Notes by doctor Claudio Italiano
La sindrome nefrosica Glomerulopatie
Glomerular diseases are renal diseases due to primitive alterations of the
glomeruli, different from those in which the glomeruli are altered by an
ischemia, as already considered in nefroangiosclerosis; and also different from
those due to systemic diseases such as diabetes mellitus. These are diseases in
which the glomeruli are the only affected component, at least at the onset,
while the possible tubulointerstitial changes are secondary: anatomical-clinical
pictures that are exactly the opposite of what happens in nefroangiosclerosis or
in chronic pyelonephritis. These are very rare diseases that the practicing
physician is unlikely to encounter in his professional activity and for which
there is still no definitive therapy. Nevertheless, they attract considerable
interest in medical culture. One of the reasons is linked to the fact that many
of them are immune-mediated diseases and that historically their study has
allowed fundamental progress in the field of the basic immuno-pathology and of
the immuno-chemistry.
The
modifications of the structure of the glomerulus can occur in many forms but
they are schematically due to a few essential injuries:
I. The biochemical structure of the basement membrane is affected: the filter
function is no longer effective and there is loss of protein in the urine (ie
proteinuria and / or nephrotic syndrome): these are pathological events due to
the inborn lack of one or more structural proteins of the capillary wall or
alterations of the glomerular filter function by circulating factors that induce
proteinuria: in both cases no morphological lesions of the basal membrane are
produced which are visible with the methods available today;
II. a rupture of basal membrane traits occurs due to congenital defects as
occurs in Alport syndrome; in these cases there is blood loss in the urine (haematuria);
III. always due to inflammation, the inflammatory cells accumulate in the
capillary lumens; the blood no longer flows into the glomeruli: little urine
(oliguria) is produced, or not produced at all (anuria), and the renal function
of water and salt exchange is compromised (renal failure); the inflammation also
causes small and isolated breakages of the capillary wall with evident losses of
blood in the urine (macro haematuria); impaired renal flow and reduced urine
production also entail hypertension: the combination of renal failure, oliguria,
haematuria and hypertension is known as nephrisis syndrome;
IV. the necrosis of the convoluted capillary involves the precipitation of
fibrin in Bowman's space and the proliferation of the podocytes, especially of
the parietal ones; the proliferation compresses the convoluted capillary with
impediment, also in this case, to the blood flow in the capillaries (oliguria
and renal failure) and haematuria due to the extensive rupture, within the
necrosis of capillary walls: symptom complex then similar to the nephritic
syndrome in but hypertension is rarer;
They can also have clinical-pathological pictures with the same areas of
glomerular necrosis, not diffuse, but focal, with small and isolated breakages
of the capillary wall: in this case the renal function is not compromised but
there is a loss of a few red blood cells ( micro hematuria);
V. there may also be various combinations of the injuries and events already
referred to in the preceding paragraphs.
Instead of the morphological lesions, glomerular diseases can be considered
depending on the symptoms that distinguish them, and in this case we can
distinguish:
1. diseases with isolated hematuria (macro or micro hematuria);
2. acute or rapidly progressive nephritic syndrome;
3. asymptomatic proteinuria;
4. massive proteinuria (nephrotic syndrome);
5. combination of the previous symptoms.
As we can see, the two ways of classifying glomerular diseases are partly
overlapping, but there are many limitations, above all because many lesions,
different for morphological aspects and for pathogenesis, are associated with
the same symptomatic picture.
All the morphological and functional alterations described, are mediated by a
large number of circulating factors and by the injurious actions performed by
the inflammatory cells. It is a field of research in continuous evolution with
results that already today are clinically relevant, but which will certainly be
even more in the future, because it will allow the targeted pharmacological
therapy of glomerular damage, currently still very approximate therapy.
The different morphological manifestations of
glomerular damage in primitive glomerulopathies, whatever the cause, are
mediated by complex mechanisms of inflammatory and non-inflammatory type.
Non-inflammatory mechanisms of glomerular damage are supported by:
1. glomerular permeabilization factors;
2. complement attachment complex (C5b9) to the membrane.
They are molecules that do not induce appreciable inflammatory manifestations in
the glomeruli, but induce increased permeability, compromising the glomerular
capillary wall, probably the podocyte: clinically it follows more or less severe
proteinuria or nephrotic syndrome. The permeabilized factors, (we do not yet
know what the exact molecular mechanism of action), have been researched for
some time to explain some phenomena: for example the speed (even a few hours)
with which some diseases (nephropathy to minimal lesions and sclerosis focal),
recurrent renal transplants. The time between a transplant and the onset of
severe proteinuria is sometimes so short that one must admit the existence of a
factor already present in the circulation. Probably they are molecules able to
interfere with the nephron or other molecules of the diaphragms (slit diaphragms)
of the podocytes.
The attachment complex of the complement system (C5 b9) to the membrane is
another factor, in this case better identified, which significantly increases
the permeability of the glomerular basement membrane and is particularly
relevant in the membranous glomerulopathy. It is incorporated into the
cytoplasmic membrane of the podocyte and is thus damaged. Although C5b9 is
involved in the production of severe proteinuria, it does not involve
inflammatory manifestations because it is separated from the blood capillary by
the glomerular basement membrane
The glomeruli inflammation (leukocyte infiltration, necrosis, thrombosis,
proliferation of glomerular cells) almost always involves the fixation /
presence of immune complexes, especially when the immune complexes are deposited
in the mesangium or along the internal side of the capillaries, below the
endothelium (deposits under endothelial): in the proximity of the blood stream,
since it is not separated from it by the basement membrane. In this case the
activation of the complement, caused by the immune complexes, produces three
consequences:
1. a recall of inflammatory cells (macrophages and neutrophil granulocytes);
2. a proliferation of mesangial cells;
3. appearance of lithic or necrotizing lesions.
As
a consequence, the most evident microscopic aspect of the glomerular lesion will
be hypercellularity and is generically described as glomerulonephritis
(glomerulo glomerulo) proliferative. The following pathological events occur:
1. the immune complexes present in the glomerulus activate the complement;
2. neutrophil granulocytes and macrophages are attracted by the complement
activated by the immune complexes, in particular from the component C5 a;
3. neutrophil granulocytes are located close to endothelial cells, through the
interaction between adhesins or endothelial integrins and ligands present on the
neutrophil;
4. neutrophil granulocytes phagocytate immuno-complexes and are activated;
5. the neutrophil activated in this way releases a series of tissue-damaging
factors (with capillary necrosis or basal membrane rupture), such as hydrogen
peroxide and proteases.
As can be seen, the main causes of the lytic and / or necrotizing lesions of the
glomerulus are the neutrophils granulocytes. Macrophages also produce oxidants
and proteases, but above all secrete TGFbeta and PDGF, with consequent induction
of glomerular sclerosis (increase in extracellular matrix).
The same factors that induce accumulation of inflammatory cells also produce the
proliferation of two types of glomerular cells: mesangial and podocytes, (especially
of the parietal sheet of the Bowman capsule) and to a much smaller extent of the
endothelium.
Since the mesangium can come into direct contact with immune complexes, the
proliferative stimulus on the mesangial cells is easily understood.
The proliferation of cells in Bowman's space, on the other hand, is produced
only after the necrosis of the capillary walls has occurred with the outflow of
blood and formation of a fibrin network in Bowman's space. And fibrin is the
real one responsible for the proliferation of the glomerulus parietal cells. The
fibrin deposition also stimulates the recall and infiltration of macrophages: so
that Bowman's hypercellularity (called extracapillary because located outside
the capillary lumen) is partly due to:
- proliferating podocytes
- and, in part, to infiltration of macrophages.
These details are important because from a clinical point of view the
proliferation of the parietal podocytes involves a very poor prognosis. When the
proliferation of the podocytes (extra-capillary proliferation) represents the
prevalent histological lesion, the corresponding form of glomerulonephritis is
called rapidly progressive because in a few weeks it evolves towards renal
failure. Endothelial cells rarely proliferate so they do not usually participate
significantly in glomerular hypercellularity. Sometimes, however, in some
diseases (for example uremic-hemolytic syndrome) they are the direct target. In
this case they detach from the basement membrane, go into necrosis or on the
contrary proliferate and in any case release vasoactive substances (endothelin,
nitric oxide) and coagulation factors: the endothelial damage entails thrombosis
in the capillaries.
In children and less in adults, it is an event, frequent of nephrotic syndrome, sensitive to steroid therapy. The frequency in children is so high that in the case of a nephrotic syndrome in pediatric age no renal biopsy is used to formulate the diagnosis, but we proceed directly to therapy assuming that it is a disease with minimal injuries: in fact, in the child the great the majority of proteinurias fades with steroid therapy precisely because it is due to minimal injury to nephropathy. The disease has aetiology not yet clarified. It seems to be due to a primitive alteration of the podocytes and that it is linked to the celluliticated immunity. Histologically glomeruli look normal. For many years it was therefore erroneously believed that the primitive alteration was in the tubules: in fact the glomeruli under the light microscope are normal while in the tubules accumulate large amounts of lipids and being the macroscopically yellowish kidneys, the term lipoid nephrosis was coined. Today we know that the tubular alterations are secondary to hyperlipidemia and the conspicuous reabsorption of proteins from the glomerular filtrate and we also know that the glomeruli, if they are histologically normal, are no longer if examined at high magnification with electron microscopy techniques. It was thus possible to point out that the pedicellar processes of the podocytes have disappeared and large continuous strokes of the cytoplasm of the podocyte cover the outer side of the basement membrane. This is the only morphological alteration so far identified in this disease. However, the disappearance of pedicel processes is not likely to be the cause, but a consequence of proteinuria. The true etiology then escapes again and is perhaps to be found in a molecular alteration of the capillary wall, basement membrane or diaphragms, which unite the pedicels. The fusion of podocyte pedicles is in fact a phenomenon that is observed in all cases of severe proteinuria whatever the cause.
It is a disease generally characterized by nephrotic syndrome and sclerosis of some groups of capillaries (segmental) in some glomeruli (focal). Also of this disease we ignore the pathogenesis, and also in this case it can be assumed that there is a molecular alteration of the podocyte at the base. The belief is justified by the study of some familiar forms of the disease (very rare in truth, but very instructive to understand the pathogenesis of the most common sporadic forms); forms that have made it possible to identify in the gene that codes the a-actinine 4 (ACTN4) the site of the mutation responsible for the nephropathy. Recall that the alpha-actinin is a specific surface molecule of the podocyte that serves to aggregate actin filaments. We also know other forms of familial nephrotic syndrome, also related to mutation of genes of podocyte proteins: one of them, the congenital nephrotic syndrome (so called because originally described in Finnish families) is due to mutation of the gene that codes for the nephrine (nphs-1), already mentioned as a trans-membrane protein of the diaphragms placed between the pedicellar processes of the podocytes. Another form is the autosomal recessive resistant steroid nephrotic syndrome (SRNS): it is caused by mutation of NPHS-2 on chromosome 1, the gene coding for podocin, a protein that anchors nefrin to the diaphragms of pedicel processes. All these known forms of congenital and hereditary nephrotic syndrome have in common the molecular alteration of one or more proteins associated with the podocyte: refrine in the Finnish form, podocin in the resistant steroid form, a-actinine in the family focal sclerosis. This is the reason that suggests that even the inborn nephrotic syndromes, very infrequent, (nephropathy with minimal lesions and focal sclerosis) are due to defect of a protein of the capillary wall, probably of the podocyte, even if to date not we could identify it, since all the molecules considered are normally expressed. It is interesting to note that the congenital forms share many histological features: the fusion of the pedicellar processes of the podocytes and the progressive histological alteration of the glomeruli, initially normal and, at the end, partially or completely sclerotic. Non-hereditary segmental focal sclerosis is a frequent cause of nephrotic syndrome in adults. Unlike the minimal lesion nephropathy, it is not sensitive to steroid therapy, it progresses in a shorter or longer time towards renal failure and, to complete an already serious picture, it recurs very often in the transplanted kidney.
The morphological aspect of a kidney with focal segmental sclerosis obviously depends on the phase of the disease that is
being considered: when the lesion is advanced and the sclerosis has already
involved most of the glomeruli causing renal insufficiency, the findings are
scleroatrophy of the whole parenchyma . It should be kept in mind that when the
glomeruli are completely sclerotic, the surrounding tubules are indirectly
affected by ischemia due to the impeded blood flow in the glomerular capillaries,
causing scleroatrophy of the whole nephron. In the initial phases instead, the
histological alterations affect only some glomeruli, while the most are
apparently normal (this is the meaning of the focal term: only some glomeruli
are damaged). Moreover, the sclerosis process (basically the collapse of the
glomerular capillaries and the increase of the extracellular matrix) in the
affected glomeruli does not involve all the capillaries, but only a part of them.
It justifies the term segmental (a part of the glomerulus affected another no).
The mechanism by which the possible molecular anomaly produces the sclerosis
lesion of the glomerulus is only partially known: there is never inflammation
but a primitive degeneration of the podocytes, perhaps due to some biochemical
defect currently unknown.
The process is characterized by an adhesion between the remaining basal membrane
without epithelial lining and the Bowman capsule: the parietal cells, in the
presence of a substrate to adhere to, proliferate and deposit an excess of
extracellular matrix forming adhesions between capillaries and capsule of Bowman.
It is a focal lesion, which affects only some glomeruli, while most appear
normal. But this is only true at the histological level: at a more detailed
examination, with an electron microscope, even in the glomeruli not involved in
sclerosis there is a widespread disappearance of pedicellar processes of the
podocytes, exactly as observed in the disease with minimal lesions.
The process is characterized by an adhesion between the remaining basal membrane
without epithelial lining and the Bowman capsule: the parietal cells, in the
presence of a substrate to adhere to, proliferate and deposit an excess of
extracellular matrix forming adhesions between capillaries and capsule of Bowman.
It is a focal lesion, which affects only some glomeruli, while most appear
normal. But this is only true at the histological level: at a more detailed
examination, with an electron microscope, even in the glomeruli not involved in
sclerosis there is a widespread disappearance of pedicellar processes of the
podocytes, exactly as observed in the disease with minimal lesions. It is
evident that the primary molecular defect of focal segmental sclerosis affects
all the glomeruli, which justifies the severe proteinuria, while sclerosis
lesions represent a more advanced process of the disease, appearing later and
being visible only in some glomeruli. It is important to distinguish the disease
from minimal lesions from the glomerulo focal segmental sclerosis. Both present
with nephrotic syndrome, both are characterized by histologically normal
glomeruli and by the widespread disappearance of pedicellar processes. But one
has excellent prognosis and often heals with steroid therapy while the focal
segmentary glomerulo-sclerosis inexorably, progresses to irreversible renal
failure. If it is obvious the importance of distinguishing two diseases and
diagnosing them with accuracy, it is also obvious that renal biopsy (the way to
resolve the differential diagnosis of two clinically similar entities, both
characterized by nephrotic syndrome) can be very difficult to interpret. A
biopsy specimen usually contains about ten glomeruli: if all are unscathed we
can assume that the disease in question is a nephropathy with minimal lesions,
but we can not be sure: a lesion of focal sclerosis could be present elsewhere
and be missed to bioptic sampling. The interpretation of histological findings
of renal biopsy in cases such as this, and in focal lesions in general, is one
of the most difficult chapters of all renal disease.
It is the most common cause of nephrotic syndrome in adults. It is an autoimmune disease due to the production of antibodies against a still unknown podocyte protein, perhaps located at the base of the pedicellar processes. The highest incidence is in the fifth and sixth decade of life and men are affected more frequently than women. The disease can regress spontaneously or may progress towards renal failure, but always slowly. If there is hematuria this is at most microscopic ie detectable only with microscopic examination of the urine. The histological lesion consists of the presence of discontinuous deposits of immunoglobulins (IgG) and of the C3 fraction of the complement along the basement membrane of the glomeruli, on the side facing the podocyte (hence the term subepithelial that is given to the deposits) realizing with appearance of granular type of capillary walls when examining glomeruli with immunofluorescence techniques. Under the electron microscope, the same deposits appear as electrondensive nodules located between the basement membrane and the podocytes. The pedicellar processes have disappeared as in all nephrotic syndromes. With time, the basal membrane, under the stimulus of deposits, thickens and thickens becomes clearly visible under an optical microscope, justifying the term "membranous" given to this nephropathy. The absence of inflammation is the reason why the term used in the past of membranous glomerulonephritis has been replaced by that of membranous glomerulopathy. The capillary lumens are pervasive, the normal glomerular blood flow, as normal are the tubules and the renal function. The disease has slow evolution and renal function remains well-preserved for a long time. Glomerular sclerosis and interstitial fibrosis take place only after many years. As in many diseases with nephrotic syndrome, membranous nephropathy predisposes to thromboembolic phenomena, particularly to renal vein thrombosis.
The membrano-proliferative glomerulonephritis, also known as mesangio-capillary
glomerulonephritis, is a nosological entity that fits in the context of a
nephrotic syndrome and is characterized by membrane filtration (membrano)
lesions and by intense proliferation of glomerular cells (proliferative) . There
are 3 types of membrano-proliferative glomerulonephritis, which, while sharing
similar anatomopathological lesions in optical microscopy, are differentiated by
triggering and by the glomerular deposition. Mesangial cellularity is increased.
MPGN of type I
It is an immune complex disease and is characterized by electromagnetic (dark in
electron microscopy) subendothelial and mesangial deposits of C3, IgM and IgG.
Circulating immune complexes may be the products of infections, autoimmunity or
neoplasms. The infections responsible are sustained by HCV, HBV, HIV or bacteria
able to trigger endocarditis.
MPGN of type II
It is an autoimmune disease, also called dense deposit disease, characterized by
the deposition of markedly electrondensate material in the basal membranes of
the glomeruli. Differently from type I, in type II the deposits are formed by
only the C3 fraction of the complement, without there being a marked presence of
IgG or IgM. The disease is triggered by the presence of an autoantibody IgG (nephrogen
C3 factor) that binds C3-convertase.
MPGN of type III
Type III is very rare; it is characterized by an intermediate framework between
the type I MPGN and the membranous glomerulonephritis. Specific alterations of
chromosome 1 appear to be responsible for increased predisposition
cfr lNefrology