Renal Biopsy Research Articles

Caseous Calcification of the Mitral Annulus: Calcified Toothpaste of the Heart.

Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification (MAC) usually described as an antemortem finding. We report a case of sudden cardiac arrest in a 39-year-old male with end-stage renal disease undergoing hemodialysis with a history of Fabry disease by kidney biopsy. Autopsy revealed significant circumferential annular calcification in both mitral and aortic valves with a caseous gross appearance. Histologically, these areas consisted of amorphous basophilic material accompanied by a surrounding granulomatous-appearing infiltrate. Von Kossa staining on non-decalcified tissue revealed strong positive staining, confirming CCMA diagnosis. While identifiable, the atrioventricular node was displaced and distorted by caseous deposits. Toluidine blue staining of myocardium showed osmophilic accumulations, and electron microscopy (EM) showed myeloid/zebra bodies, consistent with Fabry disease. We posit that Fabry disease leads to end-stage kidney disease, altering calcium phosphate metabolism, a proposed mechanism for CCMA. This case highlights the multifactorial nature of sudden cardiac death in decedents with various structural cardiac changes and potential renal-disease-induced electrolyte imbalances. We aim to bring awareness to this rare entity, its potential role in a sudden cardiac death, and to highlight the need to use non-decalcified tissue when staining for calcium to establish the diagnosis.

Impact of non-alcoholic fatty liver disease and fibrosis on mortality and kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A multi-cohort longitudinal study.

To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.

Autosomal-dominant tubulointerstitial kidney disease with a novel UMOD mutation, overlapping with Sjogren's syndrome: a case report.

Autosomal-dominant tubulointerstitial kidney disease caused by UMOD (encoding uromodulin) mutation (ADTKD-UMOD) is a rare hereditary disease. A strong family history of hyperuricemia or gout and inherited kidney disease raises the suspicion of ADTKD-UMOD. Genetic testing can confirm the diagnosis without a kidney biopsy. However, when complicated by other diseases that can cause tubulointerstitial disease, renal biopsy is indispensable for the diagnosis and decisions on treatment strategy. We report the case of a 44-year-old woman referred for evaluation of kidney dysfunction. She had an attack of gout 1month before referral and a family history of hyperuricemia. She was diagnosed with primary Sjogren's syndrome through an immune workup and ophthalmological examination. However, a kidney biopsy revealed histological features suggesting ADTKD rather than gouty kidney or tubulointerstitial nephritis associated with Sjogren's syndrome, and immunostaining revealed a characteristic staining pattern with UMOD. Comprehensive genetic testing of 93 genes responsible for polycystic kidney disease revealed a novel heterozygous missense variant (c.649T > A:p. Cys217Ser) in UMOD, and the patient was diagnosed with ADTKD-UMOD. In this case, kidney biopsy contributed to the correct diagnosis of tubulointerstitial kidney disease. This case emphasizes the importance of suspecting ADTKD-UMOD based on family history and careful evaluation of kidney biopsy findings.

Activation of the inflammasome and pyroptosis cascade in podocytes of patients with minimal change disease

Abstract Background In contrast to childhood minimal change disease (MCD), adult-onset MCD frequently recurs and requires prolonged immunosuppressive therapy. Accordingly, an investigation of the pathogenesis of adult MCD is required. MCD is usually accompanied by severe dyslipidaemia. Oxidized low-density lipoprotein (ox-LDL) is known to function in a damage-associated molecular pattern (DAMP) through CD36, triggering the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and programmed cell death called pyroptosis. However, the relationship between MCD pathogenesis and NLRP3 inflammasome/pyroptosis activation via CD36 is not fully understood. Methods We conducted comprehensive histological and clinical evaluations by analyzing renal biopsy (RBx) specimens and urine samples obtained from 26 patients with MCD. These samples were compared to control kidneys from 15 transplant donors and urine samples from 15 healthy volunteers. Results The number of podocytes was lower in the MCD group than in the control group. Urinary ox-LDL levels were higher in the MCD group than in the control group. Immunofluorescence staining revealed that NLRP3 and CD36 were upregulated in MCD podocytes. Urinary interleukin (IL)-18 levels increased in patients with MCD. Steroid therapy performed before RBx appeared to maintain the podocyte number and reduce urinary ox-LDL and IL-18 levels. Conclusion In MCD, the NLRP3 inflammasome and pyroptosis cascade seem to be activated via upregulation of CD36 in podocytes, associated with increased urinary ox-LDL. Elevated urinary IL-18 levels suggest that pyroptosis may occur in MCD. Further research is required to confirm the significance of the podocyte NLRP3 inflammasome/pyroptosis in MCD.

Concomitant Histological Features of Membranous Nephropathy and Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis

The simultaneous occurrence of vasculitic glomerulonephritis and membranous nephropathy is unusual. We report two cases that presented to our outpatient department with rapidly progressive renal failure. On evaluation, in one patient, anti-myeloperoxidase (MPO) titers were high, and renal biopsy was suggestive of concurrent necrotizing and diffuse crescentic anti-MPO anti-neutrophil cytoplasmic antigen-associated glomerulonephritis with the circumferential cellular crescent formation and membranous glomerulopathy. He responded to plasmapheresis followed by maintenance immunosuppression with oral cyclophosphomide. Another patient was treated with Methylprednisolone and two doses of rituximab. Both the patients showed marked symptomatic improvement and became dialysis independent with stable creatinine at 3 months.

Outcomes of Covid-19 Vaccine-Associated Glomerular Diseases (CVAGD) – A Case Series from India

Background Several cases of glomerular diseases following Covid-19 vaccination, especially mRNA vaccines, have been reported. However, there is little data on glomerular diseases associated with the two vaccines widely available in India (Covaxin and Covishield) and their long-term outcomes. Materials and Methods This was a prospective observational study conducted between May 2021 and May 2023. Patients with new-onset or relapse of proteinuria, hematuria, or renal failure within 30 days of Covid-19 vaccination were included. Data on pre-existing renal disease, vaccine type, symptomatology, laboratory reports, kidney biopsy findings, and treatment details were collected. The clinical course and long-term renal outcomes were studied. Results Sixteen patients with Covid-19 vaccine associated glomerular disease (CVAGD) were studied. The median age was 28 years (IQR 20.5–40) and median time of symptom onset was 14 days (IQR 10–16.5) after vaccination. Renal syndromes at presentation were nephrotic syndrome in seven patients (43.75%), nephritic syndrome in seven patients (43.75%), and rapidly progressive renal failure in two patients (12.5%). Kidney biopsy revealed minimal change disease in five patients (31.2%); IgA nephropathy in four patients (25%); C3 glomerulopathy, lupus nephritis, and focal segmental glomerulosclerosis in two patients each (12.5%); and pauci-immune glomerulonephritis (ANCA-associated vasculitis) in one patient (6.25%). Eleven patients were treated with immunosuppressive drugs. Median duration of follow-up was 20 months (IQR 18–21). At last follow-up, 11 patients had complete recovery of renal failure and proteinuria and 4 patients had partial recovery. Conclusion The most common lesions in this series were minimal change disease and IgA nephropathy. The overall long-term outcome of CVAGD appears good.

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the REN (renin)-angiotensin system. Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. Exome sequencing for a gene panel associated with renal disease was performed. The REN-angiotensin system was assessed by comprehensive biochemical analysis in blood. REN expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma REN concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of REN. Angiotensin II and aldosterone in blood were not abnormally elevated. Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the renin-angiotensin system in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of REN in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).

Anti-C5 monoclonal antibody treatment showing pathological resolution of complement-mediated atypical hemolytic uremic syndrome: a case report

BackgroundNo reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies.Case presentationA 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening.ConclusionsThis is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.

Signal Regulatory Protein α Expression in Systemic Vasculitis.

Signal regulatory protein α (SIRPα) is found primarily on myeloid cells, including macrophages and neutrophils; binds to CD47; and regulates phagocytosis, antigen presentation, cellular fusion, cell proliferation, and migration. Therefore, SIRPα may be involved in the pathogenesis of autoimmune diseases, including systemic vasculitis. This study aimed to assess SIRPα expression in tissue samples from patients with vasculitis. Immunohistochemical staining for SIRPα was performed on temporal artery (TA), kidney, and lung biopsy samples from patients with giant cell arteritis (GCA), patients with microscopic polyangiitis (MPA), patients with granulomatosis with polyangiitis (GPA), and patients without vasculitis. A score of SIRPα+ expression was calculated, derived from the percentages of monocytes, macrophages, and dendritic cells and neutrophils with different staining intensities in affected tissues. A total of 46 samples from patients with different vasculitides (GCA, MPA, and GPA) were included in the study. Tissue samples included TA samples from 15 patients with GCA; kidney samples from 11 and 9 patients with GPA and MPA, respectively; and lung samples from 11 patients with GPA. Most tissue samples from patients with active vasculitis (15 of 15 TA samples, 17 of 20 kidney samples, and 9 of 11 lung samples) showed SIRPα staining. SIRPα staining intensity was less in kidney samples compared to TA and lung samples. This study demonstrates high-level expression of SIRPα in macrophages and monocytes in affected tissue in systemic vasculitis. These findings provide a foundation for further studies exploring the role of the SIRPα-CD47 pathway in the pathogenesis of systemic vasculitis and the potential for the blockade of SIRPα and/or the depletion of SIRPα+ cells as treatment of systemic vasculitis.

Diagnosis and treatment of secondary nephrotic syndrome with rash as the first symptom: a case report

BackgroundMembranous nephropathy (MN) is a common type of nephrotic syndrome (NS) in adults, accounting for about 20–30% of cases. Although secondary to specific factors, the coexistence of MN and mantle cell lymphoma (MCL) has been scarcely reported in clinical literature.Case presentationA 59-year-old Chinese male was admitted to the hospital with a generalized pruritic rash with bilateral lower extremity edema, which did not improve significantly after symptomatic treatment. He had undergone renal biopsy, and the diagnosis was thought to be secondary MN (SMN), therefore, we did a lymph node biopsy on the patient and found that MN was complicated with MCL. Soon after, the patient was admitted to the hematology department for a BR chemotherapy regimen (composed of bendamustine 90 mg/m2 BSA (body surface area), rituximab 375 mg/m2 BSA and dexamethasone 5 mg), and during the post-treatment follow-up, both his symptoms and renal function improved.ConclusionsThe mechanism underlying the combination of SMN and MCL remains elusive and exceedingly rare, consequently often overlooked in clinical practice. This case serves to offer valuable clinical insights for diagnosis and treatment, while emphasizing the pivotal role of renal pathology in clinical assessment.

Avacopan for anti-neutrophil cytoplasm antibodies-associated vasculitis: a multicenter real-world study.

Avacopan, a selective C5aR1 inhibitor, recently emerged as a glucocorticoid (GCs) sparing agent in ANCA-associated vasculitis (AAV). We aim to evaluate the tolerance and efficacy of avacopan given outside randomized clinical trials or with severe kidney involvement. In this multicentre retrospective study, we reviewed the clinical charts of patients with AAV and contraindication to high dose of GCs who received avacopan 30 mg b.i.d plus standard-of-care regimen owing to the French early access program between 2020 and 2023. Efficacy and safety data were recorded using a standardized case report form. Among the 31 patients (median age 72 years), 10 had a relapsing AAV, twenty had anti-myeloperoxidase antibodies, and thirty had kidney vasculitis. Induction regimen included rituximab (n = 27), cyclophosphamide (n = 2), or both (n = 2). Five patients did not receive GCs. Despite rapid GCs tapering (which were withdrawn in 23 patients before month 3), 25 patients (81%) had a favorable outcome and no severe adverse event. The estimated glomerular filtration rate increased from 19 [15; 34] to 35 mL/min/1.73m2 [23; 45] at month 12 (p< 0.05), independently of kidney biopsies findings. One patient developed refractory AAV and two had a relapse while receiving avacopan. At month 12, ANCA remained positive in 10/18 patients (55.5%). Two patients developed severe adverse events leading to a withdrawal of avacopan (hepatitis and age-related macular degeneration). The GCs' sparing effect of avacopan was confirmed, even in patients with severe kidney vasculitis, but further studies are required to identify the optimal dosing of GCs when avacopan is used.

Sonological predictors of complications of percutaneous renal biopsy-a prospective observational study.

This was a prospective study done from April 2022 to April 2023 on all adult patients undergoing native or transplant kidney biopsy. Baseline clinical, laboratory and renal sonological parameters were noted prior to biopsy. USG-guided renal biopsy was done and any haematoma at 0h, 12h and 24h post-biopsy noted. Biopsy complications including need for any interventions were noted. Out of the 240 patients enrolled in the study, 58.3% experienced post-biopsy complications. Among these, 5% of patients encountered major complications, with 3.33% necessitating medical intervention following renal biopsy procedures. A high percentage, 98.89%, exhibited hematoma formation within 12h post-biopsy. Furthermore, our analysis revealed that a hematoma size exceeding 1.2cm at the 12-h mark exhibited a sensitivity of 100% and specificity of 71% in predicting the need for blood transfusion. Renal parenchymal changes were the most reliable sonological parameters for predicting post-biopsy complication on multivariate analysis. The incidence of major complications requiring interventions following renal biopsy is notably low. Our study highlights the significance of renal sonological characteristics, including parenchymal thickness, cortical thickness and parenchymal changes, in predicting these complications. Furthermore, we emphasize the utility of hematoma surveillance immediately post-biopsy and at the 12h, as a valuable tool for predicting the necessity of post-biopsy interventions. This approach can aid in efficiently triaging patients and determining the need for further observation post-renal biopsy.

Influenza vaccination-associated cryoglobulinemic vasculitis.

Mixed cryoglobulinemia is a small vessel vasculitis associated with viral infections, mainly hepatitis C virus, however, other important causes include lymphoproliferative and autoimmune disorders. Influenza vaccine-induced cryoglobulinemia has been rarely reported. A 68-year-old male presented on three occasions following influenza vaccination with purpuric rash and lower extremities swelling. His lab work showed mixed cryoglobulins. On his most recent presentation, in addition to the purpura, he presented with thrombocytopenia and nephritic syndrome. A kidney biopsy showed endocapillary proliferative glomerulonephritis with organized deposits, consistent with mixed type cryoglobulinemic glomerulonephritis. The patient was treated with rituximab infusion with progressive improvement of the acute kidney injury (AKI) and complete recovery. It is unclear why cryoglobulins are produced as a response to a vaccination, but this association is important to be aware of for prompt monitoring and treatment.

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

BackgroundProteinuria is a prevalent symptom of pediatric nephrology, while kidney biopsy remains the gold standard for kidney tissue analysis, and it is currently controversial. We report the rare case that the mutation in the AMN gene was considered to cause chronically isolated proteinuria and also suggest that renal biopsy should be chosen with caution in children with chronic isolated non-nephrotic levels of proteinuria and that genetic testing may be feasible for the early precise diagnosis.Case presentationA 35-month-old boy presented with excessive urine foaming for more than half a month; his proteinuria was considered non-nephrotic range and urine protein electrophoresis was suggestive of mixed proteinuria; other than that, the investigations are non-specific. Given the child’s chronic isolated proteinuria and good renal function, we chose to refine the genetic test rather than a renal biopsy; a compound heterozygous variant was found in the AMN gene of this child which was caused by a point mutation in the father, and a partial chromosomal deletion in the mother.ConclusionsCubilin(encoded by CUBN), amnionless(encoded by AMN), and megalin form a multiligand receptor complex; CUBN or AMN gene variants have been implicated as a hereditary cause of megaloblastic anemia, proteinuria, and neurological impairment. In the past few decades, chronic isolated proteinuria caused by CUBN gene variants is benign, non-progressive, and has normal renal function. However, the child is the first reported case of isolated proteinuria of AMN gene mutation, indicating that the earlier diagnostic genetic sequencing in an otherwise well, not nephrotic proteinuria child may be a convenient, cost-effective, and harmless option, challenging the traditional paradigm.

Elevated polyclonal IgG4 mimicking a monoclonal gammopathy in IgG4-related disease-a case-based review.

IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the β and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.

Clinicopathological phenotype and outcomes of NCAM-1+ membranous lupus nephritis.

No studies explored the long-term outcomes of neural cell adhesion molecule 1 (NCAM1) associated membranous lupus nephritis (MLN) patients. We performed immunohistochemical studies on kidney biopsy specimens against NCAM1 in consecutive MLN patients. The clinical and histopathological characteristics and outcomes of cases of NCAM1 associated MLN patients are described and compared with NCAM1 negative patients. In addition, we detected serum circulating anti-NCAM1 antibodies through western blotting and indirect immunofluorescence assays. Among 361 MLN cases, 18 (5.0%) were glomerular NCAM1-positive. NCAM1 positive MLN patients were older [35 years (IQR 27-43) versus 28 (22-37); P=0.050) and had lower systemic lupus erythematosus disease activity index [11 (IQR 8-12) versus 14 (10-18); P=0.007], serum creatinine [60 μmol/L (IQR 50-70) versus 70 (54-114); P=0.029], activity index [3 (IQR 2-6) versus 6 (3-9); P=0.045] at kidney biopsy compared with NCAM1 negative patients. The percentage of positive anti-Sjogren's syndrome related antigen A antibodies in NCAM1 positive patients was significantly greater (83.3% versus 58.2%; P=0.035) than in the NCAM1 negative patients. However, no evidence of neuropsychiatric disorders was found in these 18 patients. There were no significant differences in the treatment response and the risk of end stage renal diseases between NCAM1 positive and negative groups (P=0.668 and P=0.318, respectively). But the risk of death was much higher in the NCAM1 positive group than the NCAM1 negative group (27.8%vs. 8.1%, P=0.007). Moreover, the risk of death was also much higher in the NCAM1 positive group than the matched NCAM1 negative group (Log-rank P=0.013). Additionally, circulating anti-NCAM1 antibodies can be detected in 1/5 (20%) patients who had serum available. The prevalence of NCAM1 positivity was 5.0% in our cohort of MLN and the high mortality in these subgroup patients are needed to validate in future studies.

The ANGPTL4-HIF-1α loop: a critical regulator of renal interstitial fibrosis

BackgroundRenal interstitial fibrosis (RIF) is a progressive, irreversible terminal kidney disease with a poor prognosis and high mortality. Angiopoietin-like 4 (ANGPTL4) is known to be associated with fibrosis in various organs, but its impact on the RIF process remains unclear. This study aimed to elucidate the role and underlying mechanisms of ANGPTL4 in the progression of RIF.MethodsIn vivo, a chronic kidney disease (CKD) rat model of renal interstitial fibrosis was established via intragastric administration of adenine at different time points (4 and 6 weeks). Blood and urine samples were collected to assess renal function and 24-h urinary protein levels. Kidney tissues were subjected to HE and Masson staining for pathological observation. Immunohistochemistry and real-time quantitative PCR (qRT‒PCR) were performed to evaluate the expression of ANGPTL4 and hypoxia-inducible factor-1α (HIF-1α), followed by Pearson correlation analysis. Subsequently, kidney biopsy tissues from 11 CKD patients (6 with RIF and 5 without RIF) were subjected to immunohistochemical staining to validate the expression of ANGPTL4. In vitro, a fibrosis model of human renal tubular epithelial cells (HK2) was established through hypoxic stimulation. Subsequently, an HIF-1α inhibitor (2-MeOE2) was used, and ANGPTL4 was manipulated using siRNA or plasmid overexpression. Changes in ANGPTL4 and fibrosis markers were analyzed through Western blotting, qRT‒PCR, and immunofluorescence.ResultsANGPTL4 was significantly upregulated in the CKD rat model and was significantly positively correlated with renal injury markers, the fibrotic area, and HIF-1α. These results were confirmed by clinical samples, which showed a significant increase in the expression level of ANGPTL4 in CKD patients with RIF, which was positively correlated with HIF-1α. Further in vitro studies indicated that the expression of ANGPTL4 is regulated by HIF-1α, which in turn is subject to negative feedback regulation by ANGPTL4. Moreover, modulation of ANGPTL4 expression influences the progression of fibrosis in HK2 cells.ConclusionOur findings indicate that ANGPTL4 is a key regulatory factor in renal fibrosis, forming a loop with HIF-1α, potentially serving as a novel therapeutic target for RIF.

Antibody Mediated Rejection and T-cell Mediated Rejection Molecular Signatures Using Next-Generation Sequencing in Kidney Transplant Biopsies

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing.

A case of Fanconi syndrome that developed following a year of consumption of a red yeast rice supplement.

Although some dietary supplements have been reported to cause renal dysfunction, there have been few reports of supplement-induced Fanconi syndrome. We present the case of a 56-year-old woman with Fanconi syndrome that developed after she consumed a red yeast rice supplement. She was referred to our hospital because of renal dysfunction, and was found to have electrolyte abnormalities, including hypophosphatemia and hypouricemia, renal diabetes, and hyperchloremic metabolic acidosis, and was, therefore, diagnosed with Fanconi syndrome. Renal biopsy revealed proximal tubular injury characterized by severely degenerated tubular epithelial cells as well as mild hypocellular fibrosis. We speculated that the red yeast rice supplement, which the patient had been consuming for approximately 1year, might be a cause of her syndrome, because reports of renal dysfunction associated with the consumption of red yeast rice supplements have emerged in Japan since 2024. After the supplement was discontinued and oral prednisolone treatment was initiated, the patient's renal function improved and her electrolyte abnormalities were ameliorated. Furthermore, even after tapering off and discontinuing the prednisolone over approximately 12weeks, her renal function remained. Because Fanconi syndrome may be caused by various exogenous substances, the taking of a thorough medical history is crucial, including with respect to the use not only of prescription medications, but also other substances, including supplements.

A case of Fanconi syndrome that developed following a year of consumption of a red yeast rice supplement.

Although some dietary supplements have been reported to cause renal dysfunction, there have been few reports of supplement-induced Fanconi syndrome. We present the case of a 56-year-old woman with Fanconi syndrome that developed after she consumed a red yeast rice supplement. She was referred to our hospital because of renal dysfunction, and was found to have electrolyte abnormalities, including hypophosphatemia and hypouricemia, renal diabetes, and hyperchloremic metabolic acidosis, and was, therefore, diagnosed with Fanconi syndrome. Renal biopsy revealed proximal tubular injury characterized by severely degenerated tubular epithelial cells as well as mild hypocellular fibrosis. We speculated that the red yeast rice supplement, which the patient had been consuming for approximately 1year, might be a cause of her syndrome, because reports of renal dysfunction associated with the consumption of red yeast rice supplements have emerged in Japan since 2024. After the supplement was discontinued and oral prednisolone treatment was initiated, the patient's renal function improved and her electrolyte abnormalities were ameliorated. Furthermore, even after tapering off and discontinuing the prednisolone over approximately 12weeks, her renal function remained. Because Fanconi syndrome may be caused by various exogenous substances, the taking of a thorough medical history is crucial, including with respect to the use not only of prescription medications, but also other substances, including supplements.