Focal and segmental glomerulosclerosis FSGS is a disease characterized morphologically by segments of sclerosis in some glomeruli. It can be primary or secondary and it usually present as nephrotic syndrome NS. Nevertheless, in FSGS some of the segmental lesions are not sclerosis, but hyaline deposits: Hyalinosis. This feature originated the classical denomination, more of the French school, focal and segmental hyalinosis. There is no a clear explanation why in some cases there are hyaline segments and in other no. Some authors consider that hyaline lesions are precursory of those sclerosing; nevertheless, seems that in many cases sclerosing lesions begins thus, without a phase of hyalinosis.
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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.
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. 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.
FSGS refers to a histologic pattern that is a characteristic of perhaps six distinct underlying etiologies sharing a common theme of podocyte injury and depletion.
The diagnosis and evaluation of FSGS rely on integration of the clinical history family history, birth history, peak weight and body mass, and medication use , clinical laboratory findings serum albumin, urine protein, and viral serologies , and renal histopathology. Proteinuria may be in the nephrotic or subnephrotic range.
Critical is the elimination of other systemic diseases or primary renal diseases that may result in a similar presentation. Many reviews cover various aspects of FSGS and include comprehensive reviews 1 — 4 , disease mechanisms 5 — 8 , pediatric disease 9 , immunologic aspects 10 , treatment in children 11 , and treatment in adults 12 — We focus here on a practical approach to FSGS assessment on clinical and histopathologic grounds in the context of our current understanding of disease mechanisms and genetics.
However, the absolute incidence and prevalence of FSGS are difficult to ascertain given the large global variations in the indications, accessibility, and pathology support for kidney biopsy. McGrogan et al. Australia, with a liberal biopsy policy, had among the highest incidence of FSGS 15 , A population-based study in the southwestern United States examined adult kidney biopsies performed between the years and Although the average incidence rate was 2.
FSGS incidence rates are generally higher in men, being approximately 1. In , Kitiyakara et al. Incident rates, expressed as patients per million, were 6. The rise in FSGS prevalence has been observed in other populations as well.
In Nigeria, the leading cause of nephrotic syndrome has shifted from quartan malaria ca. The factors responsible for the increasing incidence and prevalence of FSGS are largely unknown. Some of the increase is likely attributable to improved recognition particularly where indications for kidney biopsy are broadening and the procedure is more available.
There may well be an absolute rise in incidence of adaptive FSGS compounded by obesity and chronic inflammation, but epidemiologic data are lacking. Histologic variants portend outcome with variable rates of progression collapsing variant greater than not otherwise specified [NOS] greater than tip lesion.
Classification of FSGS is multifaceted and includes pathophysiologic, histologic, and genetic considerations. Clinical response and prognosis may relate to the histologic variant, most notably the glucocorticioid responsiveness of the tip lesion and the aggressive, unrelenting nature of the collapsing variants 21 , It is with this in mind that the variants are included in standard pathology reports.
Putting together the genetic susceptibility, pathophysiologic drivers, clinical history, and response to therapy summarized in Table 1 , we believe that it is useful to cluster FSGS into six clinical forms Figure 1 , Table 2.
With regard to primary FSGS, some would prefer the term idiopathic FSGS; both are defined as a disease that arises spontaneously or is of unknown cause, and we would view these terms as interchangeable. Histopathology of minimal change disease and focal segmental glomerulosclerosis. A specific instance of collapsing variant can be appreciated in the setting of endothelial tubuloreticular inclusions seen on ultrastructural analysis.
The red arrowhead indicates the relative response to therapy and propensity of progression of these various forms, with minimal change disease and tip lesion being most responsive and least progressive and collapsing glomerulopathy being most therapy resistant and rapidly progressing. Modified from Kopp 24 , with permission. Historically, degenerative glomerular lesions of FSGS were those seen in the progression of minimal change disease MCD; formerly lipoid nephrosis , and it was subsequently noted that these patients had an accelerated clinical course 25 , Tubulointerstitial scarring indicative of glomerular disease may also be observed.
It is not uncommon that a biopsy with minimal glomerular changes may have tubulointerstitial damage, suggesting that FSGS might have been present on unsampled glomeruli. For the biopsy to exclude FSGS as a cause of nephrotic syndrome and assess the degree of cortical involvement, adequate renal cortical sampling is required.
The involvement of glomeruli in focal glomerular processes follows a binomial distribution, and thus, for focal disease, more glomeruli are necessary to observe an affected glomerulus 27 , Fogo et al. A simulation study has highlighted two issues with respect to diagnostic yield of renal biopsies in FSGS This suggests caution when making treatment recommendations on the basis of the extent of involved glomeruli Supplemental Figure 1. The Columbia classification of FSGS recognized five morphologic patterns, all of which involve obliteration of the capillary lumens and for the most part, have good reproducibility across independent observers 20 , 32 Figure 2.
Two distinctive forms are the tip lesion and the collapsing variant. Tip lesions affect the portion of the glomerular tuft juxtaposed to the tubular pole. Microcystic tubular dilation is frequently present.
The cellular lesion is perhaps the most difficult lesion to identify reproducibly and shows segmental endocapillary hypercellularity occluding lumens with or without foam cells and karyorrhexis Nonetheless, this classification system was designed to rely solely on pathologic criteria and does not integrate these findings with clinical and genetic information. The six forms of FSGS. These forms are probably of approximately equal prevalence in the United States adult population. The approximate relative distribution of these variants in the United States population at present is shown by the size each cloud, although firm data on prevalence are lacking.
Complete renal pathologic evaluation includes immunofluorescence analysis and electron microscopy, which help to exclude focal and segmental glomerular scarring as an injury pattern that can be seen as an element of any chronic progressive renal diseases, including lupus nephritis, IgA nephropathy, and diabetic nephropathy As such, to avoid confusion, it is probably best to avoid using the term FSGS in this setting.
Thurman and colleagues 37 have proposed that IgM may bind neoepitopes in the mesangium that are exposed after nonimmune injury, resulting in complement deposition and glomerular injury. Ultrastructural examination adds to the assessment in three ways. First, it can exclude the presence of immune complexes and abnormal deposits, such as amyloid. Second, it can exclude basement membrane abnormalities seen in genetic disorders of collagen; the appearance of COL4 mutations among the list of genes associated with FSGS suggests that the alterations in basement membrane at the ultrastructural level may be subtle or undetectable.
Third, it can provide an estimate of the severity of podocyte injury fractional foot process effacement and injury pattern microvillus transformation. The use of all three renal pathology modalities light microscopy, electron microscopy, and staining for Ig and complement is critical in making the distinction between MCD and FSGS. Extensive podocyte injury at the ultrastructural level with adequate numbers of normal-appearing glomeruli and nonscarred tubulointerstitium by light microscopy suggests MCD.
Nevertheless, individuals with a diagnosis of MCD who are resistant to glucocorticoid therapy or manifest deterioration in renal function may have FSGS that was not sampled on the first biopsy and is shown on a subsequent renal biopsy. FSGS is a diverse syndrome that arises after podocyte injury from diverse causes: some known and others unknown The sources of podocyte injury are varied circulating factors [primary FSGS], genetic abnormalities, viral infection, and medication , although the effect on podocytes is similar.
For the most part, the interplay among these drivers is unclear and likely complex. For instance, adaptive FSGS involves both podocyte stress a mismatch between glomerular load and glomerular capacity and a genetic susceptibility. Wiggins and colleagues 40 have elegantly shown this in a rat model that combines genetic susceptibility, renal mass reduction uninephrectomy , and obesity increased glomerular load.
Importantly, podocyte injury from any of the forms of FSGS or from other glomerular diseases will initiate a similar process, resulting in the pathologic features of adaptive FSGS.
It is thought that there is progressive loss of injured podocytes into the urinary space. Podocyte depletion arising from an inability to replicate although nuclear division may occur, at least in animals and results in podocyte catastrophe To balance this deficit, podocytes compensate by hypertrophy to cover more of the glomerular capillary surface.
In a recent insightful and provocative review, Kriz and Lemley 42 proposed that shear stress forces on podocytes are a critical factor driving podocyte injury. In adaptive FSGS, glomerular hypertrophy occurs early in the disease process; in other forms of FSGS and other glomerular diseases, glomerular hypertrophy occurs with progressive nephron loss, leading to increased pressures and flows in the remaining patent glomeruli.
The following sections address pathologic mechanisms, therapy, and treatment for each of the FSGS syndromes. The typical onset ages and approximate relative incidence rates are shown schematically in Supplemental Figure 1. Primary FSGS is a distinct entity, and paradoxically, it is best defined, at this time, as what it is not i.
As a practical matter, this means assessing the likelihood of other forms. This includes ruling out adaptive FSGS by medical history, peak or current body weight, renal biopsy features, serum albumin, or proteinuria response to renin-angiotensin-aldosterone system [RAAS] antagonism , genetic FSGS via genetic test panels on the basis of family history and age of onset , viral FSGS by appropriate virologic testing , and medication-associated FSGS by medication history.
The mechanism of podocyte injury in at least some patients with primary FSGS likely involves a circulating factor, possibly a cytokine that makes particular subjects susceptible. The best evidence for a circulating factor comes from the experience with recurrent FSGS immediately on a scale of hours to several weeks after kidney transplant.
The cytokine or cytokines responsible for recurrent FSGS after kidney transplant remain to be defined. In an unusual and striking case that supports the cytokine hypothesis, a kidney was transplanted into a recipient with FSGS; proteinuria developed, and the transplanted kidney showed podocyte foot process effacement.
Subsequently, the kidney was removed and transplanted into a patient with ESRD due to diabetes, and in the new host, the kidney functioned well without proteinuria Current candidates for the recurrent FSGS factor, reviewed recently 44 , include cardiotrophin-like cytokine factor 1 45 , apoA1b an isoform of ApoA1 46 , anti-CD40 antibody 47 , and serum urine—type plasminogen activator receptor suPAR The role of suPAR remains controversial In primary and adaptive FSGS 51 , elevated levels may 52 or may not 53 predict glucocorticoid sensitivity, and a role for different forms of suPAR has been suggested as reviewed recently Recurrent FSGS plasma affects the cytoskeleton of cultured podocytes, including promoting cell mobility by phosphorylating vasodilator-stimulated phosphoprotein 55 and disassembling focal adhesion complexes The lack of suitable animal models has hindered progress in this area.
Primary FSGS has several prototypical characteristics. It is probably the most common form in adolescents and young adults, although it may occur at any age. It is commonly associated with nephrotic-range proteinuria sometimes massive , reduced plasma albumin levels, and hyperlipidemia. Histologically, it may manifest as the tip variant, collapsing variant, or NOS variant.
Current therapy for primary FSGS is on the basis of immunosuppressive agents; it is now apparent that a number of these, including glucocorticoids and calcineurin inhibitors, directly modulate the podocyte phenotype Despite the limitations of a retrospective study design, this provides new evidence to support therapy.
Recurrent FSGS remains a vexing clinical problem. The histologic variant in the native kidney does not predict recurrence, although it is notable that only one of 77 initial kidney biopsies from subjects who subsequently had recurrent FSGS showed the perihilar variant
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. 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.
Benchimol C. Focal segmental glomerulosclerosis: pathogenesis and treatment. Curr Opin Pediatr. Korbet SM. Treatment of primary focal segmental glomerulosclerosis.
Focal segmental glomerulosclerosis
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Focal segmental glomerulosclerosis FSGS is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults. Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy : . Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis i. The collapsing variant is associated with higher rate of progression to end-stage renal disease , whereas glomerular tip lesion variant has a low rate of progression to end-stage renal disease in most patients. Cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between these two variants. However, because collapsing and glomerular tip variant show overlapping pathologic features with cellular variant, this intermediate difference in clinical outcomes may reflect a sampling bias in cases of cellular focal segmental glomerulosclerosis i. The prognostic significance of perihilar and NOS variants has not yet been determined.