Journal of Pathology and Translational Medicine

Review

Pathogenesis of Focal Segmental Glomerulosclerosis: Beom Jin Lim, Jae Won Yang, Woo Sung Do, Agnes B. Fogo; J Pathol Transl Med. 2016;50(6):405-410. Published online October 16, 2016; DOI: https://doi.org/10.4132/jptm.2016.09.21

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Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

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Original Articles

C1q Nephropathy: A Distinct Pathologic Entity.: Jung Ha Shin, Tae Eun Kim, Kyo Young Lee, Sang In Shim, Yeong Jin Choi; Korean J Pathol. 2009;43(4):335-341.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.4.335

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Abstract PDF: BACKGROUND
C1q nephropathy (C1qN) is a controversial diagnostic entity defined by Jennette and Hipp in 1985. The prevalence is very low and a few large scale studies have been reported. Application of the criteria for clinical diagnostics of C1qN may cause confusion with other glomerulonephropathies, such as minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). In order to clarify the confusion with glomerulonephropathies, we did this study to identify the clinicopathological characteristics and the exact disease entity of C1qN.
METHODS
A total of 5,258 kidney biopsies at Kangnam St Mary's Hospital were reviewed. Twenty three cases (0.44%) met the criteria of C1qN. Twenty eight cases showing dominant C1q deposits without electron dense depostis (EDD) grouped as C1q+EDD-, and previously diagnosed typical cases of MCD and FSGS were selected for this study. Four groups were compared to each other with regard to the clinical and pathological aspects of the disease. RESULTS: C1qN patients had an average age of 30.4 years. Eighteen were males and 5 were females. Eighty seven percent had proteinuria and 18% had hematuria. By electron microscopy analysis, 100% had mesangial EDD and 47.8% showed foot process effacement. C1qN had some significant differences compared with C1q+EDD-, MCD and FSGS. CONCLUSIONS: C1qN is clinically and morphologically different from MCD and FSGS. However, additional long term studies are needed to fully define C1qN from other glomerulonephritis with C1q deposits.

Glomerular Hypertrophy in Focal Segmental Glomerulosclerosis.: So Dug Lim, Tae Sook Kim, Hyun Soon Lee; Korean J Pathol. 1995;29(4):423-430.

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Abstract PDF: It is not clear whether glomerular hypertrophy is related to the pathogenesis of focal segmental glomerulosclerosis (FSGS). We analyzed renal biopsies from 20 adults with FSGS by morphometry, and the data were compared with those from age- and sex-matched patients with minimal lesion. Mean glomerular volume in the FSGS group was significantly larger than that in the minimal lesion group[(3.4 + 1.1 vs 2.5 0.5)x10(6) micrometer3, P<0.01]. The percentage of glomeruli with global and segmental sclerosis in FSGS group was significantly correlated with the mean glomerular volume (r=+0.66, P<0.001). Relative interstitial volume of renal cortex in the FSGS group was correlated with the serum creatinine concentration(r=+0.5, P<0.05). These results suggest that glomerular hypertrophy observed in our patients with FSGS was related to nephron loss caused by glomerulosclerosis. The interstitial fibrosis may lead to obliteration of postglomerular interstitial capillary network with secondary elevation of glomerular capillary pressure resulting in progressive loss of renal function.

Morphometric Analysis of Preeciamptic Nephropathy with Focal Segmental Glomerulosclerosis.: Tae Sook Kim, Hyun Soon Lee; Korean J Pathol. 1995;29(5):624-633.

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Abstract: To evaluate the structural characteristics that might be related to the clinical features noted in preeclamptic patients with focal segmental glomerulosclerosis(FSGS), we analyzed post-partum renal biopsies of 8 preeclamptic patients with FSGS (group 1) by morphometry and glomerular studied the structural-functional relationships. These findings were also compared with those from three postpartum cases with minimal change lesion(group 2) and normal age-matched women(group 3). Mean glomerular volume (MGV) in group 1 and group 2 was (2.64 +/- 0.49) x 10(6) micrometer3 and (2.56+/-0.25)x 10(6) micrometer3, respectively. MGV in both groups was significantly increased compared with that of the control group [(1.11+/-0.22)x10(6) micrometer3](p<0.0005). The volume density of the mesangium/glomerulus [Vv(mes/glom)] in the group 1 patients was significantly increased (p<0.0001) when compared with that of the group 2 and the control group patients. The increment of Vv(mes/glom) was related to both the mesangial cell proliferation and expansion of mesangial matrix. The volume density of the capillary lumen/glomerulus [Vv(cap/glom)] in group I was significantly decreased(p<0.0001) when compared with that of group 2 and the control group. Vv(cap/glom) was directly related to Ccr in group l(r=0.70, p=0.05). These results suggest that reduced capillary luminal area caused by mesangial interposition is related to the decreased glomerular filtration rate in preeclamptic FSGS.

Comparison of Glomerular Size between Focal Segmental Glomerulosclerosis and Minimal Lesion in Children.: Jung Yeon Kim, Hyun Soon Lee; Korean J Pathol. 1996;30(10):903-911.

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Abstract PDF: The pathogenetic mechanism of focal segmental glomerulosclerosis (FSGS) is not known. Some authors suggest glomerular hypertrophy may precede the development of FSGS in patients with minimal lesion. It was recently reported that the size of nonsclerotic glomeruli in adults with FSGS is significantly larger than that of cases with minimal lesion. It is not clear whether glomerular hypertrophy observed in adults with FSGS is also seen in children with FSGS. Thus, we have analyzed 37 renal biopsies from children with FSGS by morphometry and the data were compared with 37 renal biopsies from age- and sex-matched patients with minimal lesion. The number of glomeruli submitted for morphometric analysis was 22.6+/-14.2 in cases with FSGS and 30.9+/-11.4 in cases with minimal lesion. Mean glomerular volume (MGV) in FSGS group was significantly larger than that of minimal lesion [(13.1+/-3.9) x10(5) microm3 vs. (10.1+/-1.9) x10(5) microm3, p<0.001]. The relative interstitial volume of renal cortex in patients with FSGS was significantly larger than that of minimal lesion [(0.106+/-0.051) microm3/microm3 vs. (0.029+/-0.012) microm3/microm3, p<0.0001]. In FSGS, the percentage of glomeruli with FSGS was significantly correlated with relative interstitial volume of renal cortex (r=0.79, p<0.0001). As is the case for adult FSGS, MGV of children with FSGS is significantly larger than that of minimal lesion. Thus, the presence of glomerular hypertrophy observed in biopsies with minimal lesion nephropathy seems to be an indication that the coexistent FSGS lesions are undetected due to sampling problems.

The Effects of Cyclosporine A on Minimal Change Nephrosis and Focal Segmental Glomerulosclerosis Induced by Administration of Puromycin Aminonucleoside in Rats.: Sun Hee Sung; Korean J Pathol. 1996;30(11):981-997.

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Abstract PDF: Cyclosporine A(CsA) is known as a potent immunosupressive agent, and recently its supressive effects of proteinuria in minimal change nephrotic syndrome, and other glomerular diseases have been demonstrated. But the mechanism of supression of proteinuria is not clear. This study aimed to investigate the mechanism of supression of proteinuria in puromycin aminonucleoside (PAN) induced minimal change nephrosis(MCN), by a single dose of PAN, and focal segmental glomerulosclerosis(FSG) by long term repeated administration of PAN with unilateral nephrectomy in Sprague-Dawley rats, using transmission electron microscopy. We also analysed the effects of CsA on the histopathologic changes such as glomerular sclerosis, and subtypes of infiltrated mononuclear cells in glomeruli and renal interstitium. The results are as follows: Marked proteinuria was developed in MCN and FSG groups. It was significantly reduced by administration of CsA. BUN and creatinine were significantly increased in FSG with the administration of CsA, compared with FSG without CsA. On ultrastructural examination, MCN group showed effacement of foot processes, and microvillous transformation. Occasional focal detatchment of podocytes from the GBM, vacuolar degeneration, and electron dense droplets in the podocytes were also seen. The latter findings were remarkably reduced by CsA. The Above ultrastructural findings, seen in the MCN group, were more severe in the FSG groups. On comparison of ultrastructural fingings of FSG with or without CsA groups, severe vacuolar degeneration, abundant electron dense granules, and focal detatchment of foot processes were more frequently seen in FSG groups and they were significantly reduced by CsA. But irregularity and thickening of GBM were deepend in FSG with CsA group. There were no significant differences of glomerular sclerosis, adhesion to the Bowman's capsules in both the MCN and the FSG groups by administration of CsA. Foamy degeneration of endothelial and mesangial cells, epithelial proliferation, hyalinosis and mononuclear infiltration were significantly reduced by CsA in FSG groups. Microcalcification was commonly seen in CsA administrated groups. The main sutype of infiltrated mononuclear cells in glomeruli and interstitium were monocytes in FSG groups. The proportion of T cells were higher in interstitium by disease progression and it was significantly decreased by CsA. On conclusion the most important ultrastructural changes, regarded as the main mechanism of supression of proteinuria is that the CsA stabilize the podocytes, by preventing vacuolar degeneration and focal detatchment. But CsA does not influence the progression of glomerular sclerosis in PAN induced nephrosis.

Experimental Study of the Progressive Glomerulosclerosis Induced by Long-term Administration of Puromycin Aminonucleoside in Rats.: Mi Kyung Kim, Hyun Soon Lee; Korean J Pathol. 1993;27(1):1-10.

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Abstract PDF: Pathogenetic mechanisms of progressive glomerulosclerosis are not clear. We studied the long-term(10 weeks) effects of puromycin aminonucleoside(PAN) in Sprague-Dawley rats with or without uninephrectomy(UN). Compared to rats with PAN injections only, rats with uninephrectomy and PAN injections showed significantly higher serum levels of urea nitrogen(153 +/- 155 mg/dl vs. 16 +/- 4 mg/dl, p<0.01), ceatinine(2.96 +/- 1.21 mg/dl vs. 0.92 +/- 0.36 mg/dl, p<0.01), cholesterol(466 +/- 125 mg/dl vs. 94 +/- 27 mg/dl, p<0.01), and triglyceride(337 +/- 237 mg/dl vs. 111 +/- 36 mg/dl, p<0.05) as well as increased amounts of proteinuria(428 +/- 90 mg/day vs. 136 +/- 130 mg/day, p<0.01). Lesions of focal segmental glomerulosclerosis(FSGS) were more frequently observed in rats with UN and PAN injections than rats with PAN infections only(39.5 +/- 17.2% vs. 4.3 +/- 4.7%, p<0.01). Ultrastructural examination of the glomeruli from rats with UN and PAN injections revealed severe epithelial cell changes including foot process effacement, vaculoar change or pseudocyst formation and focal detachment of epithelial cells from the underlying basement membrane. The results suggest that chronic nephrosis induced by PAN showed functional and morphologic features similar to those of human FSGS. Cytotoxic effect of PAN on the glomerular epithelial cells may be an initiating factor for the development of FSGS. which may be aggravated by some hemodynamic changes induced by uninephrectomy.

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