Elemental lesions of glomeruli

Elemental lesions of glomeruliIntroduction:

The classification of glomerular nephropathies is currently based on the histological analysis of the cortical renal parenchyma obtained by transparietal renal biopsy or more rarely transjugular.The realization of a renal biopsy is of diagnostic, therapeutic and prognostic interest.

The renal biopsy should allow in all cases a study by optical microscopy and immunofluorescence. Ultrastructural analysis is sometimes necessary. The fragment intended for optical microscopy must be immediately fixed for 1 to 3 hours, preferably in the AFA (alcohol, formaldehyde and acetic acid) in order to obtain an excellent morphology for standard staining. The Dubosq-Brazil fixer, long used, is currently abandoned. The systematic colorations are Masson’s trichrome, Schiff’s periodic acid (PAS), silvering according to the Jones technique and hemateineosin-saffron. They allow an accurate analysis of the different glomerular structures. The sample reserved for immunofluorescence must be rapidly frozen in liquid nitrogen. The direct immunofluorescence examination looks for deposits essentially of immunoglobulins and complement.

Antibodies against the heavy chains of the immunoglobulins A, M and G and the light chains j and k , certain fractions of the complement (C1q, C3 and C4) and fibrinogen are usually used. When an electron microscopy study is contemplated, a biopsy fragment should be fixed in the glutaraldehyde admixed extemporaneously with cacodylate buffer.

Histological examination leads to a precise diagnosis in the majority of glomerular nephropathies. The interpretation of the renal biopsy however requires a good knowledge of the histology of the normal kidney and the main elemental lesions that can be encountered there. We will therefore first consider the histology of the normal glomerulus then the glomerular elementary lesions and finally the main anatomoclinic frames.

Normal Glomerulus:

The normal glomerulus in adults is 150 to 250 μm.

In the glomerulus, the basement membrane of the capillary delimits two spaces: one situated inside, called endocapillary or endomembranous space; the other situated outside, called extracapillary or extramembrane space.The first corresponds to the blood compartment and the second to the urinary compartment of the glomerulus. The endocapillary space comprises a central part corresponding to the mesangium and a peripheral part corresponding to the capillary loops. Mesangium consists of cells (3 to 5 cells per mesangial area) and a conjunctive matrix. The extracapillary space includes the podocytes which cover the capillary loops, the urinary chamber, the parietal epithelial cells and the Bowman capsule. The glomerular basement membrane (MBG) is located between the podocytes and the endothelial cells and between the podocytes and the mesangium.

Glomerular Elemental Lesions:

Cell proliferation:

• Endocapillary proliferation corresponds to the increase in the number of endocapillary cells: mesangial cells and cells of blood origin, mainly of the monocyte / macrophage and polynuclear lineage. This proliferation is said to be pure when there is no parallel increase of the extracellular matrix nor mesangial slip (eg, acute post-infectious glomerulonephritis).

• The extracapillary or increasing proliferation corresponds to the multiplication of the epithelial cells of the Bowman capsule, associated in variable proportion with histiocytic cells of blood origin. Initially, the crescent contains fibrin. The evolution is towards a fibrous healing (example: extracapillary glomerulonephritis). The multiplication of podocytes is only observed in rare circumstances, especially in HIV-associated nephropathy.

Abnormal glomerular deposits:

• Extramembrane deposits are immune deposits located on the external side of the MBG. They may be diffuse and of small size (eg extramembraneous glomerulonephritis) or scattered and of great size, bearing the name humps (example: acute post-infectious glomerulonephritis).

• Endomembranous deposits are immune deposits located within the MBG. Parietal deposits (eg, lupus nephropathy) and mesangial deposits (eg, glomerulonephritis with mesangial IgA deposits) are distinguished. The latter may be either subendothelial, ie located between MBG and capillary endothelial cells, or in the mesangium interposed between MBG and capillary endothelial cells.

• Intramembranous dense deposits are immune deposits located in the MBG, which appears thickened and banded.They sit in the lamina densa. They are characteristic of the disease of the dense deposits (stage II membranoproliferative glomerulonephritis). Similar deposits are present in the basal membranes of Bowman tubes and capsule.

Changes in extracellular matrix (glomerular basement and mesangium):

• Folding of the MBG is encountered during the ischemia of the flocculus, which is often retracted at the vascular pole (eg, malignant nephroangiosclerosis).

• In response to the presence of deposits on the external side of the MBG, the MBG thickens. It then appears on its external side expansions in the form of a club that gradually come together to form chains, well visualized on the silverations (example: extramembrane glomerulonephritis stages II and III).

• The so-called double-contour appearance observed on silver staining is most often related to mesangial proliferation, with cells progressively slipping between MBG and endothelial cells (eg type I membranoproliferative glomerulonephritis). The double contour is also observed in the absence of mesangial slip in thrombotic microangiopathies.

• Flocculocapsular adhesion by fibrous tissue corresponds to the terminal evolution of either a segmental hyalinosis lesion that will be described later, or a crescent.

• Glomerulosclerosis is defined as an increase in the mesangial matrix. It may be diffuse or more rarely nodular (eg diabetic glomerulonephritis, disease of light chain deposits).

• Mesangiolysis is a rare lesion of the mesangial matrix which assumes a loose, evanescent appearance (eg, treatment with mitomyne C, thrombotic microangiopathy).

• A glomerulus of sealing bread is a glomerulus transformed into a block of fibrosis. It is the result of all severe glomerular involvement, whatever the mechanism.

Other lesions:

A hyaline plug corresponds to the obliteration of capillary loops by proteins (examples: renal involvement in mixed cryoglobulinemia, Waldenström disease or lupus).

Main anatomoclinic entities:

Lipoid nephrosis – Minimal glomerular lesions:

The classic forms of lipoid nephrosis are defined by the absence of significant glomerular lesions in light microscopy and the absence of deposits in immunofluorescence.

Only the electron microscopy analysis shows an alteration of the podocytes to the type of swelling of the podocytes, accompanied by an eradication of the pedicels. There are, however, histological variants. We can thus observe a discrete mesangial proliferation or even mesangial deposits of IgM.

Extramembraneous glomerulonephritis:

Primary and secondary extramembrane glomerulonephritis are defined by the presence of immune deposits located on the epithelial side of the MBG. These deposits are only visible in light microscopy when they are of sufficient size.All glomeruli are affected. The histological lesions of extramembraneous glomerulonephritis evolve with time and allow to describe three histological types.

In Stage I, MBG is normal on silver colorations. In Stage II, the MBG has club-like expansions on its outer side. In stage III, the MBG is very thickened. The clubs meet to surround the deposits and thus form chains. Segmental and focal hyalinosis, described later, may be observed. The study of immunofluorescence is essential, especially for the diagnosis of type I extramembrane glomerulonephritis because small deposits may be poorly visible on optical microscopy alone. In the primitive forms, the deposits constantly fix the anti-IgG serum and in about 50% of the cases the anti-C3 serum. The fixation is always granular but, in stage I, it may appear pseudolinear due to the small size of the deposits.

Segmental and focal hyperalosis:

The term segmental and focal hyalinosis is ambiguous because it refers to a non-specific glomerular elemental lesion encountered in a large number of nephropathies, and an anatomoclinic entity, on the other hand, associating clinically a nephrotic proteinuria, mesangial deposits of IgM and focal IgM and C3. The segmental and focal hyalinosis lesion associates three types of glomerular lesions   : initially podocytic cell alterations, hyaline deposits and sclerosis. These lesions are called segmental because they partially interest the glomerulus and are focal because not all glomeruli are affected. In optic microscopy, vacuolation and hypertrophy of the podocytes are observed, and then the latter move away from the MBG, separated by a clear band consisting of hyaline material.

Under the affected podocytes, sclerotic and hyaline lesions of the flocculus develop. Sclerosis is related to collapse of the capillary loops and increase of the mesangial matrix. Hyaline deposits of endomembranous obliterated some capillary lights. They correspond to plasma proteins trapped in the collapsed capillary loops. Lipid droplets are readily associated with it. Foam cells can also be found. The ultimate evolution is the constitution of a flocculocapsular adhesion. Lesions of different age can coexist on the same biopsy fragment.

The immunofluorescence examination revealed diffuse mesangial deposits of IgM and deposits of C3 and IgM at the level of the segmental lesions. There are other forms of segmental and focal hyalinosis outside the classical form we have just described.

• Segmental and focal hyalinosis of the urinary pole (“tip lesion”) is peculiar in its topography. The diagnosis is made if there is at least one segmental lesion at the urinary pole.

The evolution of the lesions is identical to that described in the classical form.

• The diagnosis of segmental and focal cell hyalinosis is made when there is at least one endocapillary cell proliferation in a glomerulus. This cellular form appears to correspond to an early lesional aspect evolving towards classical segmental and focal hyalinosis.

• Segmental and focal hyalinosis with glomerular collapse is defined by the presence in at least one of the glomeruli of a segmental or global collapse of the flocculus with hyperplasia and hypertrophy of the podocytes. Podocytes are vacuolated and contain many droplets of protein reabsorption. Among them, many are detached from the MBG. This form of segmental and focal hyalinosis rapidly evolves towards terminal renal failure, particularly in the black subject. It characterizes, with the cystic dilatation of the tubes, the nephropathy associated with HIV.

Diabetic glomerulonephritis:

Renal impairment of type I or type II diabetes is mainly due to glomerulosclerosis occurring 5 to 15 years after the onset of diabetes. This glomerulosclerosis can be either simply diffuse or diffuse and nodular. The nodules are of variable size, 30 to 200 μm.

A thickening of the MBG is detected early by electron microscopy; from the second year of diabetes evolution, it becomes clearly visible in light microscopy in more advanced forms. Exudative lesions can also be encountered: the fibrin cap and the capsular drop.

A segmental lesion at any point identical to a lesion of hyalinosis is described as fibrin cap. This lesion is present in 60% of diabetic glomerulosclerosis. The capsular drop corresponds to a localized hyaline deposit between the epithelial cells and the basal membrane of the Bowman capsule. The presence of voluminous subendothelial circumferential hyaline deposits in the juxtaglomerular arterioles is almost constantly observed. The immunofluorescence study often shows a low linear binding of the anti-IgG serum along the MBG. This binding is not related to an immune process.


Amylose corresponds to extracellular amorphous deposits presenting a characteristic yellow-green dichroism, observed after staining by Congo red, under examination in polarized light. If the deposits are of interest to all kidney structures, the lesions usually predominate in the glomeruli. In the latter, an accumulation of amyloid substance in the mesangium, in diffuse or nodular form, is first observed. At a later stage, there may be an involvement of the wall of the glomerular capillaries, sometimes giving a bristle-like appearance of the basement membrane, not to be confused with stage II glomerulonephritis. The evolution is towards the complete obliteration of the flocculus.

The immunofluorescence study makes it possible to specify the type of light chain involved, or more often k when it is an AL amyloidosis. Immunohistochemistry, with antiprotein AA, allows the diagnosis of AA amyloidosis. There are also antibodies directed against other amyloid precursors such as transtyrethrin, ApoA1, fibrinogen α- chain, lysozyme and gelsoline. Electron microscopic analysis shows amyloid fibrils of 7.5 to 10 nm in diameter in all types of amyloidosis without any particular orientation.

Disease of light chain deposits:

The disease of light chain deposits is a systemic disease whose main target is the kidney. Typical glomerular involvement is in the form of nodular glomerulosclerosis. Glomerular nodules are very positive at PAS. A discrete mesangial proliferation and double-contour aspects are common. There is also a thickening of the glomerular, tubular and vascular wall membranes. The coloring by Congo red is negative.

The study in immunofluorescence is characteristic. It reveals linear diffuse deposits of a monotypic light chain, usually j, along all the basal membranes of the kidney. In 100% of the cases, there is a positivity of the tubular basal membranes, in 85% of the cases the positivity of the MBG and, in 65% of the cases, a positivity of the basal membranes of the vascular walls. Vascular deposits individually surround each myocyte of the media. A lower fixation on the mesangium is usual. Ultrastructural analysis shows along the basal membranes of finely granular deposits dense to electrons.

Thrombotic microangiopathy:

Glomerular involvement can be schematically twofold. Thromboses in one or more capillary loops may be observed, thereby producing a glomerular form of thrombotic microangiopathy. The second aspect is characterized by abnormalities of the capillary walls with the appearance of a subendothelial clear space containing fibrin degradation products and red cell fragments. This clear space overlooks the silverings a double-contoured appearance. Authentic lesions of mesangiolysis are possible. In some forms of thrombotic microangiopathies, with more severe prognosis, thromboses are of interest for juxtaglomerular arterioles (so-called arteriolar form). The immunofluorescence study shows deposits of fibrin in the mesangium and along the walls of the injured glomerular capillaries. The presence of less IgM, C3 and C1q is often noted.

Glomerulonephritis with mesangial deposits of IgA:

As the name suggests, the study in immunofluorescence is the essential step for the diagnosis of glomerulonephritis with mesangial deposits of IgA. Mesangial deposits also contain about 40% of IgG and less than 20% of IgM. In 10% of cases, fibrinogen is found. The presence of fibrinogen in the capillary loops and the glomerular chamber is generally associated with extracapillary proliferation. The C3 fraction of the complement is constantly present. Fractions C4 and C1q are usually absent. While the appearance in immunofluorescence is relatively uniform, the lesions observed in light microscopy are very diverse. In some cases, there is only thickening and / or mesangial hypercellularity, sometimes leading to a double contour appearance. In more than 75% of cases in adults, the appearance in optical microscopy is that of a segmental and focal glomerulonephritis. They may be prolonged endo- or extracapillary lesions affecting one or more lobules, sometimes with necrotic lesions. Glomerulonephritis with mesangial deposits of IgA can be seen in the context of Berger’s disease, rheumatoid purpura and some cirrhotic glomerulonephritis.

Extracapillary glomerulonephritis:

The term extracapillary glomerulonephritis refers to an elementary histological lesion corresponding to a “growing” cellular proliferation occupying the urinary chamber of the glomerulus. The number of affected glomeruli is variable.The crescent may be segmental or occupy the entire urinary chamber. This is a reaction lesion to underlying necrosis of the flocculus. The rupture of the MBG allows irruption of circulating factors, fibrin and inflammatory cells in the urinary chamber, stimulating the proliferation of glomerular epithelial cells that form the crescent. The current classification of extracapillary glomerulonephritis is based on immunofluorescence examination. Three categories of extracapillary glomerulonephritis are distinguished:

• Extracapillary glomerulonephritis with linear deposits of IgG along the MBG are the rarest (<15%). They most often come under the Goodpasture syndrome and are caused by the production of antibodies directed against the α 3 chains of collagen IV of the glomerular and alveolar basal membranes. They may also be secondary to taking poisons;

• Extracapillary glomerulonephritis with granular deposits of immunoglobulins or complement in glomeruli represent about 30% of glomerulonephritis with crescents. They correspond, in fact, to the severe, complicated forms of croissants of a great variety of primary or secondary glomerulonephritis, particularly in the course of systemic lupus erythematosus, rheumatoid purpura, severe infections and certain cancers;

• Extracapillary glomerulonephritis with no significant deposition of immunoglobulin and complement, known as pauci-immune, are the most frequent forms (> 50%). They may represent the renal localization of a systemic vasculitis such as microscopic polyangiitis, Wegener’s disease, or more rarely Churg syndrome and Strauss syndrome. There are also idiopathic forms.

Acute post-infectious glomerulonephritis:

Typically, it is a pure endocapillar proliferative glomerulonephritis. Histologically, in all glomeruli there is a proliferation of variable intensity of the mesangial cells. It is associated, especially when the renal biopsy is early, glomerular infiltration by circulating cells (polymorphonuclear neutrophils, monocytes, lymphocytes) and large abnormal deposits, eosinophils, placed on the external side of the MBG (humps) . Other lesions, especially crowns and subendothelial deposits, may occur. In immunofluorescence, there are deposits of C3 sometimes associated with IgG. These deposits are usually finely granular, located in the mesangium and along the glomerular capillaries. These deposits may persist for several months despite clinical cure.

Glomerulonephritis membranoproliferative:

The membranoproliferative glomerulonephritis is defined by the association of a mesangial proliferation, a double contour appearance and deposits. All glomeruli are affected. On the data of immunofluorescence and ultrastructural analysis, three types of membranoproliferative glomerulonephritis are distinguished.

• Type I membranoproliferative glomerulonephritis or subendothelial deposits are the most frequent. They are characterized by endomembranous deposits of immunoglobulins and complement. The intensity of mesangial proliferation varies from case to case. It is accompanied by an increased, more or less important, production of mesangial matrix. This thickening of the mesangial matrix is ​​classically moderate and diffuse. In some cases, however, it may be important and nodular. At the same time, the presence of polymorphonuclear neutrophils and monocytes is observed in the lumen of the glomerular capillaries.

The double contour appearance is due to the slippage of mesangial cells between MBG and endothelial cells.

The endomembranous deposits are constant and the extramembrane deposits are frequent. In immunofluorescence, the deposits contain IgG, IgM and the complementary fractions C3, C4 and C1q.

• Type II membranoproliferative glomerulonephritis or dense deposits are peculiar to the dense, banded appearance of MBG. This ribboned appearance is also observed at the level of Bowman’s capsule. It corresponds in ultrastructural study to a thickening of the lamina densa, which is replaced by an amorphous, homogeneous material, very dense to electrons. There are other glomerular lesions: mesangial proliferation associated with an increase in the matrix more or less important, double contours usually less marked than in type I, mesangial deposits nodular and deposits extramembranous frequent. In immunofluorescence, only C3 is present in the glomeruli, in the form of granular deposits in the mesangium and the glomerular walls.

Dense deposits also set C3.

• C3-isolated membranoproliferative glomerulonephritis with no dense deposits is a variety of type I glomerulonephritis with only C3 deposits. Mesangial proliferation may be minimal. Infiltration of flocculus by neutrophils is evident. Some granite formations, purplish with Masson trichrome are present in the mesangial axes. In immunofluorescence, numerous mesangial and parietal deposits of C3 are found. C3 deposits are also present along the Bowman capsule.

Fibrillary and immunotactic glomerulonephritis:

The fibrillar and immunotactic glomerulonephritis are characterized by the presence of glomerular fibrillary deposits, Congo red negative. Electron microscopy is necessary to establish the diagnosis. It shows fibrils measuring less than 30 nm in diameter, arranged without precise orientation in fibrillar glomerulonephritis and microtubules measuring more than 30 nm in diameter, arranged in parallel in immunotactic glomerulonephritis. The distinction between these two types of glomerulonephritis remains controversial by some authors. The optical microscopic aspect of fibrillar glomerulonephritis is varied. It occurs most often by an impingement of the mesangium with thickening of the capillary loops. The immunofluorescence examination shows polyclonal deposits composed predominantly of IgG4.