In this study, we designed experiments to investigate the renoprotective effects of TFA in CRF progression and its underlying mechanisms involved in gut microbiota and microinflammation, compared with febuxostat (FEB), a potent non-purine selective inhibitor of xanthine oxidase.Methods In vivo, the CRF rat models were induced by uninephrectomy, potassium oxonate, and proinflammatory diet, and received either TFA suspension, FEB, or vehicle after modeling for 28 days. In vitro, the RAW 264.7 cells were exposed to lipopolysaccharide (LPS) with or without TFA or FEB. Changes in parameters related to renal injury, gut microbiota dysbiosis, gut-derived metabolites, and microinflammation were analyzed in vivo. Changes in macrophage polarization and autophagy and its related signaling were analyzed both in vivo and in vitro.ResultsFor the modified CRF model rats, the administration of TFA and FEB improved renal injury, including renal dysfunction and renal tubulointerstitial lesions; remodeled gut microbiota dysbiosis, including decreased Bacteroidales and Lactobacillales and increased Erysipelotrichales; regulated gut-derived metabolites, including d-amino acid oxidase, serine racemase, d-serine, and l-serine; inhibited microinflammation, including interleukin 1β (IL1β), tumor necrosis factor-α, and nuclear factor-κB; and modulated macrophage polarization, including markers of M1/M2 macrophages. More importantly, TFA and FEB reversed the expression of beclin1 (BECN1) and phosphorylation of p62 protein and light chain 3 (LC3) conversion in the kidneys by activating the adenosine monophosphate-activated protein kinase-sirtuin 1 (AMPK-SIRT1) signaling. Further, TFA and FEB have similar effects on macrophage polarization and autophagy and its related signaling in vitro.ConclusionIn this study, we demonstrated that TFA, similar to FEB, exerts its renoprotective effects partially by therapeutically remodeling gut microbiota dysbiosis and inhibiting intestinal metabolite-derived microinflammation. This is achieved by adjusting autophagy-mediated macrophage polarization through AMPK-SIRT1 signaling. These findings provide more accurate information on the role of TFA in delaying CRF progression.

The profiles of biopsy-proven renal tubulointerstitial lesions in patients with glomerular disease.

BackgroundRenal tubules and interstitium are vulnerable to injury and play a central role in the progression of various chronic kidney diseases (CKDs). However, high quality epidemiologic study on the profiles of biopsy-proven tubulointerstitial lesions (TILs) is extremely limited.MethodsWe conducted a retrospective renal biopsy series including 62,569 native biopsies at 1,211 hospitals across China from 2015 to 2017. The TILs, including the shedding of tube epithelial, renal tubular atrophy, renal interstitial fibrosis, edema and inflammatory infiltration, were identified from the pathological report. We analyzed the severity and chronicity of TILs stratified by gender, age groups, biopsy indications, and concurrent glomerular diseases. We also examined the correlation between TIL and glomerulosclerosis.ResultsOf 56,880 patients with biopsy-proven glomerular disease, 79.5% had TILs. Renal interstitial inflammatory infiltration was the most common type of TIL (77.7%), followed by renal tubular atrophy (56.0%) and renal interstitial fibrosis (32.8%). Severe and chronic TILs were more common in adults than in children. The three glomerular diseases with the highest proportion of moderate-to-severe and chronic TIL were diabetic nephropathy, immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis. The severity of TILs was moderately correlated with glomerulosclerosis score (r=0.51). Moderate-to-severe and chronic TIL were more common in southern China. After adjusting for age, sex, hospital level, region, biopsy indication and type of concurrent glomerular diseases, adults with renal arteriole injury had a six-fold higher risk of moderate-to-severe TIL [odds ratio (OR), 7.12; 95% confidence interval (CI), 6.42 to 7.91] and a three-fold higher risk of chronic TIL (OR, 4.58; 95% CI, 4.37 to 4.79).ConclusionsTILs were common in patients with biopsy-proven glomerular disease. The type and severity of TILs varied with age, region and concurrent glomerular diseases. Renal arteriole injury and glomerulosclerosis was associated with a significantly increased risk of TIL.

Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner.

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.