Frecuencias de Glomerulopatías Primarias en cuatro períodos de ingreso al Registro CHI-CUADRADO P < 0.001 Figura 2

Registro Uruguayo de Glomerulopatías HFS

PRESENTACIÓN CLÍNICA

Proteinuria al Ingreso

Creatininemia al ingreso

Tasa evolución. IRE RR (edad, sexo, período) Vasculitis 33.3 9.1 (100 ptes/ años) RR (edad, sexo, período) Vasculitis 33.3 9.1 Amiloidosis 25.5 5.9 MPGN 18.7 5.1 HFS 9.9 3.9 Nef. Lúpica 5.8 3.6

FSGS ESRD rates Beaufils et al 1978 con SN 7,99 sin SN 1,05   Beaufils et al 1978 con SN 7,99 sin SN 1,05 Cameron et al 11,14 1,63 Korbet et al 1986 5,80 0,83 Velosa et al 1983 6,73 1,74  

February 2004 • Volume 43 • Number 2 Editorial Pathologic classification of focal segmental glomerulosclerosis: A working proposal Vivette D. D’Agati, MDa Agnes B. Fogo, MDb Jan A. Bruijn, MDc Charles Jennette, MDd                                    

Table 1. Etiologic Classification of FSGS Primary (idiopathic) FSGS Secondary FSGS 1. Familial/genetic A. Mutations in -actinin 4 B. Mutations in podocin C. Mutations in WT-1 D. Mutations in integrin 2.Virus-associated A. HIV-1 (HIV-associated nephropathy) B. Parvovirus B19 3. Drug-induced A. Heroin (heroin nephropathy) B. Interferon- C. Lithium D. Pamidronate 4. Mediated by adaptive structural-functional responses A. Reduced renal mass Oligomeganephronia Unilateral renal agenesis Renal dysplasia Reflux nephropathy Sequela to cortical necrosis Surgical renal ablation Chronic allograft nephropathy Any advanced renal disease with reduction in functioning nephrons B. Initially normal renal mass Hypertension Atheroemboli or other acute vaso-occlusive processes Obesity Cyanotic congenital heart disease Sickle cell anemia

Tabla 2. Glosario de términos Adhesión: Continuidad de la matriz de colágeno entre el ovillo glomerular y la cápsula de Bowman Colapso: Colapso implosivo de la pared capilar con plegamiento de la membrana basal glomerular causando obliteración de la luz capilar sin aumento de la matriz o células intracapilares Confluencia de los podocitos con las células parietales o epiteliales tubulares en la luz tubular o cuello: contacto celular directo de los podocitos con las células epiteliales parietales o las células tubulares epiteliales en la luz tubular o el cuello

Hipercelularidad endocapilar: Oclusión de los capilares glomerulares por un aumento absoluto en el número de las células intraluminales, que pueden incluir células espumosas, células endoteliales, macrófagos, y otros leucocitos, a veces asociada con hialinosis, kariorrexis, y raramente fibrina, frecuentemente produciendo una lesión expansiva Focal: Que compromete algunos pero no todos los glomérulos Global: Que afecta todo el ovillo glomerular Glomerulomegalia: Ovillo (Tuft) glomerular de mayor tamaño que los controles de la misma edad ( con la medida de área glomerular > 1.5 x normal)

Hialino: acumulación de material proteinaceo eosinofílico homogéneo “vidrioso” (smooth and glassy) Hipercelularidad Mesangial: >de 3 células mesangiales rodeadas por matiz mesangial en un segmento glomerular intacto, observado en cortes de 3 µm de espesor Perhiliar: Compromiso segmentario vecino al hilio glomerular Hiperplasia podocitaria: Aumento del número de los podocitos, usualmente con acumulación y formación de multicapas; a diferencia de las semilunas verdaderas, estas lesiones típicamente carecen de eje celular, matriz peri-celular, fibrina extracapilar o continuidad con las células epiteliales parietales

Hipertrofia podocitaria: aumento del tamaño de los podocitos con o sin gotas de reabsorción proteica intracitoplasmática, vacuolas, agrandamiento y vesiculización nuclear y nucléolos prominentes Esclerosis: Aumento de la matriz glomerular extracelular con obliteración de la luz capilar glomerular Segmentaria: compromiso del ovillo glomerular < 100% con algunos capilares glomerulares evidentes Dominio TIP: porción externa del ovillo glomerular (25%) cercana al origen del túbulo proximal (el polo tubular debe ser identificado) Ovillo (Tuft): El flóculo glomerular, no incluye la cápsula ni el espacio de Bowman

Propuesta Clasificación morfológica Para profundizar en etiología debe realizarse inmunofluorescencia y M.Electrónica Inicialmente debe descartarse HFS secundaria a otras glomerulopatías Base para evaluar posibles evoluciones diferentes

CLASIFICACIÓN NOS (clásica) Perhiliar Celular Lesión Tip Colapsante

FSGS (NOS) (Not Otherwise Specified) - clásica- Criterios de Inclusión: Por lo menos 1 glomérulo con aumento segmentario de la matriz obliterando la luz capilar Puede existir colapso segmentario de la pared capilar glomerular sin hiperplasia podocitaria por encima Criterios de exclusión Variante Perhiliar Variante Celular Variante Tip Variante Colapsante

(A) FSGS (NOS). A low-power view shows segmental lesions of sclerosis in all 4 glomeruli pictured. Lesions of sclerosis are characterized by increased matrix, causing obliteration of the capillary lumina. Distribution of lesions within the tuft is variable, affecting both peripheral and perihilar segments. In some glomeruli, the location of the sclerosis cannot be ascertained because of the plane of section. (JMS; original magnification 100.) (B) FSGS (NOS). High-power view of a glomerulus shows a discrete segmental lesion of sclerosis with wrinkling and collapse of glomerular basement membranes (stained blue) and hyaline deposits (stained red).Overlying the wrinkled capillaries, there is detachment of podocytes, which form a “cap,” with intervening deposition of looser neomembrane that is weakly trichrome-blue positive. Although the capped podocytes appear hypertrophied,there is no podocyte hyperplasia. (Masson trichrome; original magnification400.)

(C) FSGS (NOS). There is segmental obliteration of the glomerular tuft by increased matrix and hyaline material. Sclerosed segments form adhesions to Bowman’s capsule. There is no obvious podocyte hypertrophy or hyperplasia. The location of the sclerotic lesion within the glomerular tuft cannot be determined because neither the tubular nor the vascular pole are represented in the plane of section. (PAS; original magnification250.)

FSGS Perhiliar Criterios de inclusión Criterios de exclusión Por lo menos 1 glomérulo con hialinosis perhiliar con o sin esclerosis >50% de los glomérulos con lesiones segmentarias deben tener esclerosis o hialinosis perhiliar Criterios de exclusión Variante Celular Variante Tip Variante Colapsante

(D) FSGS perihilar variant (D) FSGS perihilar variant. On low-power examination, 1 of the 3 glomeruli pictured contains a discrete lesion of segmental sclerosis affecting the vascular pole region. The lesion shows both increased matrix (sclerosis) and hyalinosis. There is adhesion of the sclerotic segment to Bowman’s capsule in the vascular pole region. Perihilar lesions were identified in more than 50% of glomeruli with segmental sclerosis. Both the glomerulus with segmental sclerosis and the 2 nonsclerotic glomeruli are hypertrophied in this patient with morbid obesity. (PAS; original magnification 100.) (E) FSGS perihilar variant. High-power view of the perihilar lesion in (D) shows both the increased matrix (sclerosis) and glassy hyalinosis deposited in the vascular pole segment of the tuft,identified by the incoming arteriole and macula densa. There is no obvious podocyte hypertrophy or hyperplasia. (PAS;original magnification 250.)

(F) FSGS perihilar variant (F) FSGS perihilar variant. A very early lesion illustrates the mild increase in matrix and hyaline surrounding the glomerular hilus. There also is hyalinosis of the adjacent preglomerular arteriole. The glomerulus is hypertrophied in this patient with a solitary functioning kidney. (PAS; original magnification 250.)

FSGS Celular Criterios de Inclusión Criterios de exclusión Por lo menos 1 glomérulo con hipercelularidad segmentaria endocapilar ocluyendo la luz con o sin células espumosas o kariorrexis, comprometiendo por lo menos 25% del ovillo Habitualmente existe hipertrofia e hiperplasia podocitaria pero no es un hecho requerido para el diagnóstico Criterios de exclusión Variante Tip Variante Colapsante

FSGS cellular variant. (A) The defining glomerulus in this patient with primary FSGS shows segmental endocapillary hypercellularity. Involved segments are engorged with endocapillary cells, including some infiltrating mononuclear leukocytes. (H&E; original magnification 250.) (B) In the cellular variant, silver stain shows expansion of the involved segments by endocapillary cells (not matrix), including foam cells and some karyorrhectic leukocytes. No glomerular capillary wall collapse is seen. There is hypertrophy and hyperplasia of the overlying podocytes. (JMS; original magnification 400.)

(C) This example of the cellular lesion shows numerous endocapillary leukocytes, mimicking a segmental endocapillary proliferative glomerulonephritis. There is hypertrophy and hyperplasia of overlying podocytes. Adjacent glomerular segments have mild mesangial hypercellularity. (H&E; original magnification 400.) (D) High-power view of a cellular lesion shows karyorrhectic nuclear debris, admixed with foam cells and hyaline material. Overlying podocytes are hyperplastic. (H&E; original magnification 600.)

FSGS Tip Criterios de inclusión Criterios de exclusión Por lo menos 1 lesión segmentaria que compromete el dominio tubular (Tip) (25% externo del tuft cercano al origen del túbulo proximal) El polo vascular debe estar identificado en la lesión La lesión debe tener o una adhesión o confluencia de podocitos con células parietales o tubulares en la luz o el cuello tubular La lesión puede ser celular (<50% ovillo) o esclerosante (<25% ovillo) Criterios de exclusión Variante colapsante Cualquier lesión perhiliar

FSGS tip variant. (A) Low-power view shows a segmental lesion involving the tip domain at the origin of the tubular pole. The vascular pole is not visible in this plane of section. (PAS; original magnification 250.) (B) High-power view of the lesion in A shows the involved segment to contain endocapillary foam cells and form an adhesion to Bowman’s capsule at the mouth of the proximal tubule. There is capping of the overlying podocytes, which become confluent with the adjacent tubular epithelium. (PAS; original magnification 600.)

(C) Low-power view shows the portion of the glomerular tuft involving the tip domain to be expanded by a segmental lesion with cellular features located at the tubular pole. (PAS; original magnification250.) (D) High-power view of the tip lesion in C shows endocapillary foam cells admixed with a few leukocytes. There is a small adhesion of the tuft to Bowman’s capsule at the tubular pole. Overlying podocytes appear confluent with the adjacent tubular epithelial cells. (PAS; original magnification 600.)

(E) Opposite the vascular pole, the origin of the proximal tubule is visible.In this area, there is an early tip lesion with inframembranous hyalinosis, a few endocapillary foam cells, and confluence of swollen podocytes with the tubular epithelium. (PAS; original magnification 250.) (F) In this glomerulus, the tip lesion appears to herniate into the tubular lumen and forms a capsular adhesion. (PAS; original magnification 250.)

FSGF Colapsante Criterios de inclusión Criterios de exclusión Por lo menos 1 glomérulo con colapso segmentario o global con hipertrofia e hiperplasia podocitaria por encima Criterios de exclusión No

FSGS collapsing variant FSGS collapsing variant. (A) A low-power view shows 4 glomeruli, all of which have global collapse of the tuft and podocyte hypertrophy and hyperplasia. There are associated tubular degenerative changes. (JMS; original magnification 100.) (B) On high-power view, the lesion of collapsing sclerosis shows global occlusion of capillary lumina by implosive collapse of glomerular basement membranes. There is no appreciable increase in intracapillary cells or matrix. Overlying podocytes form a cellular corona over the collapsed tuft. Some of the enlarged podocytes appear binucleated and have lost their cohesion to the tuft. (JMS; original magnification 400.)

(C) An example of global collapse of the glomerular tuft with marked overlying podocyte hyperplasia, forming a pseudocrescent that fills the urinary space. An apoptotic podocyte has detached from the tuft and is passing into the tubular pole. (JMS;original magnification 400.) (D) Hyperplastic podocytes contain numerous intracytoplasmic protein resorption droplets, which appear red with trichrome stain. The collapsed tuft, shown in blue, has no patent capillary lumina. (Masson trichrome; original magnification 400.)

(E) Hyperplastic podocytes form several layers of cells over the collapsed tuft. Some of the swollen podocytes contain intracytoplasmic vacuoles. Podocyte nuclei have a vesicular chromatin pattern with prominent nucleoli. (JMS; original magnification 400.) (F) A segmental lesion of collapsing sclerosis spares more than half the tuft. Collapsed capillaries have prominent overlying podocyte hypertrophy and hyperplasia, with abundant trichrome-red intracytoplasmic protein resorption droplets. (Masson trichrome; original magnification 400.) (G) By electron microscopy, the collapsed loop has folded glomerular basement membranes, with complete effacement of foot processes. Overlying podocytes are detached from the glomerular basement membrane with intervening layering of neomembrane material. (Original magnification 2,500.)