Primary Focal Segmental Glomerulosclerosis (FSGS) is an important cause of end-stage renal disease (ESRD). Primary FSGS recurrence rates in transplanted kidneys are high, with 25-50% in first transplants and up to 80% in second transplants, often leading to graft loss. To investigate the molecular and cellular events underlying recurrent primary FSGS (reFSGS), we performed single-nucleus RNA sequencing (snRNA-seq) on kidney transplant biopsies from patients with reFSGS and controls with normal allograft function. Our analysis revealed that podocyte loss in reFSGS is driven by metabolic and structural dysregulation rather than apoptosis. Overexpression of vascular endothelial growth factor (VEGF)-A by podocytes was observed, potentially disrupting glomerular endothelial cell growth and permeability. Parietal epithelial cells (PECs) exhibited dedifferentiation towards a podocyte-like state, potentially compensating for podocyte loss, but this was associated with increased collagen deposition and glomerular sclerosis. Ligand-receptor interactions between glomerular cells and B cells further promoted extracellular matrix deposition and fibrosis. Additionally, tubular cells demonstrated evidence of tubular sclerosis and impaired regenerative potential, accompanied by increased interactions with T cells. These findings provide novel insights into the pathogenesis of reFSGS and identify potential therapeutic targets. This study establishes a foundation for future research to further investigate cell-type-specific interventions in recurrent FSGS.

As obesity and chronic kidney disease (CKD) remain a public health issue, we aim to elaborate on their complex relationship regarding pathogenetic mechanisms and therapeutic potential as well. The purpose of this review is to enhance our understanding of the interplay between obesity and CKD in order to timely diagnose and treat obesity-related CKD.

Obesity and CKD pose significant intertwined challenges to global health, affecting a substantial portion of the population worldwide. Obesity is recognized as an independent risk factor, intricately contributing to CKD pathogenesis through mechanisms such as lipotoxicity, chronic inflammation, and insulin resistance. Recent evidence highlights additional factors including hemodynamic changes and intestinal dysbiosis that exacerbate kidney dysfunction in obese individuals, leading to histologic alterations known as obesity-related glomerulopathy (ORG). This narrative review synthesizes current knowledge on the prevalence, pathophysiology, clinical manifestations, and diagnostic strategies of obesity-related kidney disease. Furthermore, it explores mechanistic insights to delineate current therapeutic approaches, future directions for managing this condition and controversies. By elucidating the multifaceted interactions between obesity and kidney health, this review aims to inform clinical practice and stimulate further research to address this global health epidemic effectively.

Mitochondria are the main sites of aerobic respiration in the cell and mainly provide energy for the organism, and play key roles in adenosine triphosphate (ATP) synthesis, metabolic regulation, and cell differentiation and death. Mitochondrial dysfunction has been identified as a contributing factor to a variety of diseases. The kidney is rich in mitochondria to meet energy needs, and stable mitochondrial structure and function are essential for normal kidney function. Recently, many studies have shown a link between mitochondrial dysfunction and kidney disease, maintaining mitochondrial homeostasis has become an important target for kidney therapy. In this review, we integrate the role of mitochondrial dysfunction in different kidney diseases, and specifically elaborate the mechanism of mitochondrial reactive oxygen species (mtROS), autophagy and ferroptosis involved in the occurrence and development of kidney diseases, providing insights for improved treatment of kidney diseases.

The Columbia classification identified five histological variants of focal segmental glomerulosclerosis (FSGS). The prognostic significance of these variants remains controversial.

To evaluate the relative frequency, clinicopathologic characteristics, and medium-term outcomes of FSGS variants at a single center in Pakistan.

This retrospective study was conducted at the Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan on all consecutive adults (≥ 16 years) with biopsy-proven primary FSGS from January 1995 to December 2017. Studied subjects were treated with steroids as a first-line therapy. The response rates, doubling of serum creatinine, and kidney failure (KF) with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis, and Chi-square tests as appropriate. Data were analyzed by SPSS version 22.0. P-value ≤ 0.05 was considered significant.

A total of 401 patients were diagnosed with primary FSGS during the study period. Among these, 352 (87.7%) had a designated histological variant. The not otherwise specified (NOS) variant was the commonest, being found in 185 (53.9%) patients, followed by the tip variant in 100 (29.1%) patients. Collapsing (COL), cellular (CEL), and perihilar (PHI) variants were seen in 58 (16.9%), 6 (1.5%), and 3 (0.7%) patients, respectively. CEL and PHI variants were excluded from further analysis due to small patient numbers. The mean follow-up period was 36.5 ± 29.2 months. Regarding response rates of variants, patients with TIP lesions achieved remission more frequently (59.5%) than patients with NOS (41.8%) and COL (24.52%) variants (P < 0.001). The hazard ratio of complete response among patients with the COL variant was 0.163 [95% confidence interval (CI): 0.039-0.67] as compared to patients with NOS. The TIP variant showed a hazard ratio of 2.5 (95%CI: 1.61-3.89) for complete remission compared to the NOS variant. Overall, progressive KF was observed more frequently in patients with the COL variant, 43.4% (P < 0.001). Among these, 24.53% of patients required kidney replacement therapy (P < 0.001). The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57 (95%CI: 1.87-113.49) as compared to patients with the TIP variant.

In conclusion, histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.

A 72-year-old man was admitted for examination of proteinuria (9.14 g/day) and leg edema. Essential thrombocythemia (ET) was diagnosed because of thrombocytosis (platelet count, 57.9×10⁴/μL), elevated megakaryocytes in bone marrow biopsy, and JAK2 V617 mutation. Kidney biopsy led to a diagnosis of focal segmental glomerulosclerosis (FSGS) cellular variant (characterized by glomerular capillaries filled with swollen endothelial cells containing foam cells) in 6 glomeruli, FSGS tip variant in 5 glomeruli, and additional FSGS variants in other glomeruli. Affected glomeruli had anti-CD61 antibody staining-positive megakaryocyte infiltrations. ET mayinduce FSGS because megakaryocyte infiltration increases intraglomerular pressure, resulting in hypertension and proteinuria.

Despite acceptable survival for Fontan operation, there are concerns about late complications affecting the major organs. We herein present two cases of adults after Fontan operation who developed focal segmental glomerulosclerosis. These cases suggest that focal segmental glomerulosclerosis is owing to haemodynamic incompetence associated with Fontan operation, including congestion, hypoxia, and hyperviscosity, which may be called Fontan-associated renal disease.

Focal segmental glomerulosclerosis (FSGS) has a high recurrence rate after renal transplantation, which significantly impacts renal graft survival. However, the factors related to recurrence remain unclear.

This study aimed to analyze focal segmental recurrence and evolution of glomerulosclerosis after renal transplantation.

This was a descriptive, retrospective study involving 88 adults who underwent renal transplantation within a 15-year period. Demographic and clinical characteristics, as well as the occurrence of graft loss, were analyzed. Over the study period, 88 patients with a diagnosis of FSGS after transplantation were identified.

The mean age of the patients (n=54, males) was 29.1 years. Transplants with deceased donors predominated (60.9%). Calcineurin and prednisone inhibitors were present in 96.4% of the initial immunosuppression regimens. The mean time of onset of proteinuria greater than 0.5 g/g was 20.51 days. At 60 months after transplantation, 44.16% of the patients had partial remission, 25.97% had complete remission, and 29.87% had no remission. However, 50.60% of the patients developed graft loss throughout the analyzed period. Eight patients (9.4%) died within 60 months, of which five (62.5%) were attributed to infection.

Our results indicate that FSGS after renal transplantation is a disease of high recurrence that is commonly precocious, and the histological alterations in light microscopy are not simultaneous to the appearance of proteinuria. Hypertension is considered a risk factor causing progression and recurrence. Thus, prospective studies are required to better evaluate progression and recurrence factors.

Nephrotic syndrome is traditionally defined using the triad of edema, hypoalbuminemia, and proteinuria, but this syndrome is very heterogeneous and difficult to clarify. Its idiopathic form (INS) is probably the most harmful and essentially comprises two entities: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). We will consider some hypotheses regarding the mechanisms underlying INS: (i) the presence of several glomerular permeability factors in the sera of patients that alter the morphology and function of podocytes leading to proteinuria, (ii) the putative role of immune cells. Thanks to recent data, our understanding of these disorders is evolving towards a more multifactorial origin. In this context, circulating factors may be associated according to sequential kinetic mechanisms or micro-environmental changes that need to be determined. In addition, the resulting proteinuria may trigger more proteinuria enhancing the glomerular destabilization.

Bevacizumab is a humanized monoclonal IgG1 antibody, which neutralizes vascular endothelial growth factor and is used for treating multiple cancer types. As a known and frequent adverse event, this therapy can lead to renal damage including proteinuria and nephrotic syndrome. In a retrospective approach, we analyzed 17 renal biopsies from patients receiving bevacizumab treatment. We observed a distinctive histopathological pseudothrombotic pattern different from the previously reported thrombotic microangiopathy. Since this pattern includes some features similar to acute and chronic thrombotic microangiopathy, focal segmental glomerulosclerosis and cryoglobulinemic membranoproliferative glomerulonephritis, biopsies with these diagnoses were included for comparison. Clinical, laboratory, light microscopic, immunohistochemical (including a proximity ligation assay), proteomic and electron microscopic features were assessed. Nephrotic syndrome was present in 15 of the 17 bevacizumab-treated patients. All 17 displayed a patchy pattern of variably PAS-positive hyaline pseudothrombi occluding markedly dilated glomerular capillaries in their biopsies. Mass spectrometry-based proteome analysis revealed a special protein pattern demonstrating some features of thrombotic microangiopathy and some of cryoglobulinemic glomerulonephritis, including a strong accumulation of IgG in the pseudothrombi. Proximity ligation assay did not show interaction of IgG with C1q, arguing for accumulation without classic pathway complement activation. In contrast to thrombi in thrombotic microangiopathy cases, the hyaline pseudothrombi did not contain clusters of CD61-positive platelets. Electron microscopy of bevacizumab cases did not show fibrin polymers or extensive loss of podocyte foot processes. Even though cases of bevacizumab-associated microangiopathy share some features with thrombotic microangiopathy, its overall histopathological pattern is quite different from acute or chronic thrombotic microangiopathy cases. We conclude that bevacizumab therapy can lead to a unique hyaline occlusive glomerular microangiopathy, likely arising from endothelial leakage followed by subendothelial accumulation of serum proteins. It can be diagnosed by light microscopy and is an important differential diagnosis in cancer patients with nephrotic syndrome.

The etiology of steroid-resistant nephrotic syndrome, which manifests as FSGS, is not completely understood. Aberrant glycosylation is an often underestimated factor for pathologic processes, and structural changes in the glomerular endothelial glycocalyx have been correlated with models of nephrotic syndrome. Glycans are frequently capped by sialic acid (Sia), and sialylation's crucial role for kidney function is well known. Human podocytes are highly sialylated; however, sialylation's role in podocyte homeostasis remains unclear.

We generated a podocyte-specific sialylation-deficient mouse model (PCmas^-/- ) by targeting CMP-Sia synthetase, and used histologic and ultrastructural analysis to decipher the phenotype. We applied CRISPR/Cas9 technology to generate immortalized sialylation-deficient podocytes (asialo-podocytes) for functional studies.

Progressive loss of sialylation in PCmas^-/- mice resulted in onset of proteinuria around postnatal day 28, accompanied by foot process effacement and loss of slit diaphragms. Podocyte injury led to severe glomerular defects, including expanded capillary lumen, mesangial hypercellularity, synechiae formation, and podocyte loss. In vivo, loss of sialylation resulted in mislocalization of slit diaphragm components, whereas podocalyxin localization was preserved. In vitro, asialo-podocytes were viable, able to proliferate and differentiate, but showed impaired adhesion to collagen IV.

Loss of cell-surface sialylation in mice resulted in disturbance of podocyte homeostasis and FSGS development. Impaired podocyte adhesion to the glomerular basement membrane most likely contributed to disease development. Our data support the notion that loss of sialylation might be part of the complex process causing FSGS. Sialylation, such as through a Sia supplementation therapy, might provide a new therapeutic strategy to cure or delay FSGS and potentially other glomerulopathies.

Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0-3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico-medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.

Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury demonstrated by renal biopsy that can arise from a diverse range of causes and mechanisms. It has an estimated incidence of 7 per 1 million and is the most common primary glomerular disorder leading to end-stage renal disease in the United States. This review focuses on damage to the podocyte and the consequences of this injury in patients with FSGS, the genetics of FSGS, and approaches to treatment with a focus on the effects on podocytes.

The podocyte is central to the glomerular filtration barrier and is particularly vulnerable because of its highly differentiated post-mitotic phenotype. The progressive structural changes involved in the pathology of FSGS include podocyte foot process effacement, death of podocytes and exposure of the glomerular basement membrane, filtration of nonspecific plasma proteins, expansion of capillaries, misdirected filtration at points of synechiae, and mesangial matrix proliferation. Although damage to and death of podocytes can result from single-gene disorders, evidence also suggests a role for soluble factors, such as soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine-1, and anti-CD40 antibodies, that promote FSGS recurrence post transplant. Several classes of medications, including corticosteroids, calcineurin inhibitors, endothelin receptor antagonists, adrenocorticotropic hormone, and rituximab, have been shown to be effective for the treatment of FSGS and have been demonstrated to have significant protective effects on podocytes. Key Messages: Greater understanding of podocyte biology is essential to the identification of new treatment targets and medications for the management of patients with FSGS.

Renal biopsy is the gold standard to determine the pathologic type of primary nephrotic syndrome, which is critical for diagnosis, choice of treatment and evaluation of prognosis. However, in some cases, renal biopsy cannot be performed.

To explore the possibility of predicting the histology type of primary nephrotic syndrome without the need for biopsy, we trained and validated a machine learning algorithm using data from 222 patients with biopsy-confirmed primary nephrotic syndrome treated at our hospital between May 2008 and January 2016. The model was then tested prospectively on another sample of 63 patients with biopsy-confirmed primary nephrotic syndrome.

Overall accuracy of prediction from the retrospective set of 222 patients was 62.2% across all types of nephrotic syndrome. The accuracy of model prediction for the prospectively collected dataset of 63 patients was 61.9%. The algorithm identified 17 of 33 variables as contributing strongly to type of renal pathology.

To our knowledge, this is the first such application of machine learning to predict the pathologic type of primary nephrotic syndrome, which may be clinically useful by itself as well as helpful for guiding future efforts at machine learning-based prediction in other disease contexts.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.