FSGS is a chronic progressive disease that occurs at a high rate in patients with NS. In addition, it has a high recurrence rate after kidney transplantation6. In recent years, the incidence of FSGS has increased, hormone therapy is not sensitive, and the prognosis is relatively poor. Approximately 50% of patients gradually progress to CKD within 5–10 years7. Glomerulosclerosis is defined as the increase of the mesangial matrix, the disappearance of capillary loops, and the hyaline degeneration of affected segments. According to the distribution, it can be divided into diffuse (sclerotic glomerulus ≥ 50% of all glomeruli in the sample are diffuse), focal (sclerotic glomerulus < 50% of all glomeruli in the sample), spherical (sclerotic glomerulus ≥ 50% of glomerular capillary loops), and segmental (sclerotic glomerulus < 50% of glomerular capillary loops are spherical). In our FSGS cohort, the total SGR was 13%, and the SGR was higher in the F2 group (22.0%) than that in the F1 group (12.5%), which, combined with the reduced podocyte density and the degree of foot process effacement, suggested that the glomerular injury was more severe in the F2 group. FSGS is characterized by focal and segmental glomerulosclerotic lesions under LM. According to the Colombian classification criteria, FSGS is divided into non-specific, perihilar, cellular, tip, and collapse types4,5. Matsusaka et al. constructed a FSGS mouse model (NEP25), and the amount of urine protein was positively correlated with the intervention factors in a dose- and time-dependent manner. They also found that podocyte damage can be transmitted to adjacent podocytes to form a vicious circle, segmental sclerosis spreads from one glomerulus to another, nephrons are gradually lost, and residual glomerular compensatory hypertrophy and pathological changes become progressively worse8. However, few studies have investigated the proportion of segmental sclerosis glomeruli in renal biopsy specimens. In this study, we focused on the glomerular proportion of segmental sclerosis; we performed a statistical analysis of its correlation with clinical symptoms and prognosis to provide a more intuitive and quantitative theoretical basis for the treatment and outcome of FSGS.
Podocytes, a type of visceral epithelial cell, are inherent cells of the kidney. These are located in the outermost layer of the glomerular filtration membrane. Podocytes, which play a vital role in the renal system, have multiple functions, such as participating in selective glomerular filtration, biosynthesis, and maintenance of the glomerular capillary structure. Podocytes are terminally differentiated cells; therefore, their ability to divide and proliferate is limited. In 2002, Pollak first proposed the concept of podocytopathy, which is a group of glomerular diseases characterized by a reduction in the number and/or density of glomerular podocytes, thickening of the glomerular basement membrane, changes in the composition of the glomerular matrix, foot process fusion, etc.9. FSGS is the most common type of podocytopathy disorder. The damage or loss of podocytes plays a crucial role in the occurrence and development of FSGS. We observed that the fluorescence intensity of synaptopodin was significantly reduced in patients with FSGS with a higher proportion of glomerular segmental sclerosis. The decreased intensity of synaptopodin, a specific marker of podocytes10, suggested a much greater reduction in the density and loss of podocytes; moreover, FSGS was more severely damaged. We also observed that foot process fusion was more evident in the F2 group under EM. Foot process fusion is a characteristic ultrastructural change in podocyte injury, and the foot processes became flat, fused, and almost disappeared under EM (Electron Microscopy). Foot process fusion and podocyte loss suggest more severe damage to the podocytes. Our analysis indicated that podocyte damage severity was closely related to the proportion of glomerular segmental sclerosis in FSGS.
FSGS lesions not only show structural and functional disorders of podocytes but are also often accompanied by damage to other intrinsic glomerular cells, such as mesangial cells and endothelial cells. Therefore, we added the analysis of other pathological changes in FSGS and found significant differences between the two groups in the degree of mesangial cell proliferation, vascular injury, and renal tubulointerstitial injury. At the same time, dual-factor correlation analysis showed that the intensity of IgM deposition, proportion of glomerular sclerosis, and proportion of renal tubulointerstitial injury were significantly related to the proportion of glomerular segmental sclerosis. Some scholars have developed a podocyte-deficient mouse model for studying FSGS in a podocyte-specific sialylation-deficient mouse model and observed the kidney tissue of mice under LM. Podocyte damage leads to severe glomerular lesions, including mesangial cell proliferation and adhesion11. In 2022, Jarcy Zee et al.12 applied 48 quantifying histological and 20 ultrastructural indicators to the NEPTUNE (Nephrotic Syndrome Study Network) digital pathology scoring system to diagnose and evaluate MCD (minimal change disease) and FSGS. Through model prediction analysis, they found that glomerulosclerosis was one of the most predictive factors. A comparative study of 207 FSGS patients from three different cohorts found that glomerulosclerosis beyond age adjustment was associated with prognosis. The Cox proportional hazard model showed that FSGS patients with glomerulosclerosis had a 3.2-fold risk of ESRD13.
The renal tubules are mainly responsible for recollection, excretion, and concentration functions and maintain the balance of liquids, electrolytes, and acid–bases. We studied 206 patients with FSGS; IFTA (renal tubule/interstitial score) 0/1/2:149/35/22 (72%, 17%, and 11%), and the overall distribution trend of IFTA injuries was similar to that of Ossareh14; 71/24/5 (71%, 24%, and 5%). However, the renal tubule atrophy/interstitial fibrosis scores between the two groups differed significantly according to the proportion of segmental sclerotic glomeruli. The dual-factor correlation analysis also confirmed that there was a significant correlation between them, indicating that the FSGS subgroup could better quantify renal lesions. Ossareh et al. also found that the IFTA was a predictor of ESRD in a predictive model designed for the prognosis of FSGS. The risk of ESRD increased 1.06 times with an increase in tubule atrophy and interstitial fibrosis14.
Complement fragment C4d is an inert product produced by the cleavage of iC4b in the process of complement activation, which can occur during the activation of the classical complement and mannose lectin pathways. Complement C4, which is activated through the classical pathway, gradually splits into C4d, which can be used as a marker of humoral immune responses15. Originally, C4d was mainly used in follicular lymphoma and organ transplantation antibody-mediated rejection. In recent years, C4d has been found to be strongly positive in immune complex-mediated glomerulonephritis, such as thrombotic microangiopathy, lupus nephritis, and membranous nephropathy. In IgA nephropathy (38%) and FSGS, positive expression of C4d was distributed to different degrees16. Some studies showed that C4d could be an important indicator of poor prognosis in patients with IgA nephropathy. It was reported that C4d in FSGS could be deposited linearly along the basement membrane in segmental sclerosis through clumps in the mesangial area and coarse granular shapes in vascular poles. The shape and position of C4d deposition in FSGS can not only be used as an effective activity indicator but also as an important indicator of disease prognosis17. It was reported that the deposition of C4d in the mesangial region was an independent factor for predicting disease progression and efficacy in FSGS patients18. Our study found that C4d is closely related to the proportion of glomerular segmental sclerosis in FSGS.
FSGS is a common pathological type of NS. Damage to podocytes results in injury to the filter barrier, and a large amount of protein leaks out, often leading to hypoalbuminemia and severe proteinuria. Proteinuria remission is an important indicator of the therapeutic effects of nephropathy. Thomas et al. found that the renal survival rate of patients with complete or partial remission of proteinuria was significantly higher than that of patients without remission when they conducted a prognostic analysis of 60 children with FSGS from the glomerular disease collaboration network; complete remission of albuminuria was associated with a 90% risk reduction of ESRD19. Prognostic analysis of 116 adult FSGS patients showed that due to the use of immunosuppressants, severe proteinuria at baseline did not affect the prognosis; however, remission of proteinuria was still an independent predictor of renal survival, and even patients with partial remission of proteinuria had a better prognosis20. In this study, we analyzed the effect of the FSGS subgroup on proteinuria remission and found that although there was no difference in the baseline proteinuria values between groups, the F1 group was higher than the cumulative remission rate of proteinuria in the other group. The prognosis of FSGS was influenced by many factors21. The remission of proteinuria suggested that renal damage was reduced, and renal outcomes were improved22. In 2012, some scholars conducted a cross-sectional study on the correlation between globular sclerosis, segmental sclerosis, and serum creatinine levels and clearance rate in fifty patients. They found that in addition to the degree of interstitial fibrosis, serum creatinine levels and clearance rates were closely related to the proportion of segmental sclerosis and global sclerotic glomeruli23. This finding is consistent with the results of our study. We further analyzed the survival of the two subgroups of FSGS, and the results showed a significant difference in renal survival rate between the two groups. The Cox multifactor correlation analysis showed that the risk of patients in the F2 group entering ESRD was 2.3 times and the GSR > 20% was 4.6 times higher than that in the F1 group, and the increased serum creatinine value at different levels was also a high-risk factor for FSGS patients to progress to ESRD. Ossareh et al. also reached a consistent conclusion on 201 patients with FSGS using the model to predict the prognosis14.
There are some limitations in this study: as a single-center, retrospective observational study, the deviation error of test results increased and a vastly expanded and diverse cohort would be recruited in the future.
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- Source: https://www.nature.com/articles/s41598-024-59007-5