Focal Segmental Glomerulosclerosis Lesions Research Articles

Obesity, diabetes, and chronic kidney disease

Similar to diabetes, obesity is associated with the early onset of glomerulomegaly, hemodynamic changes of a hyperfiltering kidney, and increased albuminuria, which are potentially reversible with weight loss. However, the pathologic lesions of focal segmental glomerulosclerosis in experimental models of sustained obesity, and in obese humans presenting with massive proteinuria, are different from those of classic diabetic nephropathy. In addition, several observational, cross-sectional, and longitudinal studies document obesity as an independent risk factor for the onset, aggravated course, and poor outcomes of chronic kidney disease, even after adjustment for confounding comorbidities, including diabetes and hypertension, the two major causes of chronic kidney disease.

Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy

The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.

Renovascular Hypertension: A Unique Cause of Unilateral Focal Segmental Glomerulosclerosis

A 48-year-old man presented with malignant hypertension and massive proteinuria. Renal angiography showed complete obstruction of the left renal artery and 99mTc-mercaptoacetylglycine (MAG3) renography showed a nonfunctioning left kidney. Percutaneous transluminal renal angioplasty of the left renal artery was unsuccessful; hence, the patient underwent left nephrectomy because of uncontrolled hypertension and proteinuria. Histological examination of a right kidney specimen revealed lesions of focal segmental glomerulosclerosis with benign nephrosclerosis. In contrast, histology of the left kidney showed typical ischemic kidney with hypertrophy of arteriolar smooth muscle cells. The patient responded favorably to the nephrectomy, as his blood pressure and urinary protein dramatically decreased with no antihypertensive medication. This case illustrates the heterogeneous effect of the renin-angiotensin system on either kidney in patients with renovascular hypertension due to unilateral renal artery stenosis.

The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is one of the most common patterns of glomerular injury encountered in human renal biopsies. Epithelial hyperplasia, which can be prominent in FSGS, has been attributed to dedifferentiation and proliferation of podocytes. Based on observations in a mouse model of FSGS, we pointed to the role of parietal epithelial cells (PECs). In the present study we investigated the relative role of PECs and podocytes in human idiopathic FSGS. We performed a detailed study of lesions from a patient with recurrent idiopathic FSGS by serial sectioning, marker analysis and three-dimensional reconstruction of glomeruli. We have studied the expression of markers for podocytes, PECs, mesangial cells, endothelium, and myofibroblasts. We also looked at proliferation and composition of the deposited extracellular matrix (ECM). We found that proliferating epithelial cells in FSGS lesions are negative for podocyte and macrophage markers, but stain for PEC markers. The composition of the matrix deposited by these cells is identical to Bowman's capsule. Our study demonstrates that PECs are crucially involved in the pathogenesis of FSGS lesions.

Signs and symptoms of thin basement membrane nephropathy: A prospective regional study on primary glomerular disease—The Limburg Renal Registry

To chart the epidemiology of primary glomerular disease by means of a prospective regional study in the southern part of The Netherlands. Experienced renal technicians collected renal biopsies, blood, and 24-hour urine samples at the bed site in each of the participating hospitals. The material was processed and analyzed at the University Hospital Maastricht. Analysis included light microscopy, immunohistochemistry, and electron microscopy of the biopsies as well as serologic and chemical analysis. Primary IgA nephropathy (IgAN), membranous glomerulopathy, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and thin basement membrane nephropathy (TBMN) are the most common primary glomerular diseases in this order of sequence. Our data show the clinical and histologic phenotype of TBMN to be diverse: the vast majority of TBMN has chronic microscopic hematuria, frequently associated with hypertension in late middle age; about 15% of TBMN has in addition substantial proteinuria which is associated in the majority of cases with the lesions of focal segmental glomerulosclerosis (FSGS). In 5% of TBMN a nephrotic syndrome is observed, occasionally associated with FSGS tip lesions. These results support the notion that TBMN is a disease of genetic heterogeneity; it is not a benign renal condition in a substantial number of patients, particularly those in late middle age.

Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants.

The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P = 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P < 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P = 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P = 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.

The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.

Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production.

Cyclosporine nephrotoxicity: how does it affect renal allograft function and transplant morphology?

Chronic CSA nephrotoxicity is the second most important diagnosis responsible for the late graft failure. CSA associated arteriolopathy (CAA) is a well-known lesion of chronic CSA nephrotoxicity. The clinicopathological characteristics and the significance of CSA nephrotoxicity have changed following reduction in CSA doses and implementation of monitoring of blood levels. Seventy-four CAA patients on CSA therapy were classified as functioning ( n = 30) or loss groups ( n = 44). There was no significant difference in severity of CAA. The concomitant lesion of chronic rejection, but not the severity of CAA, was the most important risk factor for graft loss. Among 54 recipients with focal segmental glomerulosclerosis lesions (FGS), 32 (59%) were diagnosed as CAA associated glomerulopathy (CAG). Eighteen of the 32 CAG patients lost their grafts upon follow-up. Decreasing the CSA dosage to maintain lower blood levels than the usually optimal concentrations, but not discontinuation of CSA, has been useful to retard the progression of graft dysfunction in half of 15 isolated pure CAG patients. Patients with increasing daily proteinuria exceeding 2 grams lost their graft function despite CSA reductions. CAA is not a specific lesion of chronic CSA nephrotoxicity; the FGS lesion is also a nonspecific lesion often seen in renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy. The FGS lesion accompanying CAA is considered to be CSA-associated glomerulopathy. These data contribute to therapeutic plans for renal transplant patients during long-term CSA treatment.

Interpreting segmental glomerular sclerosis

The term ‘focal segmental glomerulosclerosis’ (FSGS) is used to describe the common morphologic lesion underlying various progressive renal diseases and also to describe the clinical syndrome with occurrence of the primary idiopathic lesion of focal segmental glomerulosclerosis. Different morphological patterns of focal segmental glomerulosclerosis are associated with different processes, reflecting the presence of diverse pathogenic mechanisms leading to focal sclerosis. The diagnosis of FSGS rests first on the recognition of segmentally sclerotic glomeruli, and then on specific morphologic features to distinguish the various types of FSGS. Five main light microscopic patterns of FSGS have been defined by the Columbia Consensus Classification of FSGS. Some of these patterns may be also observed in some secondary forms of FSGS. The location of sclerosis and the recognition of particular light microscopic patterns, immunofluorescence and electron microscopy findings can provide important information about the aetiology and prognosis of the lesion.

Cell-cycle mechanisms involved in podocyte proliferation in cellular lesion of focal segmental glomerulosclerosis

Background: Podocyte injury may induce podocyte proliferation, which results in glomerular scarring. The cellular lesion, seen in some patients with primary focal segmental glomerulosclerosis (FSGS), is characterized by proliferation of cells covering the sclerotic or collapsed glomerular tufts. Cell-cycle mechanisms by which podocyte proliferation occurs in the cellular lesion of FSGS are unclear. Methods: We examined expression patterns of cyclin D1; cyclin E; cyclin A; cyclin B1; cyclin-dependent kinase (CDK)2; CDK4; such CDK inhibitors as p21WAF1/CIP1 (p21), p27kip1 (p27), and p57kip2 (p57); and Wilms’ tumor protein-1 (WT-1) in 12 renal biopsy specimens with the cellular lesion of FSGS and 6 renal biopsy specimens with no detectable abnormalities by immunohistochemistry and immunoelectron microscopy. Messenger RNA (mRNA) expression patterns of cyclin D1, cyclin E, p21, p27, and p57 were evaluated further by in situ hybridization. Results: In controls, immunostaining for cyclin A, cyclin B1, CDK2, CDK4, and p21 was almost negligible, but positive signals for cyclin D1, cyclin E, p27, and p57 were observed in glomerular epithelial cells (GECs). In the cellular lesion of FSGS, positive signals for cyclin E, cyclin A, cyclin B1, CDK2, and p21 were present in GEC nuclei, in which WT-1, p27, p57, and cyclin D1 were undetected. Immunoelectron microscopy showed that cyclin E-, CDK2-, and p21-specific gold particles were increased significantly in GEC nuclei in the cellular lesion in which cyclin D- and p57-specific particles were absent compared with controls. An in situ hybridization study showed specific signals of cyclin D1, cyclin E, p21, p27, and p57 mRNA in GECs forming the cellular lesion of FSGS. Conclusion: Our results suggest that damaged podocytes may inhibit p27 and p57 protein expression, but activate a cyclin D1–independent cell-cycle mechanism and mitotic cell cyclins to promote GEC proliferation in the cellular lesion of FSGS.

Podocan, a Novel Small Leucine-rich Repeat Protein Expressed in the Sclerotic Glomerular Lesion of Experimental HIV-associated Nephropathy

Growing evidence suggests that human immunodeficiency virus (HIV)-1 infection of podocytes plays a central role in the glomerular disease of HIV-associated nephropathy (HIVAN). As an approach to identify host genes involved in the pathogenesis of the sclerotic glomerular lesion in HIVAN, representational difference analysis of cDNA was used to identify differentially expressed genes in HIV-1 transgenic and nontransgenic podocytes. We isolated a novel member of the small leucine-rich repeat (SLR) protein family, podocan, that is expressed at high levels in the HIV-1 transgenic podocytes. In normal embryonic kidney, a 3.2-kb podocan transcript was detected at low levels, and expression increased dramatically within 24 h following birth. Expression of a 2.3-kb transcript became evident after birth and gradually increased to 50% of the total podocan RNA in the mature kidney. Phylogenetically, podocan represents a new class in the SLR protein gene family, an expanding protein family sharing homology with the small leucine-rich repeat proteoglycans. The 3.2-kb transcript encodes a predicted 611-amino acid secretory protein with 20 leucine-rich repeats, a unique N-terminal cysteine-rich cluster pattern and a highly acidic C-terminal domain. In situ hybridization of normal kidney revealed podocan mRNA expression in podocytes and likely vascular endothelial cells within the glomerulus. The immunohistochemical staining pattern of podocan protein in normal kidney glomeruli was consistent with that of the glomerular basement membrane, and staining was markedly increased in sclerotic glomerular lesions in the transgenic HIVAN model. Thus, podocan defines a new class within the SLR protein family and is a previously unrecognized component of the sclerotic glomerular lesion that develops in the course of experimental HIVAN.

Focal segmental glomerulosclerosis in adults.

The lesion of focal segmental glomerulosclerosis (FSGS) presents even greater problems of definition, interpretation and treatment in adults than it does in children, to the point where the specificity and utility of the appearance can even be questioned. The histological diagnosis of FSGS in adults can be interpreted only if the clinical circumstances are known, but a group of nephrotic patients with FSGS can be separated from a much larger group of non-specific, probably secondary but similar lesions arising in many circumstances. This group appears even so to have a diverse aetiology, the majority being idiopathic, but a significant minority showing a family history and/or mutations in genes relating to several intracellular or surface podocyte proteins, as discussed in other articles in this symposium. This heterogeneity makes conclusions with regard to prognosis and treatment difficult to draw. Today, in contrast to 20 or even 10 years ago, it seems useful to treat all adult nephrotic patients with FSGS using an adequate course of corticosteroids lasting at least 4-6 months to establish whether they fall or not into the 20-30% who will respond to this treatment with decrease or loss of proteinuria. The prognosis of such responders (who may well suffer relapse) is relatively benign with regard to renal function, but the majority of the remainder evolve into renal failure. Their management remains a source of controversy in the absence of a proper database of randomized trials: more prolonged (up to 24 months) use of lower-dose corticosteroids with cyclosporine for 12 months or more has support from uncontrolled studies, but cyclophosphamide appears to be of less obvious benefit.

Autosomal dominant progressive nephropathy with deafness: linkage to a new locus on chromosome 11q24.

Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: -6.1 and -4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at theta = 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype.

Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation

In the past it was widely assumed that hyaline afferent arteriolosclerosis was responsible for ischemic glomerulosclerosis in the aging and hypertensive kidney. However, glomerular lesions of focal segmental glomerulosclerosis are now recognized in essential hypertension. Experimentally, such lesions are associated with loss of autoregulation of blood flow and glomerular hyperperfusion, as well as initial glomerular hypertrophy. These observations challenge the notion of ischemia as a unitary explanation for glomerulosclerosis. A morphometric study was performed on normal portions of eight kidneys removed for tumors in aging, normotensive patients. Measurements were made of 126 pairs of afferent arterioles and their associated glomeruli. In addition, the amount of extracellular matrix (ECM) in the immediate periglomerular region was quantitated. Afferent arterioles were divided into three types according to the presence or absence of hyaline deposits and whether these did or did not obstruct the lumen. Arterioles with nonobstructive hyaline deposits had lumens over twice as large as those without deposits (482 +/- 240 micro2 vs. 204 +/- 160 micro2, P=0.0000). Their associated glomeruli had significantly greater total capillary area, particularly the hilar capillaries (1276 +/- 797 micro2 vs. 667 +/- 492 micro2, P=0.002), but with larger individual capillaries elsewhere as well (P=0.03). Arterioles with obstructive deposits differed from those with nonobstructive deposits by their smaller lumens (P=0.001) and walls (P=0.004), with a higher proportion of ECM in the periglomerular region (P=0.001), all consistent with a later stage of lesion. Glomeruli were divided into four basic types: normal, hypertrophic, glomeruli with features of focal segmental glomerulosclerosis (FSGS-type), and ischemic. Compared to normal glomeruli, hypertrophic glomeruli were larger, with greater total capillary area (P=0.0005), particularly the hilar capillaries (P=0.0000), and larger capillaries in the remainder of the tuft (P=0.003), but showed no evident lesions. FSGS-type glomeruli were also larger, with larger hilar capillaries (P=0.0005), but showed an increase in ECM due to sclerotic lesions (P=0.004). The remaining capillaries showed an inverse relation with the amount of mesangial matrix, showing a spectrum of sizes from enlarged to shrunken. As anticipated, ischemic glomeruli were significantly smaller than normal ones in every parameter measured. There was a strong association between hypertrophic/FSGS-type glomeruli and hyaline arteriolosclerosis, found in 90.3% of such glomeruli, versus 29.1% for the remaining glomeruli (P=0.0001). The great majority of hyaline deposits were of the nonobstructive variety (86.2%), but some were obstructive (13.8%), particularly in FSGS-type glomeruli, consistent with a more advanced lesion. We believe we have demonstrated in the aging kidney of humans the morphologic correlates of loss of autoregulation, occurring on a focal basis, with afferent arteriolar dilatation and increase in glomerular capillary size and subsequent focal segmental glomerulosclerosis. Hyaline arteriolosclerosis of the nonobstructive sort is strongly associated with these changes and may play a role in their pathogenesis.

Clinical and morphological prognostic factors in membranous nephropathy: Significance of focal segmental glomerulosclerosis

Background: Progression of idiopathic membranous glomerulonephritis (IMGN) to renal insufficiency depends on various clinical and laboratory factors that have been taken into account in most therapeutic trials based on such aggressive drugs as alkylating agents or cyclosporine. However, few studies have envisaged the prognostic significance of morphological factors and their importance for stratification of patients enrolled in therapeutic trials. Methods: Records of patients with membranous glomerulonephritis (MGN) from 1976 to 2001 from five nephrology units were reviewed retrospectively. Secondary causes were ruled out, especially occult malignancy. Eligible cases were analyzed according to clinical profile, abundance of proteinuria, blood pressure, and standard renal pathological characteristics, including MGN staging, vascular lesions, and degree of interstitial fibrosis on a semiquantitative scale. Renal survival curves from renal insufficiency were calculated by the Kaplan-Meier method. Mean follow-up was 68 months. Results: Initial multiple regression analysis showed that the most significant prognostic variable was the presence of focal segmental glomerulosclerosis (FSGS)-type glomerular lesions (P < 0.001), and patients therefore were divided into two groups: 42 patients had MGN only (group I) and 30 patients had superimposed FSGS (group II). Group II patients were more hypertensive, and all renal lesions were significantly more severe, with a higher mean stage of membranous lesions, more obsolescent glomeruli, greater mesangial proliferation, and worse interstitial fibrosis and vascular lesions. Renal survival for group II was significantly lower (P < 0.001, log-rank test). Only one remission occurred in group II, whereas 38% of group I patients experienced remission (P = 0.002). We pooled our results with those of three previous studies in the literature, totaling 282 patients (156 patients, MGN alone; 126 patients, MGN plus FSGS). Remission rates were 32% and 12.7%, respectively (P < 0.001). The prognostic value of hypertension was noted in three of the four series, including ours. Conclusion: FSGS lesions superimposed on IMGN are common and portend a significantly worse outcome in terms of nephrotic syndrome and renal insufficiency. Therefore, we consider that future therapeutic trials of IMGN should include case stratification based on the presence or absence of FSGS on pretreatment biopsy. Am J Kidney Dis 41:38-48. © 2003 by the National Kidney Foundation, Inc.

Differential expression of platelet‐derived growth factor and transforming growth factor‐β in relation to progression of IgA nephropathy

SUMMARY: The role of platelet‐derived growth factor (PDGF) and transforming growth factor‐β1 (TGF‐β1) in relation to mesangial matrix expansion and progressive glomerulosclerosis in IgA nephropathy (IgAN) is not clearly defined. Expression of PDGF B, TGF‐β1, and extracellular matrix proteins in glomeruli was assessed by immunohistochemistry in 42 biopsies with IgAN and six renal biopsies with no detectable abnormalities. The mRNA expression of PDGF B, TGF‐β1, α1(IV) collagen, laminin B1 and fibronectin genes was further evaluated by in situ hybridization in 25 biopsies with IgAN and six controls. In IgAN, the intensity of immunostaining for PDGF B, type IV collagen, laminin and fibronectin, but not for TGF‐β1, was increased in the mesangium compared with controls. The immunoreactivity of PDGF B was closely correlated with that of type IV collagen and laminin. The number of PDGF B mRNA‐, α1(IV) collagen mRNA‐, laminin B1 mRNA‐, and TGF‐β1 mRNA‐expressing cells/glomerular section, but not the number of fibronectin mRNA‐expressing cells, was increased in IgAN compared with controls. The number of PDGF B mRNA‐expressing cells correlated significantly with the percentage of glomerulosclerosis. In the cellular lesions of focal segmental glomerulosclerosis (FSGS), expression of TGF‐β1 protein and mRNA was markedly increased in visceral glomerular epithelial cells (GEC). These results suggest that PDGF B mainly overproduced by mesangial cells may cause mesangial matrix expansion, whereas TGF‐β1 produced by GEC may be related to the formation of FSGS in IgAN. Thus, PDGF B and TGF‐β1 may play differential roles in the pathogenesis of renal fibrosis and the progression of IgAN.

Differential expression of platelet‐derived growth factor and transforming growth factor‐β in relation to progression of IgA nephropathy

SUMMARY: The role of platelet‐derived growth factor (PDGF) and transforming growth factor‐β1 (TGF‐β1) in relation to mesangial matrix expansion and progressive glomerulosclerosis in IgA nephropathy (IgAN) is not clearly defined. Expression of PDGF B, TGF‐β1, and extracellular matrix proteins in glomeruli was assessed by immunohistochemistry in 42 biopsies with IgAN and six renal biopsies with no detectable abnormalities. the mRNA expression of PDGF B, TGF‐β1, α1(IV) collagen, laminin B1 and fibronectin genes was further evaluated by in situ hybridization in 25 biopsies with IgAN and six controls. In IgAN, the intensity of immunostaining for PDGF B, type IV collagen, laminin and fibronectin, but not for TGF‐β1, was increased in the mesangium compared with controls. the immunoreactivity of PDGF B was closely correlated with that of type IV collagen and laminin. the number of PDGF B mRNA‐, α1(IV) collagen mRNA‐, laminin B1 mRNA‐, and TGF‐β1 mRNA‐expressing cells/glomerular section, but not the number of fibronectin mRNA‐expressing cells, was increased in IgAN compared with controls. the number of PDGF B mRNA‐expressing cells correlated significantly with the percentage of glomerulosclerosis. In the cellular lesions of focal segmental glomerulosclerosis (FSGS), expression of TGF‐β1 protein and mRNA was markedly increased in visceral glomerular epithelial cells (GEC). These results suggest that PDGF B mainly overproduced by mesangial cells may cause mesangial matrix expansion, whereas TGF‐β1 produced by GEC may be related to the formation of FSGS in IgAN. Thus, PDGF B and TGF‐β1 may play differential roles in the pathogenesis of renal fibrosis and the progression of IgAN.

Genetic models: clues for understanding the pathogenesis of idiopathic nephrotic syndrome

Ultrafiltration of plasma during primary urine formation in the glomerulus is one of the central functions of the kidney. The structurally complex glomerular capillary wall responsible for ultrafiltration consists of a basement membrane covered on the inner surface by fenestrated endothelium and on the outer surface by highly specialized epithelial cells, the podocytes (so called because of their characteristic interdigitating foot processes). In many acquired and inherited nephropathies, disruption of the glomerular filter is associated with extensive leakage of plasma proteins and a diffuse effacement of the podocyte foot processes, as detected by electron microscopy. The clinical hallmark of such glomerular dysfunction is nephrotic syndrome (NS), which is characterized by heavy proteinuria, edemas, hypoalbuminemia, and hyperlipidemia. Idiopathic NS represents a heterogeneous group of glomerular disorders occurring mainly in children. This group is generally divided into steroid-sensitive and steroid-resistant NS, depending on the patient’s response to steroid therapy. Most patients show a favorable outcome to this treatment, although they may be subject to more or less frequent relapses of the disease. However, 10–20% of patients fail to respond and may develop end-stage renal failure. In these cases, although only minimal histological changes of the glomeruli can be observed by light microscopy at early stages, focal segmental glomerulosclerosis (FSGS), associated in some cases with mesangial proliferation, develops during the course of the disease. In approximately a third of these cases, nephrotic syndrome recurs almost immediately, with profuse proteinuria developing within 24 hours of the onset of diuresis. The sclerotic lesions of FSGS also recur and can be detected in subsequent renal biopsies of the transplanted kidney. Late-onset recurrences, occurring more than 3 months after transplantation, are also observed. Overall, recurrences occur at a mean time of 14 days after transplantation in children (1). The effacement of podocyte foot processes observed by electron microscopy suggested a key role for the podocyte in the pathogenesis of idiopathic NS, either as a target of a glomerular permeability factor or as the site of alteration of a structural component of the foot processes. Accumulating data suggest that steroid-sensitive NS, as well as a subset of steroid-resistant NS (particularly those recurring after transplantation) have an immunological basis. Specifically, it appears that T cells in these patients promote the production of a circulating factor that alters the glomerular permeability of the filtration barrier. The nature of this factor remains elusive, but the decrease of proteinuria by ex vivo immunoadsorption using Sepharose-bound protein A or anti-Ig preparations supports the hypothesis that Ig’s are directly or indirectly (e.g., via an Ig-binding protein) involved in the mechanism causing proteinuria (2). Alternatively, other cases of steroid-resistant NS might be due to a primary defect in the glomerular filtration barrier, and these cases would not be expected to recur after transplantation, as the donor kidney does not bear the defect (Figure ​(Figure11). Figure 1 Mechanisms underlying idiopathic NS. In both its steroid-sensitive and its steroid-insensitive form, this condition can apparently arise through a T cell dysfunction that leads to the synthesis of a still-unidentified circulating factor that compromises ... Although idiopathic NS is usually regarded as a sporadic disease, genetic factors now cannot be ignored, as inherited cases of both steroid-resistant and steroid-sensitive NS have been described (3). Furthermore, idiopathic NS seems more severe in African-Americans, but the recurrence rate after transplantation is lower in this population (4). As discussed below, genetic analysis in animal models and human families has already shed considerable light on the molecular interactions that are affected in these patients.

Posttransplantation relapse of FSGS is characterized by glomerular epithelial cell transdifferentiation.

This study examined six cases of idiopathic nephrotic syndrome with primary lesions of focal segmental glomerulosclerosis (FSGS) that relapsed after renal transplantation. The glomerular lesions comprised the cellular, the collapsing, and the scar variants of FSGS and showed shedding of large round cells into Bowman's space and within the tubular lumens. Immunohistochemistry and confocal laser microscopy carried out on kidneys with FSGS relapse disclosed several phenomena. (1) Some podocytes that expressed podocalyxin, synaptopodin, and glomerular epithelial protein-1 were detached from the tuft and were free in the urinary space. (2) In the cellular variant, most podocytes had lost podocyte-specific epitopes (podocalyxin, synaptopodin, glomerular epithelial protein-1, Wilm's tumor protein-1, complement receptor-1, and vimentin). In the scar variant, these podocyte markers were absent from cobblestone-like epithelial cells and from pseudotubules. (3) Podocytes had acquired expression of various cytokeratins (CK; identified by the AE1/AE3, C2562, CK22, and AEL-KS2 monoclonal antibodies) that were not found in the podocytes of control glomeruli. Parietal epithelial cells expressed AE1/AE3 CK that were faintly, if ever, found on the parietal epithelial cells of normal glomeruli. (4) Numerous cells located at the periphery of the tuft or free in Bowman's space and within tubular lumens expressed macrophagic epitopes (identified by PGM1 [CD68], HAM56, and 25F9 monoclonal antibodies). These macrophage-like cells expressed the activation epitopes HLA-DR and CD16. (5) A number of these cells coexpressed podocalyxin + AE1/AE3 CK, podocalyxin + CD68, and CD68 + AE1/AE3. These findings suggest that in primary FSGS relapsing on transplanted kidneys, some "dysregulated" podocytes, occasionally some parietal epithelial cells, and possibly some tubular epithelial cells undergo a process of transdifferentiation. This process of transdifferentiation was especially striking in podocytes that acquired macrophagic and CK epitopes that are absent from normal adult and fetal podocytes.

Focal segmental glomerulosclerosis associated with mitochondrial cytopathy

Focal segmental glomerulosclerosis associated with mitochondrial cytopathy.BackgroundThe nonspecific lesion of focal segmental glomerulosclerosis (FSGS) can occur as a primary disease or in a variety of secondary settings. In mitochondrial cytopathies (MCs), the phenotypic expression of the disease depends on the degree of cellular dysfunction, and this correlates with the proportion of abnormal mitochondrial DNA in the cells and the dependence of tissues on oxidative metabolism. The most common renal manifestation in MCs is tubular dysfunction; little has been reported about glomerular diseases.MethodsCases of four adult patients with FSGS and MC are reported. Routine histology and mitochondrial DNA analysis were carried out on renal biopsies.ResultsFamily history and clinical manifestations in the four patients with FSGS suggested a diagnosis of MC. An A3243G transition in the mitochondrial DNA tRNAleu(UUR) was found in lymphocytes and kidney. Glomerular lesions of FSGS were associated with unusual hyaline lesions, which appeared to represent individual myocyte necrosis in afferent arterioles and small arteries.ConclusionFSGS is a renal manifestation of MCs. The renal lesion can precede other manifestations of the genetic disease by many years. The striking arteriolar lesions in these cases may have resulted in glomerular hypertension and hyperperfusion, leading to secondary epithelial cell abnormalities and, ultimately, FSGS. However, primary epithelial cell dysfunction caused by mitochondrial defects could not be ruled out on morphological grounds. MCs should be considered in cases of so-called primary FSGS, particularly if there is a familial history of diabetes, neuromuscular disorders, or deafness. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. The nonspecific lesion of focal segmental glomerulosclerosis (FSGS) can occur as a primary disease or in a variety of secondary settings. In mitochondrial cytopathies (MCs), the phenotypic expression of the disease depends on the degree of cellular dysfunction, and this correlates with the proportion of abnormal mitochondrial DNA in the cells and the dependence of tissues on oxidative metabolism. The most common renal manifestation in MCs is tubular dysfunction; little has been reported about glomerular diseases. Cases of four adult patients with FSGS and MC are reported. Routine histology and mitochondrial DNA analysis were carried out on renal biopsies. Family history and clinical manifestations in the four patients with FSGS suggested a diagnosis of MC. An A3243G transition in the mitochondrial DNA tRNAleu(UUR) was found in lymphocytes and kidney. Glomerular lesions of FSGS were associated with unusual hyaline lesions, which appeared to represent individual myocyte necrosis in afferent arterioles and small arteries. FSGS is a renal manifestation of MCs. The renal lesion can precede other manifestations of the genetic disease by many years. The striking arteriolar lesions in these cases may have resulted in glomerular hypertension and hyperperfusion, leading to secondary epithelial cell abnormalities and, ultimately, FSGS. However, primary epithelial cell dysfunction caused by mitochondrial defects could not be ruled out on morphological grounds. MCs should be considered in cases of so-called primary FSGS, particularly if there is a familial history of diabetes, neuromuscular disorders, or deafness.