Outcome Of Focal Segmental Glomerulosclerosis Research Articles

POS-460 FOCAL SEGMENTAL GLOMERULOSCLEROSIS: ABOUT A SERIES OF 18 CHILDREN.

Focal segmental glomerulosclerosis (FSGS) is a glomerular histopathological finding characterized by segmental (affecting part of the flocculus) and focal (affecting only certain glomeruli) sclerosis. It is severe kidney disease with a complex pathophysiology. To determine the epidemiology and outcome of FSGS in our patients, we conducted a retrospective study on 18 cases diagnosed between January 2010 and December 2019. Out of 345 renal biopsies performed in that period of time, the prevalence of FSGS was of 5.2%. The mean age of these FSGS patients was 9 years old. Boys were predominant with a sex ratio of 2. Consanguinity was found in one-third of our cases. Nephrotic syndrome was the main revealing pattern and was always steroid resistant (100%). Meanwhile, hypertension was found in 30% of our children, and hematuria in 47% of them. Two cases had kidney failure at diagnosis. Primitive FSGS was found in 39% of the cases, four of them reached complete remission after stating calcineurin inhibitors (CIN), while the remaining cases were resistant to CIN, and one case developed chronic kidney disease after only seven months of acute onset. As for adaptative FSGS, it was more common in our children, with 61% of cases. The outcome was marked by increased evolution towards chronic kidney disease and poor response to immunosuppressive therapies. Finally, two cases of FSGS were seen after the prolonged use of CNI inhibitors for the treatment of nephrosis. One of these patients ultimately evolved into chronic kidney disease. Management of FSGS is still challenging, especially in children. More studies, especially in the field of genetics, are needed to improve the outcome of this dreadful glomerulopathy.

Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis

Background: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. Methods: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. Results: Cell senescence (p16^INK4A, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05–0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16^INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16^INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16^INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16^INK4A, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss. Conclusions: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16^INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker.

To define cellular mechanisms underlying kidney function and failure, the KPMP analyzes biopsy tissue in a multicenter research network to build cell-level process maps of the kidney. This study aimed to establish a single cell RNA sequencing strategy to use cell-level transcriptional profiles from kidney biopsies in KPMP to define molecular subtypes in glomerular diseases. Using multiple sources of adult human kidney reference tissue samples, 22,268 single cell profiles passed KPMP quality control parameters. Unbiased clustering resulted in 31 distinct cell clusters that were linked to kidney and immune cell types using specific cell markers. Focusing on endothelial cell phenotypes, in silico and in situ hybridization methods assigned 3 discrete endothelial cell clusters to distinct renal vascular beds. Transcripts defining glomerular endothelial cells (GEC) were evaluated in biopsies from patients with 10 different glomerular diseases in the NEPTUNE and European Renal cDNA Bank (ERCB) cohort studies. Highest GEC scores were observed in patients with focal segmental glomerulosclerosis (FSGS). Molecular endothelial signatures suggested 2 distinct FSGS patient subgroups with α-2 macroglobulin (A2M) as a key downstream mediator of the endothelial cell phenotype. Finally, glomerular A2M transcript levels associated with lower proteinuria remission rates, linking endothelial function with long-term outcome in FSGS.

Urinary myo-inositol is associated with the clinical outcome in focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) have similar initial histological findings; however, their prognoses are distinct. Therefore, it is of great importance to discriminate FSGS from MCD in the early phase of disease and predict clinical prognosis. A discovery set of 184 urine samples (61 healthy control, 80 MCD, and 43 FSGS) and a validation set of 61 urine samples (12 healthy control, 26 MCD, and 23 FSGS) were collected at the time of kidney biopsy. Metabolic profiles were examined using nuclear magnetic resonance spectroscopy. Of 70 urinary metabolites, myo-inositol was significantly higher in FSGS patients than in control patients (discovery set, 2.34-fold, P < 0.001; validation set, 2.35-fold, P = 0.008) and MCD patients (discovery set, 2.48-fold, P = 0.002; validation set, 1.69-fold, P = 0.042). Myo-inositol showed an inverse relationship with the initial estimated glomerular filtration rate (eGFR) and was associated with the plasma level of soluble urokinase-type plasminogen activator receptor in FSGS patients. Myo-inositol treatment ameliorated the decreased expression of ZO-1 and synaptopodin in an in vitro FSGS model, and as myo-inositol increased, myo-inositol oxygenase tissue expression decreased proportionally to eGFR. Furthermore, urinary myo-inositol exhibited an increase in the power to discriminate FSGS patients, and its addition could better predict the response to initial treatment. In conclusion, urinary myo-inositol may be an important indicator in the diagnosis and treatment of FSGS patients.

Clinical presentation, treatment and outcome of focal segmental glomerulosclerosis in Far North Queensland Australian adults.

The aim is to describe the clinical features, treatment and outcomes in Australian adults with focal segmental glomerulosclerosis and identify predictors of disease progression and all-cause mortality. The study included all patients with biopsy confirmed focal segmental glomerulosclerosis between January 1997 and June 2014 at participating hospitals. Clinical factors, histopathological findings, biochemical markers and treatments were analysed and potential predictors of doubling serum creatinine, end stage kidney disease or death identified. A total of 98 patients were included with a median follow up of 4.3 years. Thirty-four (35%) patients were Aboriginal or Torres Strait Islander. Focal segmental glomerulosclerosis not-otherwise-specified was the most common variant. Seventeen (59%) patients initially treated with immunosuppression experienced an improvement in renal function. At the end of follow up, 43 (44%) patients had progressed to the composite outcome. Baseline tubulointerstitial scarring and lower haemoglobin predicted shorter time to doubling serum creatinine. Dual diagnosis, higher serum creatinine, lower estimated glomerular filtration rate and doubling creatinine were associated with shorter time to end stage kidney disease with remission the only protective factor. Age was the only variable associated with all-cause mortality. Focal segmental glomerulosclerosis holds serious implications for patients. Concomitant diabetic nephropathy, higher serum creatinine and lower estimated glomerular filtration rate at renal biopsy were associated with poorer renal prognosis. Indigenous people had a female predominance and are over-represented in relation to their population size, however, were not associated with poorer prognosis. Remission was the only modifiable variable and thus should be at the forefront of patient management goals and future studies.

Podocalyxin-positive glomerular epithelial cells in urine correlate with a positive outcome in FSGS

Parietal epithelial cells (PECs) and podocytes are the 2 epithelial cell types in the glomerulus. In contrast to podocytes, PECs have the ability to proliferate lifelong, and they can transdifferentiate into other cell types. We previously published that excretion of podocalyxin (PDX)-positive PECs in the urine correlates with disease activity in different glomerular diseases. In this analysis we investigated whether excretion of PDX-positive cells in the urine might have a prognostic value for proteinuria development and kidney function in focal segmental glomerulosclerosis (FSGS). We found that patients diagnosed with FSGS and with significant excretion of PDX-positive cells in the urine had a negative change in serum creatinine in the follow-up analysis. In contrast to that, FSGS-patients without excretion of PDX-positive cells showed a positive change in serum creatinine. There was a significant negative correlation between PDX-positive cells in the urine and change in serum creatinine. Mean change in urine protein in FSGS patients with excretion of PDX-positive cells in the urine did not differ significantly from patients with no cell excretion, but we could demonstrate a negative correlation between PDX-positive cells and change in total urine protein. Our data suggest that FSGS patients excreting large amounts of PDX-positive cells in their urine have a better outcome regarding kidney function and proteinuria compared with patients without excretion of PDX-positive cells. These data imply that PDX-positive cells have a positive effect on podocyte regeneration in FSGS patients.

Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population epidemiology and outcome

A working group has defined five subtypes of focal segmental glomerulosclerosis (FSGS) based on light microscopic assessment (Columbia classification). Limited information is available on the prognostic and therapeutic implications of this classification in a European population. We conducted a retrospective analysis in 93 adult patients with biopsy-proven FSGS to determine the clinical features and outcome of FSGS variants. Renal biopsy specimens of adult patients (>16 years) diagnosed with FSGS between 1980 and 2003 were reviewed according to the Columbia classification without the knowledge of clinical outcome. The medical records were reviewed for clinical data. Primary outcomes were remission rate and renal survival. The frequencies of the FSGS variants were: 32% NOS (FSGS not otherwise specified), 37% tip, 26% perihilar and 5% collapsing. Cellular FSGS was not found in the biopsies. The nephrotic syndrome was less frequent in FSGS NOS (57%) and perihilar FSGS (25%) compared to the tip variant (97%). Renal function was significantly better in patients with the tip variant compared to FSGS NOS (P<0.05). Glomerular sclerosis and hyalinosis was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant. Patients with perihilar FSGS were less likely to receive immunosuppressive medication. Renal survival at 5 years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for FSGS NOS and perihilar FSGS; P=0.02). Type of FSGS and serum creatinine concentration were independent predictors of renal survival. Remission rate was higher in patients with the tip variant (P=0.1). The collapsing variant was rare in our population. Renal survival and remission rates were higher in patients with the tip variant. Use of the classification scheme for FSGS may be clinically useful.

Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation.

Focal segmental glomerulosclerosis (FSGS) is known to recur in some patients after renal transplantation. Over a prolonged period, we followed 13 pediatric patients with FSGS who had undergone transplantation from living-related donors, analyzing risk factors for recurrent disease. Native nephrectomies were performed bilaterally in all patients at least 1 month prior to transplantation. Immunosuppressive therapy consisted of cyclosporine (CyA), mizoribine, prednisone, and antilymphocytic globulin or deoxyspergualin. We examined age at onset, time in months between diagnosis and end-stage disease (dialysis or transplantation), the duration of dialysis, age at transplantation, time since nephrectomy, doses of immunosuppressive agents, and HLA mismatch. Five patients (42.8%) developed recurrent disease in the graft; all showed proteinuria within 24 h of transplantation. However, all allografts have functioned well for 34-156 months following transplantation despite the recurrences, although 1 of these patients now shows proteinuria. The remaining 8 patients have had no recurrence for 104.6+/-30.4 months (mean+/-SD). The serum level of creatinine in patients with recurrence and without recurrence was 1.1+/-0.42 mg/dl and 0.98+/-0.29 mg/dl, respectively. The interval from diagnosis to initiation of dialysis was significantly shorter in patients with recurrence than those without recurrence ( P<0.05), but no other variables differed between these two groups. No recurrence of FSGS was observed in the protocol biopsy at 100 days after transplantation. We believe that CyA and native nephrectomy may limit or reverse progression of recurrent FSGS in renal allografts of Japanese pediatric patients, although this is a limited study.

Genetic polymorphisms of the renin-angiotensin system and the outcome of focal segmental glomerulosclerosis in children

The clinical course of primary focal segmental glomerulosclerosis (FSGS) in children is variable, with some patients having a much more rapidly progressing course than others. The purpose of our study was to compare the frequency of three polymorphisms of the renin-angiotensin system (RAS) in children with FSGS with that in healthy controls of matching ethnic groups, and to determine whether the clinical outcome of FSGS was associated with different RAS genotypes. Three RAS genotypes were examined in 47 Jewish and Arab children with biopsy-proven primary FSGS and in a large control group: the ACE insertion/deletion polymorphism in intron 16, the M235T mutation in the angiotensinogen gene, and the A1166C in the angiotensin II type 1 receptor gene (AT1R). Arab patients showed a greater tendency towards progressive renal disease than their Jewish counterparts (12 of 21 vs. 9 of 26, P = 0.05) and were less likely to achieve remission (3 of 21 vs. 11 of 26, P < 0.04), despite similar clinical presentation, medical management and follow-up. The RAS allele prevalence was similar among patients and controls of matching ethnic backgrounds, and no difference in allele frequency was found between Arabs and Jews. Homozygotes for the ACE insertion genotype (II) were significantly less likely to have progressive renal disease than patients with the other genotypes (ID and DD; 0 of 6 vs. 21 of 41; P < 0.022). The other RAS polymorphisms were not associated with variations in the clinical course of childhood FSGS. Homozygosity for the ACE insertion allele may have a protective effect in children with FSGS and can serve as a positive prognostic indicator at diagnosis. The D allele may exert a detrimental dominant effect on outcome. Neither the ACE gene polymorphism nor the other RAS polymorphisms studied are associated with disease prevalence. The AT1R and angiotensinogen gene polymorphisms are not associated with progression of renal disease in FSGS. Ethnic differences in the clinical course of the disease are not linked to these polymorphisms.

Age and Ethnicity Affect the Risk and Outcome of Focal Segmental Glomerulosclerosis in Children Presenting with Proteinuria 1692

Age and Ethnicity Affect the Risk and Outcome of Focal Segmental Glomerulosclerosis in Children Presenting with Proteinuria 1692

Evidence Suggesting Under-Treatment in Adults With Idiopathic Focal Segmental Glomerulosclerosis. Regional Glomerulonephritis Registry Study

From the Departments of Medicine, Pediatrics, and Pathology, University of Toronto, and the Metro Toronto Glomerulonephritis Registry, Toronto, Ontario, Canada. This work was supported in part by a Kidney Foundation of Canada (Ontario Branch) fellowship (Dr. Pei), and the Toronto Glomerulonephritis Registry was supported by the Kidney Foundation of Canada (Ontario Branch). Requests for reprints should be addressed to Dr. Daniel Cattran, ccrw 3-884, Toronto General Hospital, 101 College Street, Toronto, Ontario, Canada, M5G lL7. Manuscript submitted June 18, 1986, and accepted November 4, 1986. During the past 11 years, the Metro Toronto Glomerulonephritis Registry has prospectively followed all cases of glomerulonephritis starting from the time of biopsy. Focal segmental glomerulosclerosis was diagnosed by strict histologic criteria in 103 patients. Exclusion of patients with follow-up of less than 12 months reduced the number to 93 (55 adults and 38 children). Mean length of follow-up from the time of biopsy was 81 months. Ninety percent of children, but only 33 percent of adults received treatment with steroids, with or without cytotoxic drugs (p <O.OOl). Complete remission, defined as daily proteinuria of less than 250 mg, was not different in adults (39 percent) from that in children (44 percent), with a mean remission duration for all patients of 38 months. Chronic renal insufficiency, defined as a creatinine clearance of less than 0.8 ml/second/l .73 m* for more than 12 months, was slmilar in adults (40 percent) and children (34 percent). Five-year renal actuarial survival, defined as the absence of chronic renal insufficiency, was 98 percent for patients with a history of complete remission, and 55 percent for those without (p <0.0002). Logistic regression analysis showed treatment to be the only significant factor for complete remission (p <O.OOl). Complete remission, in turn, was important for renal preservatlon, defined as the absence of chronic renal insufficiency (p <O.OOl). Age did not affect the treatment response or long-term renal outcome in focal segmental glomerulosclerosis. Yet, the percent of adults treated was much lower than that of children, despite the fact that the majority of the untreated adults had the same clinical parameters as the treated adults and children. Thus, a judicious course of treatment is as much indicated in adults as in children with this disorder.

Evidence suggesting under-treatment in adults with idiopathic focal segmental glomerulosclerosis: Regional glomerulonephritis registry study

During the past 11 years, the Metro Toronto Glomerulonephritis Registry has prospectively followed all cases of glomerulonephritis starting from the time of biopsy. Focal segmental glomerulosclerosis was diagnosed by strict histologic criteria in 103 patients. Exclusion of patients with follow-up of less than 12 months reduced the number to 93 (55 adults and 38 children). Mean length of follow-up from the time of biopsy was 61 months. Ninety percent of children, but only 33 percent of adults received treatment with steroids, with or without cytotoxic drugs (p <0.001). Complete remission, defined as daily proteinuria of less than 250 mg, was not different in adults (39 percent) from that in children (44 percent), with a mean remission duration for all patients of 38 months. Chronic renal insufficiency, defined as a creatinine clearance of less than 0.8 ml/second/1.73 m 2 for more than 12 months, was similar in adults (40 percent) and children (34 percent). Five-year renal actuarial survival, defined as the absence of chronic renal insufficiency, was 96 percent for patients with a history of complete remission, and 55 percent for those without (p <0.0002). Logistic regression analysis showed treatment to be the only significant factor for complete remission (p <0.001). Complete remission, in turn, was important for renal preservation, defined as the absence of chronic renal insufficiency (p <0.001). Age did not affect the treatment response or long-term renal outcome in focal segmental glomerulosclerosis. Yet, the percent of adults treated was much lower than that of children, despite the fact that the majority of the untreated adults had the same clinical parameters as the treated adults and children. Thus, a judicious course of treatment is as much indicated in adults as in children with this disorder.