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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. FSGS is a clinicopathologic entity.

In some renal biopsies we can demonstrate segmental and focal sclerosing lesions that can be secondary to previous episodes of focal glomerulonephritis GN ; these cases are different to true FSGS, although in many cases differential diagnosis is not an easy task. The histologic features of FSGS do not allow differentiating the primary forms from the secondary ones. In order to make this differentiation we must help us with clinical findings and laboratory data, and it is very important evaluate alterations in other histologic compartments: vessels, interstitium, and tubules.

Even so, we will not be able to do, in many cases, a clear distinction between primary and secondary forms. In the future, when we will have more knowledge of the etiology and physiopathogenesis of the disease, we will be able to distinguish better the different forms from the disease. It is possible that in the future we can diagnose many of these cases according to etiology or pathogeny, and perhaps the FSGS term will become obsolete Cameron JS, The enigma of focal segmental glomerulosclerosis.

There are morphologic variants of FSGS and for the histopathologic diagnosis it is important to recognize them. Some of them are associated with clinical characteristics or demographic aspects, or a more or less aggressive evolution.

Nevertheless, this morphologic division obeys more to the necessity to learn many things that we still ignore, tries that we denominate the lesions with a homogenous nomenclature, and will be very important to determinate particular etiologic or pathogenic mechanisms. FSGS can appear to any age. Diverse works indicate a predilection by masculine sex.

The prognosis of FSGS is different to minimal change disease MCD : there is greater incidence of chronic renal failure, very little response to steroids, and greater incidence of hematuria and hypertension. The etiology of FSGS is still far from being explained, to a great extent because this disease seems to be a pathological expression of different types of injury. Therefore, it seem to have several perhaps many causes of FSGS. In addition, response to steroids in some patients has suggested the participation of the immune system in the pathogenesis.

Nevertheless, this factor has been never found. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. Hemodynamic factors have also been implicated. Glomerular hypertrophy and hyperfiltration have been, experimentally, associated to segmental glomerular lesions; this would help to explain the frequency of FSGS in diabetics and people with diminished renal mass.

This mechanism is more related to secondary forms of FSGS. Injury of tuft epithelial cells podocytes is another mechanism implicated in some forms of FSGS and it has been associated mainly to disease in intravenous drug abusers and HIV infection. Finally, and perhaps more important, it has been the discovery, and until now partial understanding, of the protein complex that interacts in the slit diaphragm of podocytes.

Podocytes have an architectural phenotype very developed and in particular the slit diaphragm; it is a unique type of cellular union, in which the permeability characteristics are determined by specific proteins. The podocyte slit diaphragm has an important and direct role in glomerular filtration. Some of its protein components are involved in the mechanism of proteinuria.

These proteins form a complex that contributes to its structure, connects the diaphragm to the intracellular actin cytoskeleton, and participates in signaling related to turnover of the glomerular filter.

Most of these proteins are essential for a functional slit diaphragm and glomerular filtration, since mutation or inactivation of the corresponding genes causes proteinuria. A great advance in the understanding of the idiopathic NS syndrome took place with the discovery, in , of the nephrin NPHS1 , the muted gene in the congenital NS of Finnish type. This allowed establishing that the podocyte is the central component of the filtration barrier. Shortly after the muted gene in the autosomal recessive steroid resistant NS was discovered: NPHS2 that codifies another exclusive protein of the podocyte: podocin.

The podocin is structurally related to the protein family: stomatins , that are transmembrane proteins implied in the scaffolding of the cytoskeleton.

This protein until now had been well-known like a molecule that binds the cytoskeleton of actin of T-cells to zones with which this cell contacts. Podocin and nephrin are united to the cytoskeleton of the podocyte transmembrane proteins and their disruption not only affects the slit-diaphragm but the integrity of all the foot processes. Podocin and nephrin are expressed in both: cellular surface and intracellularly D'Agati VD. Podocyte injury in focal segmental glomerulosclerosis: Lessons from animal models a play in five acts.

Kidney Int. In NS there are an increasing number of alterations in this complex protein structure. Some authors have found that nephrin and podocin are located separated of the cytoskeleton in cases of NS Doublier S, et al.

Nephrin, podocin, CD2AP and actin are associated in a complex with lipid rafts. One of the postulated key functions for lipid rafts is to facilitate fast transmission of signals, and nephrin and podocin have shown to be interdependent to initiate a cascade of intracellular signals, although the consequences of this are still not known Huber TB et al, Hum Mol Gen , [ PubMed link ]; Coward R.

A revision of podocitary proteins and other factors related to nephrotic syndrome in: Chen YM, Liapis H.

Focal segmental glomerulosclerosis: molecular genetics and targeted therapies. BMC Nephrol. Nevertheless, these same authors propose, in a very interesting work, that the human serum could contain factors that are crucial for development and normal distribution of these proteins of the complex: slit diaphragm-nephrin-podocin-CD2AP-podocyte cytoskeleton. Thus, it has been tentatively hypothesized that the NS would be originated by deficiency of a factor that is normally present in the human serum and not by the presence of a pathogenic circulating factor Coward R.

According to these authors, NS is a heterogeneous group of diseases and can be that in some, like FSGS, there is initially a loss or imbalance of important serum factors that produce disruption of the integrity of the slit diaphragm and later loss of the podocyte foot processes.

In other nephropathies, like lupus nephritis, generalized disruption of the slit diaphragm would be consequence of important loss of proteins.

All the previous information has allowed the formulation of an updated hypothesis of the pathogenesis of the NS. The loss or alteration of this balance can be by primary or secondary can cause disruption of signals transmitted by the nephrin or other slit diaphragm-associated proteins, producing loss of the stability of the diaphragm and reorganization of actin filaments, causing intracellular relocalization of the protein complex and effacement of foot processes Coward R.

Even so, much remains to know and it is sure that we will know new findings and theories on the etiology and pathogenesis of FSGS in the next years, but in brief: Primary or idiopathic FSGS is considered to be related to podocyte injury. 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. 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. Pathogenesis of Focal Segmental Glomerulosclerosis. J Pathol Transl Med. In the etiologic classification of FSGS is important differentiate primary forms from secondary forms.

The primary form idiopathic is that in that we do not know, although exist diverse hypotheses, the etiology. Virus-associated : HIV, parvovirus B I nduced by drugs : Heroin, interferon alpha, lithium, pamidronate, and others. Mediated by adaptive structural-functional responses : A : reduced renal mass agenesis, renal dysplasia, reflux nephropathy, surgical ablation, chronic allograft nephropathy, and so on ; and B : with normal renal mass vaso-occlusive processes, hypertension, obesity, sickle cell anemia.

Clinic features : The main manifestation is severe proteinuria, usually with complete NS. Some cases appear like asymptomatic proteinuria. There is microscopic hematuria, but occasionally it is macroscopic. Frequently there is arterial hypertension and in some cases renal failure at the time of diagnosis is detected.

There is not serum complement levels alteration. In few cases there is response to steroids. In some cases maintained remission is described, and in others there is persistence of proteinuria, but without alteration of the renal function. Laboratory features : Proteinuria in nephrotic range in most of cases, microhematuria in many of them.

Normal C3 and C4 levels. In many cases NS dyslipidemia and hypoalbuminemia. The injury can be more notorious in the vascular pole or in the periphery of the tuft. When advancing the process the sclerosis becomes global and is indistinguishable of the secondary sclerosis to other diseases. From the Fifties it is said that juxtamedullary glomeruli are more compromised by the segmental lesions. Podocytes frequently appear with protein droplets and lipid resorption. The glomeruli without sclerosing lesions can appear normal or with increase of the mesangial cellularity and, sometimes, hypertrophic glomerulomegaly.

Figure 1. Glomerular tuft segmental sclerosis in the superior half; segments in the inferior half display mesangium and capillary walls and lumens with conserved architecture. Figure 2. With methenamine-silver stain the segments with loss of the capillary structure and sclerosis are better seen.

The podocytes that cover these segments present hypertrophy and hyperplasia. Methenamine-silver, X In some cases the lesions do not have the aspect of sclerosis healing by glomerular collagen but appear as homogenous material: Hyaline deposits.

They are constituted by crystalline, eosinophilic, PAS positive, and fuchsinophilic or blue with trichrome stains material; this material is similar to glomerular material found in diabetic nephropathy. This material is negative with silver stains, in contrast to sclerosed segments, and frequently it is accompanied by lipid vacuoles.

This material probably represents accumulation of serum proteins. Hyaline lesions usually accompany sclerosing lesions, but there are cases in which all the lesions are hyaline. Although they seem to be different morphologic aspects from a same disease, could have a different physiopathogeny.



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.


Focal Segmental Glomerulosclerosis

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 : [4]. 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.

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