Tubulointerstitial Inflammation Research Articles

POS-449 Sirt6 activator, MDL-800, alleviates unilateral ureteral obstruction-induced renal fibrosis and inflammation by TGF-β/Smad signaling pathway

Tubulointerstitial inflammation and fibrosis are significant pathologic changes in progressive kidney disease, resulting in end-stage renal disease. These pathologic changes are complicated signaling pathways in the regulation of tissue homeostasis, including kidney injury and repair. Sirtuins are a family of NAD+-dependent class II histone deacetylase. Among them, Sirt6 is predominantly a nuclear protein and deacetylate diverse proteins such as H3K9, H3K56. Sirt6 regulates DNA repair, glucose and lipid metabolism, cellular senescence, and inflammation.

POS-386 EFFECT OF ANG-3070 IN THE UNILATERAL URETERAL OBSTRUCTION MOUSE MODEL OF RENAL FIBROSIS

Tubulointerstitial inflammation and fibrosis are strong predictors of progression in all kidney diseases regardless of etiology. Receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGFR) and discoidin domain receptors (DDRs) contribute to renal inflammation and fibrosis. ANG-3070 is an inhibitor of multiple tyrosine kinases receptors including PDGFR and DDR. This study evaluated whether ANG-3070 can slow the progression of fibrosis in the unilateral ureteral obstruction (UUO) mouse model of renal fibrosis.

POS-022 ACUTE TUBULO-INTERSTITIAL NEPHRITIS WITH EOSINOPHILS, SUSPECTED TO BE DRUG-INDUCED, AS SEEN ON NATIVE KIDNEY BIOPSIES: 10-YEAR EXPERIENCE FROM AN INDEPENDENT CENTRAL PATHOLOGY LABORATORY IN KENYA

Drug-induced acute tubulointerstitial nephritis (ATIN) is a well-recognised cause of unexplained AKI that can lead to CKD. The presence of eosinophils in the tubulo-interstitial inflammation associated with ATI is considered a hallmark of the diagnosis. There is scarcity of data on biopsy-proven drug-induced ATIN in Africa. The author set out to establish the extent of biopsy-proven drug-induced ATIN in native kidney biopsies a 10-year period from his experience at a pathology central referral laboratory that handles the highest number of kidney biopsies in the region. Histopathology reports in text form were searched for key words “tubulo-interstitial nephritis” and respective cases identified were further examined to confirm those that were acute or active tubule-interstitial nephritis with eosinophils present, which were deemed to be in keeping with a diagnosis of drug-induced acute tubulo-interstitial nephritis. Associated pathological findings present in the biopsies were also recorded. The results were tabulated and tallied on Excel spreadsheet to obtain the summary statistics. A total of 34 cases of suspected drug-induced ATIN were identified representing 3.2% of all native kidney biopsies in the 10-year period. The cases were reported in each year except for 2014, with 2011-2013 having a case each, 2015 had 4 cases, 2016 had 5 cases, while 2017-2019 had 6 cases each and 2020 had 4 cases. An equal gender distribution was noted with ½ the cases being males and ½ being females. The youngest patient was 15 years old and the oldest 69 years old, the mean age at 39.2 years and median of 40 years. The degree of inflammation and acute kidney injury was mild in 14 cases (41%), similarly moderate in 14 cases (41%) and severe in 6 cases (18%), while concurrent chronic kidney damage was minimal in 16 cases (47%), mild in 5 cases (15%), moderate in 12 cases (35%) and severe in 1 case (3%). All but 4 cases (12%) had an associated pathological diagnostic finding, of which the commonest associated pathological finding was hypertensive changes of benign nephrosclerosis in 6 cases (18%), membranous glomerulopathy 6 cases (18%), diabetic nephropathy 4 cases (12%), lupus nephritis 4 cases (12%), two cases each of AL amyloidosis, HIVAN and IgA nephropathy, and a case each of AA amyloidosis, primary FSGS, ascending infection and malignancy. The majority of biopsy-proven cases of drug-induced ATIN seen at this independent central laboratory in Kenya are associated with other renal pathologies on the same respective biopsies, and only 12% had no related renal pathologies on the biopsies thus only a minority of cases were 'purely' drug-induced ATIN as the primary pathology. The exact medication linked to the drug-induced ATIN was not indicated in the clinical details. Interestingly, none of the cases was actually clinically suspected pre-biopsy to be drug-induced ATIN. Although rare, biopsy-proven drug-induced ATIN is a significant cause of AKI, and based on this analysis, it appears that most cases of drug-induced ATIN compound or exacerbate other underlying renal pathologies with underlying hypertensive kidney disease, membranous nephropathy and diabetic nephropathy as the commonest associated pathologies. ATIN needs to be born in mind by nephrologists when working up patients for AKI, and also born in mind by pathologists when examining kidney biopsies.

POS-446 Loss of proximal tubular Sirtuin 6 aggravates unilateral ureteral obstruction-induced tubulointerstitial inflammation and fibrosis by regulation of β-catenin acetylation

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirt6 is a chromatin regulatory protein in the Sirtuin family of NAD+-dependent enzymes. Sirt6 has diverse roles in aging, metabolism, and disease. This study investigates the effect of proximal tubule-specific Sirt6 knock-down on unilateral ureteral obstruction-induced renal tubulointerstitial fibrosis.

Quercetin Alleviates Tubulointerstitial Inflammation by Inhibiting Exosomes-Mediated Crosstalk between Tubular Epithelial Cells and Macrophages

Quercetin Alleviates Tubulointerstitial Inflammation by Inhibiting Exosomes-Mediated Crosstalk between Tubular Epithelial Cells and Macrophages

Methyl Gallate Improves Hyperuricemia Nephropathy Mice Through Inhibiting NLRP3 Pathway.

Hyperuricemia nephropathy (HN) is a form of chronic tubulointerstitial inflammation, caused by the deposition of monosodium urate crystals (MSU) in the distal collecting duct and medullary interstitium, associated with a secondary inflammatory reaction. Numerous published reports indicated that NLRP3 inflammasome pathway play crucial roles in HN symptoms. The present study aims to investigate the protective effects of methyl gallate on HN mice and the underlying mechanisms. An HN model was established by intraperitoneal injection of potassium oxide (PO) to assess the effect of methyl gallate on renal histopathological changes, renal function, cytokine levels and expressions of NLRP3-related protein in HN mice. Moreover, in vitro models of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs) were established to explore the mechanism of methyl gallate on NLRP3 inflammasome activation. The results showed that methyl gallate significantly ameliorated HN by inhibiting uric acid production and promoting uric acid excretion as well as ameliorating renal injury induced by NLRP3 activation. Mechanistically, methyl gallate is a direct NLRP3 inhibitor that inhibits NLRP3 inflammasome activation but has no effect on the activation of AIM2 or NLRC4 inflammasomes in macrophages. Furthermore, methyl gallate inhibited the assembly of NLRP3 inflammasomes by blocking the ROS over-generation and oligomerization of NLRP3. Methyl gallate was also active ex vivo against ATP-treated PBMCs and synovial fluid mononuclear cells from patients with gout. In conclusion, methyl gallate has a nephroprotective effect against PO-induced HN through blocking the oligomerization of NLRP3 and then exerting anti-inflammatory activity in the NLRP3-driven diseases.

Intimal Arteritis and Microvascular Inflammation Are Associated With Inferior Kidney Graft Outcome, Regardless of Donor-Specific Antibodies.

Background: The prognostic role of intimal arteritis of kidney allografts in donor-specific antibody negative (DSA–) antibody-mediated rejection (ABMR) remains unclear.Methods: Seventy-two out of 881 patients who had undergone kidney transplantation from 2014 to 2017 exhibited intimal arteritis in biopsies performed during the first 12 months. In 26 DSA negative cases, the intimal arteritis was accompanied by tubulointerstitial inflammation as part of T cell-mediated vascular rejection (TCMRV, N = 26); intimal arteritis along with microvascular inflammation occurred in 29 DSA negative (ABMRV/DSA–) and 19 DSA positive cases (ABMRV, DSA+, N = 17). In 60 (83%) patients with intimal arteritis, the surveillance biopsies after antirejection therapy were performed. Hundred and two patients with non-vascular ABMR with DSA (ABMR/DSA+, N = 55) and without DSA (ABMR/DSA–, N = 47) served as controls. Time to transplant glomerulopathy (TG) and graft failure were the study endpoints.Results: Transplant glomerulopathy -free survival at 36 months was 100% in TCMRV, 85% in ABMR/DSA–, 65% in ABMRV/DSA-, 54% in ABMR/DSA+ and 31% in ABMRV/DSA+ (log rank p < 0.001). Death-censored graft survival at 36 months was 98% in ABMR/DSA-, 96% in TCMRV, 86% in ABMRV/DSA–, 79% in ABMR/DSA+, and 64% in ABMRV/DSA+ group (log rank p = 0.001). In surveillance biopsies, the resolution of rejection was found in 19 (90%) TCMRV, 14 (58%) ABMRV/DSA–, and only 4 (27%) ABMRV/DSA+ patients (p = 0.006). In the multivariable model, intimal arteritis as part of ABMR represented a significant risk for TG development (HR 2.1, 95% CI 1.2–3.8; p = 0.012) regardless of DSA status but not for graft failure at 36 months.Conclusions: Intimal arteritis as part of ABMR represented a risk for early development of TG regardless of the presence or absence of DSA. Intimal arteritis in DSA positive ABMR represented the high-risk phenotype.

Neutrophils associate with Bowman’s capsule rupture specifically in PR3-ANCA glomerulonephritis

BackgroundRenal involvement is a common and severe complication of ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (AAV) potentially resulting in a pauci-immune necrotizing and crescentic antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. We recently described that Bowman’s capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis. Herein we provide a comprehensive histological subtyping of immune cell infiltrates in association with Bowman’s capsule rupture in ANCA GN.MethodsA total of 44 kidney biopsies with ANCA GN were retrospectively included in a single-center observational study. Within a renal biopsy specimen, each glomerulus was scored separately for the presence of extensive and focal Bowman’s capsule rupture in injured glomeruli. Infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the area of total cortical inflammation.ResultsExtensive Bowman’s capsule rupture was associated with tubulointerstitial inflammation containing infiltrates of neutrophils, eosinophils and plasma cells. A similar association was observed for the presence of focal Bowman’s capsule rupture, correlating with tubulointerstitial inflammation containing neutrophils, eosinophils and plasma cells. Multiple logistic regression confirmed that extensive Bowman’s capsule rupture correlated with tubulointerstitial inflammation containing neutrophils, and focal Bowman’s capsule rupture correlated with neutrophil and plasma cell infiltration. Furthermore, this association was specifically observed in PR3-ANCA GN.ConclusionTo our knowledge, this is the first report linking Bowman’s capsule rupture directly to tubulointerstitial inflammation by immune cell subtypes. This underscores a pathomechanistic link between tubulointerstitial and glomerular lesions in ANCA GN and needs further investigation.Graphical abstract

Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy

BackgroundHypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs).ResultsIn murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4β1 and αLβ2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects.ConclusionThis synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.Graphical

Chinese Herbal Medicine Suyin Detoxification Granule Inhibits Pyroptosis and Epithelial-Mesenchymal Transition by Downregulating MAVS/NLRP3 to Alleviate Renal Injury

PurposeProteinuria is an independent risk factor of chronic kidney disease (CKD). Albumin-induced tubulointerstitial inflammation and epithelial-mesenchymal transition (EMT) via the activation of NLRP3 inflammasome is a potential therapeutic target for CKD. Suyin Detoxification Granule (SDG) improves proteinuria and postpones renal failure. However, the underlying mechanism is still unknown.MethodsFirstly, the rat model of renal failure was established using intragastric administration of adenine. Renal function, proteinuria, inflammatory indicators in serum, and renal pathology were assessed, and renal immunohistochemical staining of NLRP3 inflammasomes was performed after intervention with low and high concentrations of SDG. Secondly, the model of renal tubular epithelial HK-2 cells was established using albumin in vitro, and the cell viability, EMT phenotype, and the expression of proteins in the NLRP3 inflammasome signaling pathway were measured after the freeze-dried powder of Suyin Detoxification Prescription (SDP) and CY-09, which is a selective and direct NLRP3 inhibitor, were co-incubated with albumin. ATP, SOD, mitochondrial membrane potential, and ROS were further measured in vitro, and changes in the mitochondrial function after SDP intervention were observed. The mitochondrial antiviral signaling protein (MAVS) was knocked down using siRNA, and the interaction between MAVS and NLRP3 was verified using Western blotting, polymerase chain reaction (PCR), and immunofluorescence.ResultsSDG improved renal function and proteinuria, alleviated renal fibrosis, and reduced serum inflammation and the expression of the components of the NLRP3 inflammasome in the kidney. In vitro, SDP and CY-09 enhanced cell viability after injury with albumin and inhibited pyroptosis induced by the NLRP3 inflammatory signaling pathway and expression of proteins involved in EMT. It was further found that SDP alleviated the mitochondrial dysfunction caused by albumin. The knockdown of MAVS reduced the expression of NLRP3 pathway proteins and their mRNA levels and also weakened the co-localization of NLRP3, thus, reducing cell pyroptosis.ConclusionSDP protected renal tubular epithelial cells from cell pyroptosis and EMT by regulating the albumin-induced mitochondrial dysfunction/ MAVS/ NLRP3-ASC-caspase-1 inflammasome signaling pathway.

Urinary mRNA Signatures as Predictors of Renal Function Decline in Patients With Biopsy-Proven Diabetic Kidney Disease.

The clinical manifestations of diabetic kidney disease (DKD) are more heterogeneous than those previously reported, and these observations mandate the need for the recruitment of patients with biopsy-proven DKD in biomarker research. In this study, using the public gene expression omnibus (GEO) repository, we aimed to identify urinary mRNA biomarkers that can predict histological severity and disease progression in patients with DKD in whom the diagnosis and histologic grade has been confirmed by kidney biopsy. We identified 30 DKD-specific mRNA candidates based on the analysis of the GEO datasets. Among these, there were significant alterations in the urinary levels of 17 mRNAs in patients with DKD, compared with healthy controls. Four urinary mRNAs—LYZ, C3, FKBP5, and G6PC—reflected tubulointerstitial inflammation and fibrosis in kidney biopsy and could predict rapid progression to end-stage kidney disease independently of the baseline eGFR (tertile 1 vs. tertile 3; adjusted hazard ratio of 9.68 and 95% confidence interval of 2.85–32.87, p < 0.001). In conclusion, we demonstrated that urinary mRNA signatures have a potential to indicate the pathologic status and predict adverse renal outcomes in patients with DKD.

Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.

Protective effects of p-coumaric acid against gentamicin-induced nephrotoxicity in rats

The most important side effect of gentamicin (GM) is nephrotoxicity. p-Coumaric acid (PCA) is a phenolic compound that scavenges free radicals, reduces fibrosis, and tissue damage. This study investigates the protective effect of PCA on tissue damage and kidney function in gentamicin-induced nephrotoxicity (GIN). Thirty-five rats were separated into five groups and each group contained seven animals: control group, ethanol group, GM group, PCA group, and GM + PCA group. At the end of the seven-day treatment, the rats were sacrificed after blood and kidney tissue samples were taken. While serum urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) levels increased significantly in the GM group compared to the control, they showed a significant decrease in the GM + PCA group compared to the GM. Serum tumor necrosis factor-α (TNF-α) and tissue malondialdehyde (MDA) levels were significantly increased in the GM group compared to the control. While the tissue total oxidant status (TOS) and oxidative stress index (OSI) values of the GM group were significantly higher than the control, they showed a significant decrease in the GM + PCA group compared to the GM. In the histopathological examination, significant tubular necrosis and tubulointerstitial inflammation were detected in the proximal tubules in the GM group compared to the control, while a significant decrease was observed in the severity of these findings in the GM + PCA group compared to the GM. This study shows that PCA has biochemical and histopathological ameliorating effects on GIN in the rat model.

Dapagliflozin Induced Acute Tubulo-Interstitial Nephritis: A Case Report and Literature Review

We report a case of an elderly male patient, who presented with acute kidney injury on background of diabetic nephropathy, secondary to dapagliflozin induced acute tubulo-interstitial nephritis requiring hemodialysis sessions. Histopathological findings are consistent with moderate tubulo-interstitial inflammation with mixed lymphocytic and eosinophilic inflammatory deposits. The patient responded well to cessation of causative medication and upon initiation of high dose steroids. The direct cause and effect relationship between dapagliflozin initiation and development of acute tubulo-interstitial nephritis is indicative of dapagliflozin being responsible for marked renal deterioration, as seen in this patient.

Non-albumin proteinuria in lupus nephritis with tubulointerstitial inflammation and its clinical significance

Abstract Background Tubulointerstitial inflammation (TI) associated with systemic lupus erythematosis is an increasing finding in lupus nephritis. TI severity may have prognostic significance in the renal outcomes of lupus nephritis. Here, we aimed to determine whether non-albumin proteinuria is associated with TI severity and with the renal response in lupus nephritis. Objective To investigate the possible association between non-albumin proteinuria, tubulointerstial inflammation severity and poor renal response after immunosuppressive treatment. Patients and Methods This is a case series study which was conducted on 100 patients with systemic lupus erythematosis recruited from the outpatient clinic of Clinical Immunology at Ain Shams University Hospitals. Subject ages were between 13-53 years old, each one was subjected to detailed history, physical examination, laboratory investigations including serum creatinine before and after treatment, protein/creatinine ratio before and after treatment, albumin/creatinine ratio, ESR, CRP, CBC, C3 C4, anti DNA, eGFR and renal biopsy Results Our results showed that non-albumin proteinuria (uPCR − uACR) was significantly higher in patients with moderate-to-severe TI than in patients with no-tomild TI. Further, higher uPCR − uACR levels at baseline were associated with poor renal response after 6 months of treatment. Conclusion we found that non-albumin proteinuria (uPCR-uACR) is associated with severe tubulointerstitial inflammation (TI) in lupus nephritis.

Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI.

AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury

Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3′-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.

Nephrotic syndrome and acute kidney injury following CoronaVac anti-SARS-CoV-2 vaccine.

ABSTRACTA 67-year-old female with Type 2 diabetes mellitus developed nephrotic syndrome within 1 week of receiving the first dose of severe acute respiratory syndrome coronavirus 2 CoronaVac vaccine. A kidney biopsy was consistent with minimal change nephrotic syndrome and treatment was symptomatic with antiproteinuric therapy and improvement in proteinuria. Oedema returned within 1 week of the second dose of CoronaVac. On this occasion, acute kidney injury and massive proteinuria were noted. In kidney biopsy, glomeruli were normal, but tubulointerstitial inflammation consistent with acute tubulointerstitial nephritis was noted. Pulse followed by oral steroids was followed by recovery of kidney function. Proteinuria decreased after initiation of cyclosporine A.

Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy

BackgroundDiabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking.MethodsFourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ.ResultsThe number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model.ConclusionsUrinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.

Prediction of remodeling of arteries of kidneys of small diameter in patients with chronic glomerulonephritis

Objective: to determine the significance of clinical, laboratory and morphometric indicators of structural restructuring of kidney tissue in the prognosis of remodeling of small-diameter kidney arteries in patients with primary chronic glomerulonephritis. Materials and methods: the study included 97 patients with primary chronic glomerulonephritis and indications for puncture nephrobiopsy. In all patients, anamnestic and clinical and laboratory risk factors were recorded, and nephrobiopsy was performed. When performing morphometric analysis of nephrobiopsy, the state of the tissue and vessels of the kidneys of small diameter was studied. To achieve this goal, all patients were divided into two groups, the ranking of which was carried out according to the median wall thickness of the interlobular artery. Results: Among all the risk factors studied, a statistically significant effect of an increase in the stages of hypertension (χ2 criterion = 4.24, p = 0.03) and a decrease in GFR (χ2 criterion = 5.92, p = 0.015) on the risk of increasing the thickness of the interlobular artery was found. The indicators of structural reconstruction of the renal tissue did not have a statistically significant effect on the likelihood of remodeling of the arterial wall. However, a direct correlation of weak strength was found between the severity of tubulointerstitial inflammation and the thickness of the wall of the interlobular artery (r = 0.23, p = 0.02). Conclusions: this work shows the paramount importance of hypertension, accompanied by damage to target organs, as a marker of remodeling of the vascular wall of the interlobular artery in patients with chronic glomerulonephritis.