Variant Of Focal Segmental Glomerulosclerosis Research Articles

Aberrant localization of β1 integrin in podocyte cytoplasm of primary FSGS with cellular lesion.

Podocyte detachment is a major trigger in pathogenesis of focal segmental glomerulosclerosis (FSGS). Detachment via β1 integrin (ITGB1) endocytosis, associated with endothelial cell injury, has been reported in animal models but remains unknown in human kidneys. The objectives of our study were to examine the difference in ITGB1 dynamics between primary FSGS and minimal change nephrotic syndrome (MCNS), among variants of FSGS, as well as between the presence or absence of cellular lesions (CEL-L) in human kidneys, and to elucidate the pathogenesis of FSGS. Thirty-one patients with primary FSGS and 14 with MCNS were recruited. FSGS cases were categorized into two groups: those with CEL-L, defined by segmental endocapillary hypercellularity occluding lumina, and those without CEL-L. The podocyte cytoplasmic ITGB1 levels, ITGB1 expression, and degrees of podocyte detachment and subendothelial widening were compared between FSGS and MCNS, FSGS variants, and FSGS groups with and without CEL-L (CEL-L( +)/CEL-L( -)). ITGB1 distribution in podocyte cytoplasm was significantly greater in CEL-L( +) group than that in MCNS and CEL-L( -) groups. ITGB1 expression was similar in CEL-L( +) and MCNS, but lower in CEL-L( -) compared with others. Podocyte detachment levels were comparable in CEL-L( +) and CEL-L( -) groups, both exhibiting significantly higher detachment than the MCNS group. Subendothelial widening was significantly greater in CEL-L( +) compared with CEL-L( -) and MCNS groups. The findings of this study imply the existence of distinct pathological mechanisms associated with ITGB1 dynamics between CEL-L( +) and CEL-L( -) groups, and suggest a potential role of endothelial cell injury in the pathogenesis of cellular lesions in FSGS.

Altered Endoplasmic Reticulum Integrity and Organelle Interactions in Living Cells Expressing INF2 Variants

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.

Hydralazine use can be associated with IgM-dominated immune complex-mediated glomerulonephritis

ABSTRACT Context IgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine. Design Seven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail. Results Patients’ ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases. Conclusion The hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.

Clinicopathological features and medium-term outcomes of histologic variants of primary focal segmental glomerulosclerosis in adults: A retrospective study.

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.

Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy

Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.

Five-Year study on renal outcomes in biopsy-proven focal segmental glomerulosclerosis patients in Shiraz, Iran.

Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease that often leads to nephrotic syndrome. It is characterized by consolidating a portion of the glomerular capillary tuft connected to Bowman's capsule. This retrospective cohort study aimed to determine the demographic characteristics, risk factors, and prognostic indicators associated with FSGS in Shiraz, Iran. The study included 53 primary FSGS patients aged over 18 years who were referred to clinics affiliated with Shiraz University of Medical Sciences. Data were collected through a comprehensive data-gathering sheet encompassing demographic information, medical history, laboratory test results, and histopathological findings. Statistical analysis was performed using SPSS 18, considering a significance level of p<0.05. A five-year follow-up was conducted on the 53 patients, with the mean age of 41.0±13.3 years. The most common FSGS variants observed were "not otherwise specified" (NOS, 13.2%) and tip variant (7.5%). Older patients exhibited higher disease activity, whereas remission rates were higher among younger individuals (P=0.012). Patients achieving remission had lower creatinine and Pro/Cr ratios and higher glomerular filtration rates (p<0.05). Treatment involving a combination of corticosteroids and mycophenolate mofetil showed a significant correlation with remission (P=0.036). Older patients with higher creatinine levels, higher Pro/Cr ratios, and lower glomerular filtration rates at disease onset may require more aggressive treatment. Combination therapy with mycophenolate mofetil and corticosteroids yields better outcomes, leading to increased remission rates. These findings provide valuable insights for managing FSGS patients.

Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy

Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot–Marie–Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis.

Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.

Membranous nephropathy with collapse in a HIV negative patient; a case report with a 34-month follow-up

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in nondiabetic adults. Collapsing nephropathy (CN) is a morphological pattern that is usually classified as a variant of focal segmental glomerulosclerosis (cFSGS). The simultaneous presence of both MN and CN is rare and their combination usually foresees an unfavorable outcome. Herein, we describe a case report of a patient with PLA2 R-associated MN with collapse, its treatment and clinical course.

Focal Segmental Glomerulosclerosis in C&amp;#244;te d’Ivoire: Epidemiological, Clinical and Pathological Aspects

Focal segmental glomerulosclerosis (FSGS) is characterized histologically by hyalinosis and sclerosis of glomeruli associated or not with podocyte involvement. The objective of our work was to clarify the epidemiological aspects and histological variants of FSGS in C ôte d’Ivoire. Materials and Methods: This was a descriptive retrospective study, conducted from January 2015 to December 2019 using the renal biopsy registers (RB) of the Pathological Anatomy and Cytology departments of the Teaching Hospital of Cocody and Bouake in collaboration with the Nephrology Services of C ôte d'Ivoire and the sub-region. The biopsies underwent conventional histopathology and/or immunofluorescence techniques. The parameters analyzed were: frequency, age, gender, proteinuria, biopsy indications and histological aspects and the different correlations between histological aspects and socio-demographic characteristics. Results: FSGS represented 58.1% (n = 104) of glomerular nephropathies. The average age of patients was 32.1 ± 13.3 years, with extremes of 13 and 70 years. The sex ratio was equal to 1. Nephrotic syndrome (68.9%), chronic renal failure (14.3%) and acute renal failure (10.1%) were the main indications for renal biopsy (RB). The mean proteinuria at the time of diagnosis was 4 ± 3.7 g/24 h. It was massive (3.5 g/24 h) in 42.3% of patients. FSGS was primary in 29.8% (n = 31) and secondary in 70.2% (n = 73) of patients, of which 27.9% (n = 35) was due to HIV. According to the Columbia classification, 62.5% NOS type was found; 23.1% collapsing type; 7.7% tip lesion type; 4.8% cell type and 1.9% perihilary type. Conclusion: FSGS is a complex heterogeneous entity. It affects young people in our context with a homogeneous gender distribution. Understanding its histogenesis is essential for optimal patient management.

Focal segmental glomerulosclerosis histologic variants and renal outcomes based on nephrotic syndrome, immunosuppression and proteinuria remission.

The associations of focal segmental glomerulosclerosis (FSGS) histological variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end-stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression and proteinuria remission (PR; proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression and PR with outcomes were examined for each variant. The distribution of variants was 48% (n = 145) FSGS not otherwise specified, 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants [hazard ratio adjusted for histological variant and potential confounders (adjusted HR) 0.19 (95% confidence interval 0.10-0.34)]. NS was marginally associated with better outcome compared with non-NS [adjusted HR 0.50 (95% confidence interval 0.25-1.01)]. FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.

MO294COMPARISON OF TIP AND CELLULAR VARIANT OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims After membranous nephropathy, focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in European population. According to Columbia classification, there are five histological variants of FSGS defined on light microscopy (tip, cellular, perihilar, collapsing and not otherwise specified - NOS) and this classification has a prognostic significance. The aim is to compare features and outcomes of tip and cellular variant of primary FSGS. Method All patients with FSGS were identified by a retrospective review of the Registry of kidney biopsies at the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb, from 2003 until 2020. Each kidney specimen was analyzed by light, immunofluorescent and electron microscopy and Columbia classification was applied by experienced nephropathologist. Patients with primary FSGS met following criteria: full nephrotic syndrome and diffuse podocyte foot process effacement in absence of secondary causes of FSGS. Laboratory findings were obtained for every patient at the time of biopsy and following outpatient visits. Complete remission was defined as proteinuria &amp;lt; 0.3 g/day with normal kidney function and partial remission as proteinuria 0.3 - 3.5 g/day. Variables are expressed as median ± IQR (interquartile range) and frequencies. Statistical comparison between groups of patients with tip and cellular variant of primary FSGS and disease outcome analysis were done. Results Out of 200 patients with FSGS, 59 (29.5 %) had primary form of disease. Tip variant was the most common form of primary FSGS (22 patients, 37 %) followed by NOS (20, 34 %), cellular (13, 22 %), perihilar (2, 3.5 %) and collapsing (2, 3.5 %) variant. Demographic and clinical features with initial laboratory findings are shown in Table 1. There were no significant differences between two groups in all analyzed variables in Figure 1. All patients were treated by anti-RAAS agents and steroids. Median follow-up was 55 months (range 1 – 196 months), and followup data were unavailable for three patients. Figure 2 shows treatment regimens in both patient grouos with treatment outcomes. Remission rate was significantly higher in tip variant (90 % vs. 41 %, p = 0.002). There was no difference in relapse rate between the two groups (p = 0.717). Conclusion There were no significant differences in clinical features and laboratory findings at the time of clinical presentation between tip and cellular variant of primary FSGS. Patients with tip variant had significantly higher remission rate than patients with cellular variant.

Histologic Variants of FSGS: An Epidemiological and Pathological Perspective.

Focal segmental glomerulosclerosis (FSGS) is a conglomerate of glomerular pathological lesions unified by the segmental distribution of proliferative, sclerosing or collapsing lesions in less than 50% of glomeruli (i.e., focal distribution) in the early stages of the process and can only be diagnosed on renal biopsy. Epidemiologically, FSGS has acquired the top position among the causes of nephrotic syndrome (NS) in adults in many parts of the world and has emerged as the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. Numerous approaches have been used to classify this lesion, but all have merits and demerits and no one system is entirely satisfactory. One of the popular schemes for the classification is based on morphological features and distribution of the lesions in the glomeruli, the so-called Columbia classification of FSGS. In this review, we briefly summarize the relevant epidemiology and pathology of FSGS variants in the light of our own experience with the use of this classification.

A study on variants of focal segmental glomerulosclerosis and their relationship with various biochemical and demographic parameters in kidney biopsies; a single center study

Introduction: Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases leading to end-stage renal failure. According to Columbia classification, there are five histologic variants for FSGS. Objectives: There is no study about prevalence and clinic-pathological features of its variants up to now in Iran. Patients and Methods: The study was conducted on renal biopsy reports in a laboratory center between 2011- 2015. Of 1108 patients, 234 had FSGS (either secondary or primary). Using light and immunofluorescence microscopies, the diagnosis and the variants of FSGS were determined (according to Columbia classification). Pathological findings like interstitial fibrosis and glomerular sclerosis, para-clinical findings including serum creatinine and proteinuria, and demographic features including gender and age were also recorded. Results: Among 212 patients with primary form of FSGS, 58% were males with the male-to-female ratio of 1.38: The mean age was 38.5± 18.72 years. Classic variant (not otherwise specified; NOS) was the most prevalent variant, comprising 89.1% of all cases. Tip variant comprised of 32.5%, perihilar in 23.1%, collapsing in 0.9%, while cellular was detected in 0.5% of cases. Mean serum creatinine was 1.41± 0.84 mg/dL. Moreover, mean of proteinuria was 2201.8±1134.49 mg/day. Mean interstitial fibrosis/tubular atrophy in the variants were; NOS in 14.9 ±10.87% of cases, Tip; 7.26±11.55% of cases and in perihilar was 10.79±15.75%. Conclusion: Our study indicates that NOS variant of FSGS is a highly prevalent variant in our patients. Among them, the highest proportion of interstitial fibrosis was seen in this variant.

Collapsing glomerulopathy in older adults

Collapsing glomerulopathy has been described in settings of viral infections, drug, genetic, ischemic, renal transplant, and idiopathic conditions. It has a worse prognosis than other morphologic variants of focal segmental glomerulosclerosis, and may be treated with aggressive immunosuppression. In this study, we sought to characterize the clinical and morphologic findings in older adults with collapsing glomerulopathy. Renal biopsies and associated clinical data from patients aged 65 or older with a diagnosis of collapsing glomerulopathy were retrospectively reviewed at 3 academic institutions. Patients (n = 41, 61% male, median age 71) usually had hypertension (88%), nephrotic range proteinuria (91%), and renal insufficiency (median serum creatinine 2.5 mg/dL). A likely precipitating drug (5%) or vascular procedure (5%) was identified in a minority of cases; viral infections were infrequent. Renal biopsies contained a median of 40% globally and 16% segmentally sclerotic glomeruli. Approximately 60% of cases had moderate or severe arteriosclerosis, arteriolar hyalinosis, and/or tubular atrophy and interstitial fibrosis; 7% had atheroembolic disease and 5% had thrombotic microangiopathy. In 28 patients with available follow-up information, eight (19%) were treated with immunosuppressives, which were not tolerated by 2. At a median interval of 14 months, 5 (18%) patients had died, 12 (43%) had end stage renal disease, and 12 were alive with renal insufficiency and proteinuria. Treatment with immunosuppressive therapy did not have a significant benefit with regard to the primary outcome of overall or renal survival. One steroid-treated patient with diabetes died 6 weeks after biopsy, with invasive rhinoorbital Rhizopus infection. In conclusion, collapsing glomerulopathy in older patients is usually not associated with viral infections, and is accompanied by significant chronic injury in glomeruli, vasculature, and tubulointerstitium. Aggressive immunosuppression likely contributed to one death in a patient with diabetes, and did not yield an overall or renal survival advantage in this cohort.

First report of collapsing variant of focal segmental glomerulosclerosis triggered by arbovirus: dengue and Zika virus infection.

BackgroundThe collapsing variant of focal segmental glomerulosclerosis (FSGS) is the most aggressive form of FSGS and is characterized by at least one glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia. Viruses can act as aetiological agents of secondary FSGS. This study aims to establish an aetiological link between dengue virus (DENV) infection and the collapsing variant of FSGS and to analyse possible influences of the apolipoprotein 1 (APOL1) gene risk alleles on the disease.MethodsBiopsies and medical records were gathered from 700 patients of the Instituto de Nefropatologia, Belo Horizonte, Brazil. Screening for the collapsing variant of FSGS was performed and serological, immunohistochemical, tissue polymerase chain reaction (PCR) and genetic analysis were conducted.ResultsEight patients were identified with positive DENV serology and negative serological and/or tissue markers for hepatitis B virus, hepatitis C virus, Epstein–Barr virus, human immunodeficiency virus, cytomegalovirus and parvovirus B19. In PCR analysis, six patients had positive markers for DENV strain genetic material, one patient had positive markers for co-infection of Zika virus (ZIKV) and DENV and one patient had positive markers only for ZIKV infection. Six of the eight patients did not show risk alleles of the APOL1 gene. One patient had only one risk allele (G1) and the sample from another did not contain enough DNA for genetic analysis to be performed.ConclusionsThis study provided strong evidence that DENV can infect renal tissue and possibly functions as a second hit to the development of the collapsing variant of FSGS. Nonetheless, this study also highlights the possible implication of ZIKV infection in FSGS and supports the argument that risk alleles of the APOL1 gene may not be implicated in the susceptibility to FSGS in these patients.

Clinical and pathological characteristics of primary focal segmental glomerulosclerosis in adult

Background and objective: Focal segmental glomerulosclerosis shares overlapping patterns of injury with segmental consolidation and obliteration of glomerular architecture by the accumulation of collagenous extracellular matrix or by increased cellularity or both. This study aimed to investigate the patterns of primary focal segmental glomerulosclerosis in adults in Erbil. The specific objectives of this study included determining the frequency of histological variant of Focal segmental glomerulosclerosis, defining the clinical characteristics of the primary type in general and recognizing the clinical and pathological characteristics for each variant separately. Methods: A cross-sectional, clinico-pathologic study was conducted for 50 patients attending the Nephrology Department in Erbil Teaching Hospital between March and December 2013. This study included patients of >16 years old with biopsy-proven idiopathic focal segmental glomerulosclerosis. Results: A total of 50 patients were enrolled into this study. The median age of patients was 33 years, ranged from 18 to 54, 31 (62%) males and 19 (38%) females. The frequency of histopathological variants was 80% not otherwise specific focal segmental glomerulosclerosis, 14% glomerular tip lesion, and 6% cellular type. Nephrotic syndrome and hypertension were the main presenting features (92% and 68%, respectively). The mean percentage of sclerosed glomeruli was 40% and the mean interstitial fibrosis and tubular atrophy was 24%. Conclusion: A not otherwise specific variant is a common morphological lesion in many glomerular and non-glomerular diseases, and it is just like a junk drawer of multiple glomerular alterations with this common pattern of the lesion.

Focal Segmental Glomerulosclerosis.

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.

Cellular Variant of Focal Segmental Glomerulosclerosis Treated with Plasma Exchange

Cellular Variant of Focal Segmental Glomerulosclerosis Treated with Plasma Exchange

Collapsing glomerulopathy is common in the setting of thrombotic microangiopathy of the native kidney

Thrombotic microangiopathy (TMA) is a poorly recognized cause of collapsing glomerulopathy. The frequency and significance of collapsing glomerulopathy associated with renal TMA have not been specifically studied in native kidney biopsy specimens. Here we retrospectively documented clinicopathologic features of 53 patients withhistologically proven TMA in the native kidney, with special emphasis on changes due to focal segmental glomerulosclerosis (FSGS). Histological TMA was related tohypertensive nephropathy in 21 patients, genetic complement abnormalities in 9, drugs in 7, and to other causes in 16 patients. Almost half (26 patients) presented with arteriolar, 6 with glomerular, and 21 with mixed TMA. Using the Columbia classification system for the 53 patients with histological TMA, 33 had concurrent FSGS lesions with collapsing glomerulopathy the dominant variant in 19 patients (58% of the FSGS cases), not otherwise specified in 9 patients, cellular in 3, and perihilar or tip lesions in 1 patient each. The presence of FSGS was associated with a poor renal prognosis, with no prognostic difference between collapsing glomerulopathy and other FSGS variants. Thus, collapsing glomerulopathy is frequently found in native kidney biopsies with TMA, suggesting that endothelial injury may play an important role in the pathophysiology of FSGS.