Search Results (105)

Background: Percutaneous ultrasound-guided renal biopsy (PRB) is a key element for diagnosis and management of several renal pathologies. We aimed to lay out the experience of our pediatric nephrology unit performing PRBs. The rationale and findings of these biopsies, safety issues and considerations of the extracted data are going to be analyzed. Methods: A retrospective study was conducted from 2008 to 2023 based on the review of the medical records of pediatric patients who underwent PRBs. In total, 216 kidney biopsies in 206 patients were performed: 115 (53.2%) during the 2008–2015 period and 101 (46.8%) during the 2016–2023 period. Results: The most frequent clinical indication for PRBs was nephritic syndrome followed by nephrotic syndrome, observed in 84 (40.8%) and 72 (34.9%) patients, respectively. The predominant diagnosis was minimal change disease (MCD) (23.3%), followed by focal segmental glomerulosclerosis (FSGS) (15%) equal to lupus nephritis (LN) (15%), and immunoglobulin A nepropathy (10.2%). Minor complications, such as subcapsular hematomas were observed in approximately 15% of patients while no therapeutic intervention was needed. Conclusions: This report is the first review of pathohistological data covering a pediatric population over a 15-year period in Greece and one of the largest in southeastern Europe, especially in the Balkan region. The main indication for a PRB was nephritic syndrome; however, MCD was the main histological diagnosis. This study emphasis the fact that PRBs constitute a safe and reliable method of diagnostic approach to kidney diseases in childhood and offers important information on therapeutic approaches as well as the prognosis of these patients. Full article

Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and often leads to progressive kidney failure. Its varying clinical presentation suggests potential genetic diversity, requiring further molecular investigation. This study aims to elucidate some of the genetic and molecular mechanisms underlying FSGS. The study focuses on the use of bioinformatic analysis of gene expression data to identify genes associated with familial FSGS. A comprehensive in silico analysis was performed using the GSE99340 data set from Gene Expression Omnibus (GEO) comparing gene expression in glomerular and tubulointerstitial tissues from FSGS patients (n = 10) and Minimal Change Disease (MCD) patients (n = 8). These findings were validated using transcriptomics data obtained using RNA sequencing from FSGS (n = 3) and control samples (n = 3) from the UAE. Further validation was conducted using qRT-PCR on an independent FFPE cohort (FSGS, n = 6; MCD, n = 7) and saliva samples (FSGS, n = 3; Control, n = 7) from the UAE. Three genes (TUBB6, RPL27, and PFDN5) showed significant differential expression (p < 0.01) when comparing FSGS and MCD with healthy controls. These genes are associated with cell junction organization and synaptic pathways of the neuron, supporting the link between FSGS and the neural system. These genes can potentially be useful as diagnostic biomarkers for FSGS and to develop new treatment options. Full article

The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia–reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin–angiotensin–aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes. Full article

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes. Full article

The cytoskeleton mediates fundamental cellular processes by organizing inter-organelle interactions. Pathogenic variants of inverted formin 2 (INF2) CAAX isoform, an actin assembly factor that is predominantly expressed in the endoplasmic reticulum (ER), are linked to focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth (CMT) neuropathy. To investigate how pathogenic INF2 variants alter ER integrity, we used high-resolution live imaging of HeLa cells. Cells expressing wild-type (WT) INF2 showed a predominant tubular ER with perinuclear clustering. Cells expressing INF2 FSGS variants that cause mild and intermediate disease induced more sheet-like ER, a pattern similar to that seen for cells expressing WT-INF2 that were treated with actin and microtubule (MT) inhibitors. Dual CMT-FSGS INF2 variants led to more severe ER dysmorphism, with a diffuse, fragmented ER and coarse INF2 aggregates. Proper organization of both F-actin and MT was needed to modulate the tubule vs. sheet conformation balance, while MT arrays regulated spatial expansion of tubular ER in the cell periphery. Pathogenic INF2 variants also induced mitochondria fragmentation and dysregulated mitochondria distribution. Such mitochondrial abnormalities were more prominent for cells expressing CMT-FSGS compared to those with FSGS variants, indicating that the severity of the dysfunction is linked to the degree of cytoskeletal disorganization. Our observations suggest that pathogenic INF2 variants disrupt ER continuity by altering interactions between the ER and the cytoskeleton that in turn impairs inter-organelle communication, especially at ER–mitochondria contact sites. ER continuity defects may be a common disease mechanism involved in both peripheral neuropathy and glomerulopathy. Full article

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients. Full article

Uncovering the function of understudied G protein-coupled receptors (GPCRs) provides a wealth of untapped therapeutic potential. The poorly understood adhesion GPCR Gpr126 (Adgrg6) is widely expressed in developing kidneys. In adulthood, Gpr126 expression is enriched in parietal epithelial cells (PECs) and epithelial cells of the collecting duct and urothelium. Whether Gpr126 plays a role in kidney disease remains unclear. Here, we characterized Gpr126 expression in diseased kidneys in mice, rats, and humans. RT-PCR data show that Gpr126 expression is altered in kidney disease. A quantitative RNAscope^® analysis utilizing cell type-specific markers revealed that Gpr126 expression upon tubular damage is mainly increased in cell types expressing Gpr126 under healthy conditions as well as in cells of the distal and proximal tubules. Upon glomerular damage, an increase was mainly detected in PECs. Notably, Gpr126 expression was upregulated in an ischemia/reperfusion model within hours, while upregulation in a glomerular damage model was only detected after weeks. An analysis of kidney microarray data from patients with lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), hypertension, and diabetes as well as single-cell RNA-seq data from kidneys of patients with acute kidney injury and chronic kidney disease indicates that GPR126 expression is also altered in human kidney disease. In patients with FSGS, an RNAscope^® analysis showed that GPR126 mRNA is upregulated in PECs belonging to FSGS lesions and proximal tubules. Collectively, we provide detailed insights into Gpr126 expression in kidney disease, indicating that GPR126 is a potential therapeutic target. Full article

Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease. Full article

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental glomerulosclerosis (FSGS). Genetic testing has become a valuable diagnostic tool in defining the etiology of SRNS, leading to the identification of a genetic cause. The TRIM8 gene is expressed in various tissues, including kidney cells and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and an early onset of FSGS has been proposed but is not well described. We present a 17-year-old boy with epilepsy, early mild developmental delay, a low IgG serum level, and proteinuria, secondary to FSGS. A Next-Generation Sequencing (NGS)-based analysis revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (c.1200C>G, p.Tyr400Ter). TRIM8 gene sequencing should be considered in individuals with early onset of FSGS, particularly accompanied by symptoms of cortical dysfunction, such as epilepsy and intellectual disability. Full article

Metabolic disorders are increasingly prevalent conditions that manifest pathophysiologically along a continuum. Among reported metabolic risk factors, elevated fasting serum glucose (FSG) levels have shown the most substantial increase in risk exposure. Ultimately leading to insulin resistance (IR), this condition is associated with notable deteriorations in the prognostic outlook for major diseases, including neurodegenerative diseases, cancer risk, and mortality related to cardiovascular disease. Tackling metabolic dysfunction, with a focus on prevention, is a critically important aspect for human health. In this study, an investigation into the potential antidiabetic properties of a salmon protein hydrolysate (SPH) was conducted, focusing on its potential dipeptidyl peptidase-IV (DPP-IV) inhibition and direct glucose uptake in vitro. Characterization of the SPH utilized a bioassay-guided fractionation approach to identify potent glucoregulatory peptide fractions. Low-molecular-weight (MW) fractions prepared by membrane filtration (MWCO = 3 kDa) showed significant DPP-IV inhibition (IC₅₀ = 1.01 ± 0.12 mg/mL) and glucose uptake in vitro (p ≤ 0.0001 at 1 mg/mL). Further fractionation of the lowest MW fractions (<3 kDa) derived from the permeate resulted in three peptide subfractions. The subfraction with the lowest molecular weight demonstrated the most significant glucose uptake activity (p ≤ 0.0001), maintaining its potency even at a dilution of 1:500 (p ≤ 0.01). Full article

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently available for the management of type 2 diabetes mellitus. SGLT2i acts by inhibiting renal SGLT2, thereby increasing glucosuria and lowering serum glucose. Recent trials are emerging supporting a role for SGLT2i irrespective of the diabetic status pointing towards that SGLT2i have other mechanisms of actions beyond blood sugar control. In this review, we will shed light on the role of this group of medications that act as SGLT2i in non-diabetics focusing on pre-clinical and clinical data highlighting the mechanism of renoprotection and effects of SGLT2i in the non-diabetic kidneys. Full article

Between 15–20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (PAX2: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant. Full article

Pre-harvest sprouting (PHS) is a condition triggered by environmental factors, particularly prevalent in humid conditions, leading to substantial yield losses in black gram. While the potential for genotypic PHS tolerance exists, it has not been thoroughly assessed in black gram. Hence, the present study aimed to delve into the genetic variation for PHS tolerance in diverse black gram (Vigna mungo (L.) Hepper) germplasm, and also to comprehend the impact of various physical and physiological traits on PHS. A diverse set of 112 black gram accessions collected across the phytogeographical zones of India were examined for their seed and pod characteristics. Water absorption by pods and seeds and fresh-seed germination was calculated by following the standard procedure given by the International Seed Testing Association. The alpha-amylase activity was measured on dry seeds (0 h), 24 h, 48 h, and 72 h after germination of each accession, using a UV-VIS spectrophotometer, and hard-seededness was measured using a texture analyzer machine. The results showed a wide range in PHS tolerance and FSG, and 13 accessions were found to be PHS-tolerant (PHS value < 10%). An indicator of PHS, seed germination in a pod, ranged from 2.75% in IC485641 (highly tolerant to PHS) to 95.85% in IC530501 (highly susceptible to PHS). Correlation and multivariate analysis revealed that PHS was positively correlated with water imbibition by pod and seed, fresh-seed germination and alpha-amylase activity. PHS-tolerant accessions showed a slow increase in alpha-amylase activity, in contrast to PHS-susceptible accessions. The utilization of alpha-amylase activity as a biochemical marker has the potential for evaluating PHS tolerance across various black gram accessions. The identified PHS-tolerant accessions can be used as donors in crop improvement programs aimed at developing PHS-tolerant black gram varieties. Full article

Large-scale COVID-19 vaccination has been one of the most effective strategies to control the spread of the SARS-CoV-2 virus. However, several cases of glomerular injury related to the COVID-19 vaccine have been described in the literature. We report two cases of a tip lesion variant of focal segmental glomerulosclerosis (FSGS), which presented with significant proteinuria and improved after immunosuppression. In our literature review, the tip lesion variant of FSGS is currently the most frequent variant associated with vaccination against COVID-19. Prognosis is favorable and without significant alterations in the tubulointerstitial or vascular compartments. Adverse effects of vaccines need to be recognized early and will help us to understand the immune and pathological mechanisms of kidney damage. Full article

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options. Full article