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Medicine May 2021To investigate the clinicopathological features and outcomes of primary IgA nephropathy with nephrotic-range proteinuria in Chinese children. Patients with biopsy-proven... (Observational Study)
Observational Study
To investigate the clinicopathological features and outcomes of primary IgA nephropathy with nephrotic-range proteinuria in Chinese children. Patients with biopsy-proven IgA nephropathy and nephrotic-range proteinuria between January 2011 and December 2017 were included, and their proteinuria and renal function were followed up. A total of 90 patients were enrolled, and 21.1% (19/90) of them had decreased renal function at diagnosis. Complete remission, partial remission, and no response of proteinuria occurred in 88.6% (70/79), 10.1% (8/79), and 1.3% (1/79), respectively, of the 79 patients who were followed up for 6 to 104 months. 73.7% (14/19) of the patients with decreased renal function at diagnosis recovered to normal level while 26.3% (5/19) of them did not recover or progressed to end-stage renal disease. Two patients with normal renal function at diagnosis progressed to renal insufficiency during follow-up period. By multivariate analysis, the risk for renal function deterioration was significantly higher in the partial remission and no response groups than in the complete remission group. Remission of proteinuria was important for improving renal prognosis in children with IgA nephropathy and nephrotic-range proteinuria. The outcomes for pediatric patients appeared to be better than that reported in adults.
Topics: Adolescent; Biopsy; Child; Child, Preschool; China; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Mesangium; Glomerulonephritis, IGA; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Proteinuria; Remission Induction; Retrospective Studies; Treatment Outcome
PubMed: 34032732
DOI: 10.1097/MD.0000000000026050 -
Clinical and Translational Medicine Feb 2021Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss...
BACKGROUND
Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models.
METHODS
This study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. Mice with cell-targeted overexpression of TIMP3 in myeloid cells (MacT3), podocyte-specific ADAM17 knockout mice (∆PodA17), and DBA/2J mice, were rendered diabetic at 8 weeks of age with a low-dose streptozotocin protocol. DBA/2J mice were administered new peptides based on the human TIMP3 N-terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24-hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid-shift staining, and Real Time-PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex.
RESULTS
Our results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4), and the improvement of podocyte structural markers such as WT1, nephrin, and podocin. Moreover, the positive effects were exerted through a mechanism independent from glycemic control.
CONCLUSIONS
In diabetic mice the targeting of TIMP3 system improved kidney structure and function, representing a valid approach to develop new avenues to treat this severe complication of diabetes.
Topics: Animals; Antibiotics, Antineoplastic; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Gene Expression; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Streptozocin; Tissue Inhibitor of Metalloproteinase-3
PubMed: 33634991
DOI: 10.1002/ctm2.305 -
Lupus Science & Medicine Dec 2023This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN).
OBJECTIVE
This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN).
METHODS
EXT1 was detected in 67 renal tissues of M-type phospholipase A2 receptor (PLA2R)-negative and ANA-positive membranous nephropathy by immunohistochemistry, and cases were divided into confirmed LMN and suspected LMN. The clinicopathological data were compared among the above groups, as well as EXT1-positive group and EXT1-negative group.
RESULTS
Twenty-two cases (73.3%) of confirmed LMN and six cases (16.2%) of suspected LMN exhibited EXT1 expression on the glomerular basement membrane and/or mesangium area, showing a significant difference (p<0.001). Concurrently, lupus nephritis (LN) of pure class V demonstrated a lower frequency of EXT1 positivity compared with mixed class V LN in the confirmed LMN group (31.8% vs 68.2%, p=0.007). EXT1-positive patients in the confirmed and suspected LMN group showed significant differences in some clinicopathological data comparing with EXT1-negative patients (p<0.05). Follow-up data revealed that a greater proportion of patients in the EXT1-positive group achieved complete remission post-treatment (p<0.05). Cox regression analysis showed that EXT1 positivity was significantly correlated with complete remission across the entire study cohort (HR 5.647; 95% CI, 1.323 to 12.048; p=0.019). Kaplan-Meier analysis indicated that the EXT1-positive group had a higher rate of accumulated nephrotic remission compared with the EXT1-negative group in the whole study cohort (p=0.028).
CONCLUSIONS
The EXT1-positive group exhibited a higher active index and a more favourable renal outcome than the EXT1-negative group. It would be better to recognise suspected LMN with EXT1 positivity as a potential autoimmune disease and maintain close follow-up due to its similarities with confirmed LMN.
Topics: Humans; Clinical Relevance; Glomerulonephritis, Membranous; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis
PubMed: 38154829
DOI: 10.1136/lupus-2023-001051 -
Cell Reports Feb 2024Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional...
Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional segments of the kidney, interactions of epithelial and interstitial cells are required. Here we describe a selective differentiation of renal interstitial progenitor-like cells (IPLCs) from human induced pluripotent stem cells (hiPSCs) by modifying our previous induction method for nephron progenitor cells (NPCs) and analyzing mouse embryonic interstitial progenitor cell (IPC) development. Our IPLCs combined with hiPSC-derived NPCs and nephric duct cells form nephrogenic niche- and mesangium-like structures in vitro. Furthermore, we successfully induce hiPSC-derived IPLCs to differentiate into mesangial and erythropoietin-producing cell lineages in vitro by screening differentiation-inducing factors and confirm that p38 MAPK, hypoxia, and VEGF signaling pathways are involved in the differentiation of mesangial-lineage cells. These findings indicate that our IPC-lineage induction method contributes to kidney regeneration and developmental research.
Topics: Humans; Animals; Mice; Induced Pluripotent Stem Cells; Kidney; Cell Lineage; Regeneration; Erythropoietin
PubMed: 38237600
DOI: 10.1016/j.celrep.2023.113602 -
Renal Failure Nov 2020Immunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. Complement activation is involved in the...
BACKGROUND
Immunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. Complement activation is involved in the disease. However, the clinical significance of C4 deposition in IgAN is obscure.
METHODS
A multicenter retrospective study was conducted in biopsy-proven IgAN patients. Based on mesangial C4 deposition, patients were divided into two groups. The baseline clinical data and immunopathological phenotypes were compared. The composite endpoint was defined as eGFR decline greater than 50%, doubling of baseline serum creatinine, the occurrence of end-stage renal disease (ESRD).
RESULTS
A total of 642 IgAN patients were recruited, with 41 patients showing mesangial C4 deposition. The mesangial C4 positive group showed lower serum albumin, higher proteinuria, and a higher rate of IgG, IgM, and C1q mesangial deposition. After a median follow-up of 43.18 months, 81 (12.62%) patients achieved the composite endpoint. The multivariate Cox regression models identified glomerular C4 deposition (hazard ratios [HR] = 3.22, 95% confidence intervals [CI] = 1.51-6.87, < 0.01), global sclerosis (G1 vs. G0, HR = 1.90, 95%CI = 1.02-3.52, = 0.04; G2 vs. G0, HR = 3.72, 95%CI = 1.98-7.00, < 0.01), male (HR = 1.80, 95%CI = 1.10-2.97, = 0.02), serum creatinine (HR = 1.01, 95%CI = 1.00-1.01, < 0.01), triglyceride (HR = 1.17, 95%CI = 1.01-1.35, = 0.04), proteinuria (HR = 1.07, 95%CI = 1.01-1.13, = 0.02), serum C3 level (HR = 0.05, 95%CI = 0.01-0.25, < 0.01), and serum C4 level (HR = 99.59, 95%CI = 8.69-1140.89, < 0.01) as independent risk factors for poor renal outcomes.
CONCLUSIONS
Glomerular mesangial C4 deposition and global sclerosis are independent predictors for poor prognosis in IgAN patients.
Topics: Adult; China; Complement C4; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Prognosis; Proportional Hazards Models; Proteinuria; Retrospective Studies; Risk Factors
PubMed: 32660366
DOI: 10.1080/0886022X.2020.1786400 -
BMC Nephrology Oct 2022Immunoglobulin A dominant postinfectious glomerulonephritis (IgA PIGN) is a unique medical entity that is rare in the paediatric population. It usually presents with...
BACKGROUND
Immunoglobulin A dominant postinfectious glomerulonephritis (IgA PIGN) is a unique medical entity that is rare in the paediatric population. It usually presents with severe renal failure, heavy proteinuria, hypertension, and hypocomplementemia and frequently has an unfavourable prognosis. IgA PIGN generally occurs in association with staphylococcal infections and diabetes mellitus in adult patients. Other pathogens include Escherichia coli and Streptococcus sp. Immunofluorescence studies of kidney biopsy samples show IgA as dominant or codominant antibody.
CASE PRESENTATION
We encountered a 3-year-old girl with IgA PIGN presenting with acute renal failure, oedema, hypertension, and heavy proteinuria of 7955 mg/g creatinine. Renal biopsy specimens showed diffuse glomerular endocapillary hypercellularity with prominent neutrophil and monocyte infiltration on light microscopy. Strong deposits of IgA and C were observed along the glomerular basement membranes and the mesangium by immunofluorescence microscopy, and electron microscopy revealed the presence of subepithelial humps. The patient was managed with steroid (and probatory antibiotic) therapy and is now undergoing follow-up, with a significant improvement 6 months after the initial presentation (glomerular filtration rate (GFR) and cystatin C clearance rate of 165 ml/min/1.73m and 106 ml/min/1.73m, respectively). No signs of bacterial infection were detectable.
CONCLUSION
This variant of IgA PIGN must be distinguished from other clinical entities, especially IgA nephropathy (mesangial IgA deposits) and postinfectious glomerulonephritis (C3, IgG and occasional IgM capillary loop deposits with or without mesangial distribution), since patients with IgA PIGN may require steroid treatment in addition to antibiotic therapy. Differential diagnosis should also include C glomerulopathy. IgA PIGN is a recently identified disease entity that generally manifests in adult patients with both IgA and C3 mesangial and glomerular capillary wall deposits. We present a biopsy-proven case of IgA PIGN that manifested in a patient at an exceptionally young age and that has had a good clinical outcome. To the best of our knowledge, this is the youngest IgA PIGN patient reported thus far.
Topics: Adult; Anti-Bacterial Agents; Biopsy; Child; Child, Preschool; Creatinine; Cystatin C; Female; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Hypertension; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Proteinuria; Staphylococcal Infections
PubMed: 36253737
DOI: 10.1186/s12882-022-02965-7 -
Cureus Oct 2021Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular...
Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular tissue resulting in damage to the basement membrane, mesangium, or capillary endothelium. Two of the most well-known manifestations of glomerulonephritis are granulomatosis with polyangiitis (GPA) and IgA nephropathy (IgAN). To our knowledge, these diseases are often found separately and are rarely diagnosed in the same patient. Here, we discuss a case of a 35-year-old male who presented and was diagnosed with simultaneous GPA and IgAN. His renal biopsy was significant for extensive, crescentic, and necrotizing glomerulonephritis and IgA staining on immunofluorescence indicating severe renal damage. Despite full immunosuppressive therapy, our patient failed to recover his renal function. In our case, we hope to raise awareness of these disorders and early recognition of the clinical features. We believe that this case would prompt providers to pursue diagnostic workups to detect these diseases early on, especially when symptoms progressively worsen and become systemic. As demonstrated in our patient, delay in diagnosis can lead to irreversible damage to a patient's renal function, especially when two types of glomerulonephritis are present.
PubMed: 34786253
DOI: 10.7759/cureus.18672 -
Frontiers in Immunology 2023Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like...
Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like syndromes and severe pyogenic infections. Among these, complete C1s deficiency has been reported in nine cases so far. Here, we describe a 34-year-old male patient who presented with severe, recurrent infections since childhood, including meningitides with pneumococci and meningococci, erysipelas, subcutaneous abscess, and recurrent infections of the upper airways. The patient also exhibited adult-onset SLE, meeting 7/11 of the ACR criteria and 34 of the 2019 EULAR/ACR classification criteria, along with class IV-G (A) proliferative lupus nephritis (LN). A screening of the complement cascade showed immeasurably low CH50, while the alternative pathway (AP) function was normal. Subsequent determination of complement components revealed undetectable C1s with low levels of C1r and C1q, normal C3, and slightly elevated C4 and C2 concentrations. The patient had no anti-C1q antibodies. Renal biopsy showed class IV-G (A) LN with complement C1q positivity along the glomerular basement membranes (GBMs) and weak deposition of IgG, IgM, and complement C3 and C4 in the mesangium and GBM. In an ELISA-based functional assay determining C4d deposition, the patient's absent complement activity was fully restored by adding C1s. The genome of the patient was analyzed by whole genome sequencing showing two truncating variants in the gene. One mutation was located at nucleotide 514 in exon 5, caused by a nucleotide substitution from G to T, resulting in a nonsense mutation from Gly172 (p.Gly172*). The other mutation was located at nucleotide 750 in exon 7, where C was replaced by a G, resulting in a nonsense mutation from Tyr250 (p.Tyr250*). Both mutations create a premature stop codon and have not previously been reported in the literature. These genetic findings, combined with the absence of C1s in the circulation, strongly suggest a compound heterozygote C1s deficiency in our patient, without additional defect within the complement cascade. As in a previous C1s deficiency case, the patient responded well to rituximab. The present case highlights unanswered questions regarding the CP's role in SLE etiopathogenesis.
Topics: Adult; Humans; Male; Codon, Nonsense; Complement C1q; Complement C1s; Hereditary Complement Deficiency Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Nucleotides; Reinfection
PubMed: 38469558
DOI: 10.3389/fimmu.2023.1257525 -
Experimental and Therapeutic Medicine Dec 2020Collagen type III is commonly detected in the renal interstitium and vasculature; however, it is absent in healthy glomeruli. Deposition of collagen type III in the...
Collagen type III is commonly detected in the renal interstitium and vasculature; however, it is absent in healthy glomeruli. Deposition of collagen type III in the glomerular mesangium and capillary basement membranes may arise in two rare diseases, namely collagen type III glomerulopathy (CG) and nail patella syndrome. CG is a rare glomerular disease with no specific treatment, although supportive measures for control of hypertension and edema may help to relieve symptoms. With progression to end-stage renal disease, patients with CG may come to require dialysis and/or renal transplantation. The present study reported on a 59-year-old male who was diagnosed with CG nephrotic syndrome by immunohistochemical and electron microscopic examination of biopsy material. To the best of our knowledge, this is the first case reported in northeastern China. The angiotensin II blocker telmisartan was successfully used to alleviate renal symptoms and a literature review was performed. The present case supports the use of telmisartan as a first choice of treatment for CG.
PubMed: 33093878
DOI: 10.3892/etm.2020.9269 -
Bioengineered Mar 2022Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on...
Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on renal tubular epithelial cells were observed under the condition of CIH. Pyroptosis is a programmed mode of cell death following cell apoptosis and cell necrosis, which is mediated by NLRP3 signaling. The present study aims to investigate the effects of CIH on the pyroptosis of renal tubular epithelial cells and the underlying mechanism. Firstly, CIH was induced in two renal tubular epithelial cell lines, HK-2 cells and TCMK-1 cells. As the aggravation of hypoxia, an increasing trend of elevated apoptotic rate was observed in HK-2 cells and TCMK-1 cells, accompanied by the excessive release of ROS and LDH, and upregulation of NLRP3. Subsequently, the CIH model was established on rats. The pathological analysis results indicated that in CIH rats, the glomerular bottom membrane and mesangium were slightly thickened and edema was observed in the renal tubule epithelium. More serious injury was observed in the moderate intermittent hypoxia group. The expression level of IL-1β and IL-18 was promoted as the aggravation of hypoxia, accompanied by the elevated production of LDH and ROS. The expression level of cleaved Caspase-1, Caspase-1, GSDMD, TLR4, MyD88, NF-κB, p-NF-κB, and NLRP3 was found significantly upregulated as the aggravation of hypoxia. Lastly, the pathological changes in rats induced by CIH were dramatically abolished by MCC950, a specific inhibitor of NLRP3. Collectively, CIH triggered the pyroptosis of renal tubular epithelial cells by activating the NLRP3 inflammasome.
Topics: Animals; Caspases; Epithelial Cells; Hypoxia; Inflammasomes; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Reactive Oxygen Species; Sleep Apnea, Obstructive
PubMed: 35263214
DOI: 10.1080/21655979.2022.2047394