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APPROACH TO RENAL BIOPSY STUDY
There are relatively a low number of pathologic patterns of renal lesion that
are consequence of an immense amount of etiologic factors: several diseases
or factors can produce a same histologic type of injury, and in the same way:
a disease or etiologic factor can produce several types of morphologic changes.
Also, there are a limited number of clinical manifestations for a great number
of renal diseases. This variability depends on the type of injury and its location,
on the host response, and, logically, on the etiologic agent.
Renal diseases can be classified according to clinical manifestations, etiology, immunopathology and morphologic alterations that produce.
Based on the clinical manifestations several clinical syndromes have been defined:
Nephritic syndrome: Decreased glomerular filtration rate (evidenced by elevated creatinine or BUN or decreased creatinine clearance), hematuria, edema, mild proteinuria, and hypertension (in many cases there is oliguria). In most of these cases, the alteration of glomerular filtration is related to alterations in the glomerular capillaries that prevent the elimination of water and metabolic end products, it can be due to luminal obstruction by inflammatory cells, endothelial edema or thrombosis. Morphologically, endocapillary proliferative glomrulonephritis (GN) or membranoproliferative GN is usually evidenced. In many of these cases there is hypocomplementemia.
Nephrotic syndrome: Massive proteinuria (>3.5 gr/24 hours for adults or >40 mg/m2/hour in children), hypoalbuminemia, edema and hyperlipidemia; although severe proteinuria has finished being the most important factor for the diagnosis of the syndrome because it indicates serious renal disease. The pathogenesis in these cases is extensive (or diffuse) podocyte damage, since the main barrier to protein leakage is in the podocytes and their complex structure with pedicels, slit diaphragm, and the union of these pedicels to the glomerular basement membrane. It is essential to understand that when there is nephrotic syndrome there is extensive podocyte damage, that is the pathogenesis. This damage can be caused by alterations inherent to the podocyte (podocytopathies) or it can come from factors external to the podocyte such as immune complexes, damage to the basement membrane, hemodynamic factors, etc.
Acute kidney injury (or its previous name: acute kidney failure): Rapid decline in glomerular filtration rate (hours to days), retention of nitrogenous waste products, and perturbation of extracellular fluid volume and electrolyte and acid-base homeostasis. It can be, or no, associates to oliguria, and is often reversible. Many alterations can lead to this type of clinical alteration and these can be originated in glomeruli (eg thrombotic microangiopathy), in tubules (acute tubular necrosis, toxins with acute tubular damage), the interstitium (interstitial nephritis), or vessels (thrombosis, cholesterol embolism, severe / malignant hypertension). Some cases of acute GN may present initially as acute kidney injury.
Rapidly progressive glomerulonephritis: Subacute renal failure over weeks to months, active urine sediment, hypertension, edema, oliguria, and proteinuria. This alteration is usually related to proliferation of cells in the urinary or Bowman space: crescents or extracapillary proliferation. These crescents are usually related to inflammatory damage to capillary walls, with leakage of fibrin, cells and inflammation mediators into Bowman's space, with proliferation of cells there. This crescents usually take weeks to form, hence the clinical presentation in which progressive deterioration of glomerular filtration is evident: "rapidly progressive".
Chronic renal failure: Chronic renal disease is a pathophysiologic process resulting in the inexorable attrition of nephron number and function and frequently leading to end-stage renal disease: a clinical state or condition in which there are an irreversible loss of renal function, of a degree sufficient to render the patient permanently dependent upon renal replacement therapy (dialysis or transplantation). Uremia is the clinical and laboratory syndrome, reflecting dysfunction of organs and systems as a result of untreated or undertreated acute or chronic renal failure. In these cases there is chronic and irreversible tissue damage, therefore, regardless of the cause, we will find glomerulosclerosis, interstitial fibrosis, tubular atrophy and chronic vascular lesions.
The glomerular pathologic changes can produce any type of clinical syndrome, but, in general, some patterns of renal changes are associated to certain syndromes:
Membranous GN, Focal segmental glomeruloesclerosis, minimal change disease are associated with nephrotic syndrome.
Diffuse proliferative endocapillary GN (frequently postinfectious) and membranoproliferative GN are associated to nephritic syndrome, the latter often mixed: nephrotic-nephrotic.
IgA nephropathy and Alport syndrome usually present with hematuria and proteinuria, usually non-nephrotic, although in advanced stages it usually progresses to nephrotic. The condition called "thin basement membrane" usually presents with isolated microscopic hematuria, although sometimes with mild proteinuria.
The systemic diseases affecting the kidney have still more variability in their clinical expression.
Let us remember, again, that a type of glomerular lesion can appear clinically different in different patients.
The clinicopathologic correlation is of great importance to arrive to the correct diagnosis. A final diagnosis must never be done without the complete clinical information. In addition, in all the GN cases must have, at least, immunopathologic study (immunofluorescence or immunoperoxidase), to detect immune deposits, and some cases also require ultrastructural study (electron microscopy).
When evaluating a renal biopsy we must, initially, determine which of the four histologic compartments (glomeruli, interstitium, tubules and vessels) is/are the most comprised for the disease. If we began evaluating the glomeruli, we must see cellularity degree. It must not have more than three nuclei in each mesangial area, i.e. the mesangium among several capillaries, surrounded by them (must be distinguished from the lobes: in each lobe there are several mesangial areas - see Histology). Hypercellularity must be evaluated in thin sections: no more than 2 - 3 microns thickness; one of the main “causes” of hypercellularity is a tick section: false hypercellularity. Do not evaluate the cellularity in the mesangial areas adjacent to the vascular pole because in them there are more cells.
The second step is to determine the type of hypercellularity:
Mesangial: Proliferating cells are located in the mesangium, with nothing or little diminution of the capillary lumens. The nuclei are usually relatively homogeneous in appearance and should be completely surrounded by mesangial matrix. In recent years, mesangial hypercellularity has tended to be defined when more than 3 cells per mesangial area are clearly identified (see the definition of "mesangial area" in the chapter Normal Glomerular Histology). This morphological alteration usually presents with hematuria and mild proteinuria; however, it is a very common finding and is nonspecific in itself.
Endocapillary: In this type of injury the proliferation is not only located into capillary lumens, but the cellular proliferation occupy the glomerular tuft and compress capillaries. The proliferating cells are from diverse origin: endothelial, mesangial, and inflammatory (lymphocytes, monocytes, and neutrophils), nevertheless, it is called “endocapillary” by convention (hypercellularity within the capillary tuft). The nuclei of the cells are more variable in form and size (because there are several types of cells) and tend to obstruct the capillary lumen. The proliferation is not limited to the mesangium. It can be global or segmental. This morphological alteration usually presents as nephritic syndrome.
Extracapillary (crescents): Proliferation of cells in the Bowman’s space, with at least two layers of cells covering Bowman’s capsule. The cells that proliferate are parietal epithelial and infiltrating inflammatory cells, mainly monocytes. This type of proliferation is also known as crescents. It can be circumscribed or circumferential. The crescent can be cellular, fibrous (already scarred) or fibrocellular. This pattern of injury usually presents clinically as rapidly progressive glomerulonephritis. Examples: ANCA-associated GN, anti-GBM disease, some cases of proliferative lupus nephritis, some cases of IgA nephropathy. Almost any glomerulonephritis can lead, in severe cases, to extracapillary proliferation.
When there is endocapillary and/or extracapillary cell proliferation we say that there is a “true glomerulonephritis”.
Other important terms in the description of glomerular changes:
Global: A lesion involving the entire glomerulus.
Segmental: A lesion involving a part of the glomerulus, with al least a segment spared.
Diffuse: A lesion involving all or most of the glomeruli.
Focal: A lesion involving only some glomeruli. An exact number (or percentage) is not defined and accepted by all authors. For some it is <80% of glomeruli. In some classifications, such as lupus nephritis, IgA nephropathy, Banff's rejection, it is called diffuse when there are 50% or more of compromised glomeruli and focal if less than 50%.
Hyalinosis: Homogenous, amorphous glomerular deposits composed mainly of proteinaceous material. It is observed reddish, or green or sometimes blue, according to the technique, with the trichrome stain, and they are positive with the PAS (periodic acid of Schiff) stain. Similar lesions can be observed in arterioles: hyalin arterioloesclerosis. It must be differentiated from fibrinoid necrosis, that displays similar colour with these stains, but it is a more granular material, less homogenous and is accompanied by cellular detritus (karyorrhexis) and/or inflammatory cells.
Sclerosis: Is a glomerular scar produced with proliferation of type IV collagen (glomerular collagen).
Fibrosis: Scar produced with predominantly type I collagen (interstitial type collagen).
Fuschinofílic: Material that stains red with trichrome staining, due to the fuschina used in this staining. Any proteinaceous material, intra or extracellular, can be fusinophilic. In general, it is relevant when observed in glomeruli because it can suggest deposits of immune complexes or hyalinosis (it is not specific, it only suggests it, according to the location, e.g. subendothelial or subepithelial).
Subendothelial: It is the space located between the endothelium and the basement membrane of the glomerular capillaries (GBM). In this space, it is common to find immune complexes, and when deposits are evident in this location, a pattern of membranoproliferative lesion is usually seen. There may also be subendothelial edema, e.g. in preeclampsia endotheliosis, in MAT, antibody-mediated rejection, etc.
Subepithelial: It is the space located between the visceral epithelial cell or podocyte and the GBM. Immune complexes can also be seen in this space, which could correspond to a pattern of membranous GN or to subepithelial deposits of post-infectious GN ("humps"). Perpendicural projections to the basement membrane ("spikes") and other alterations or deposits may also be seen. This space could also be called: "subpodocyte space".
Epimembranous: It is a term formerly used to refer to the subepithelial space; It is little used nowadays.
Intramembranous: Some authors use this term to refer to deposits that are specifically located within the GBM, e.g. in dense deposit disease.
In some cases, mainly in lupus nephritis, subendothelial, subepithelial and intramembranous deposits can be seen, some of them "transmembrane", that is, with subendo and subepi deposits that connect to each other through the GBM.
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