The term glomerulonephritis with organized immunoglobulin (Ig) deposits is preferable to the term fibrillar glomerulonephritis, which includes very different anatomoclinic entities ranging from amylose, of which there are about fifteen varieties depending on the nature of the circulating precursor, to fibrillosis of collagen origin, which can be observed during diabetic glomerulopathies, via familial fibrillary glomerulonephritis, with deposits consisting, for example, of fibronectin.Moreover, the term fibrillary has been used in the literature to designate deposits consisting of fibrils (solid substructures) or microtubules (substructures with central light). The same criticism can be made for the qualifier immunotactoid proposed by the American authors.Immunotactoid glomerulonephritis was subsequently dismembered into pseudoamyloid fibrillar glomerulonephritis and microtubular glomerulonephritis. There is still confusion in the literature between these different types of organized deposits and the search for monotypy or monoclonality of Ig deposited in the glomeruli is not always carried out. The diagnosis of pseudoamyloid fibrillary glomerulonephritis and microtubular glomerulonephritis requires an ultrastructural study of the renal biopsy; the incidence of these glomerular nephropathies is certainly underestimated (less than 1% of the biopsies performed on the native kidneys).
Fibrillary glomerulopathy amyloid AL:
Patients with AL amyloidosis are generally older than 50 years of age. The kidney is reached in 50% of cases and the heart in 40%.
Less than 10% of patients have no detectable monoclonal Ig light chain in the serum or urine. Renal clinical presentation is most often nephrotic nonselective glomerular proteinuria with no significant microscopic haematuria.The search for amyloidosis on the biopsy of the kidney is almost always positive in case of clinical manifestation of the kidney. AL amyloidosis is always secondary to a monoclonal proliferation of cells of the B line which is obviously malignant or apparently benign and requires an extensive study of the bone marrow to be demonstrated. Apart from renal impairment, AL amyloidosis is often responsible for periocular cutaneous purpura, macroglossia, carpal tunnel syndrome, peripheral and autonomic neuropathy, restrictive cardiomyopathy, and d hepatomegaly. Median survival is 12 months.
NATURE AND SEAT OF DEPOSITS:
Amyloid AL fibrillar deposits are extracellular, amorphous, eosinophilic, weakly positive, positive Congo red, with birefringence and yellow-green dichroism in polarized light. In electron microscopy, these deposits are formed from rectilinear, unconnected fibrils, 8 to 10 nm in outside diameter, without centralized light. These fibrils are arranged in all directions, at random, in piles of pins and form deposits of variable density. These deposits consist of a light chain of monoclonal Ig most often lambda (kappa / lambda = 1/4) with a predominance of the subgroup of lambda 6 variability, or more exceptionally of a heavy chain c (amylose AH ) deleted in its constant region of the CH1 and CH2 domains.Associated with this immunoglobulin precursor, non-specific proteins can be detected, that is to say they can be encountered in all amyloid deposits of whatever nature: serum amyloid P component, glycosaminoglycans, apolipoprotein E and amyloid enhancing factor . The immunoglobulinic nature of an amylose can be asserted easily on frozen tissues by the use of specific anti-chains specific sera and, more exceptionally, anti-Ig heavy chains.Monoclonal gammopathies, common in the elderly, may coexist with amyloidosis of non-immunoglobulin origin, which makes it necessary to identify the deposits by the appropriate antibodies. Inherited amyloidosis consisting of the mutated alpha chain of fibrinogen, mutated transthyretin, or mutated apolipoprotein A1 may be delayed at age when AL amylosis is the most common. AA amyloidosis complicates chronic inflammatory states, familial Mediterranean fever and Muckle and Wells syndrome: a specific anti-SAA serum makes it easy to diagnose.
From a therapeutic point of view, only heavy chemotherapy followed by autograft of circulating haematopoietic stem cells can allow remission. The mortality and morbidity of this therapeutic can be reduced by a good selection of patients suffering from AL amyloidosis and its early implementation, before the occurrence of too advanced cardiac and / or hepatic involvement.
The therapeutic effect of anti-leaflet monoclonal antibodies b is demonstrated in some murine AL models of amylose.Competitive pharmacological inhibitors of amyloid P binding to amyloid fibrils are currently being studied in humans.
Glomerulonephritis with organized non-amyloid immunoglobulin deposition:
They include glomerulonephritis with pseudoamyloid fibrillar deposits and tubular deposits.
The renal presentation of these two entities is not different, with nephrotic nonselective glomerular proteinuria in two thirds of cases and frequent microscopic haematuria.
High blood pressure and chronic renal insufficiency are common. Renal insufficiency progresses rapidly towards the end stage in 50% of the fibrillar glomerulonephritis, slower and rarer in microtubular glomerulonephritis, with possible remission of the nephrotic syndrome induced by the treatment of a lymphocytic or plasma proliferation often associated with it. Extrarenal and extraglomerular lesions are exceptional. The data of the optical microscopy and the immunofluorescence of the renal biopsy make it possible to evoke the diagnosis of organized deposits of Ig. Diffuse eosinophilic mesangial deposits, PAS-positive, Congo-red negative, consisting mainly of polyclonal IgG 4 , should seek a pseudoamyloid fibrillar organization by electron microscopy. An aspect of atypical extramembranous glomerulitis or gladly lobular membranoproliferative glomerulonephritis, with deposits of monotypic IgG 1, 2 or 3, often corresponds to a microtubular organization of the deposits.
Among glomerulopathies with organized non-amyloid Ig deposition, however, pseudoamyloid fibrillar deposits and microtubular deposits have distinctive characteristics.
PARTICULARITIES OF FIBRILLARY GLOMERULONEPHRITE PSEUDOAMYLOID:
The deposits, in general only glomerular, are extracellular, amorphous, eosinophilic, strongly PAS positive and Congo red negative. In electron microscopy, they consist of rectilinear fibrils arranged at random and thus evoking amylose.This is a pseudoamylose since, on the one hand, the Congo red staining under light microscopy is negative and on the other hand, by electron microscopy, the fibrils have a larger external diameter, varying from 15 to 20 nm. These pseudoamyloid fibrils often form deposits of low density, fuzzy boundaries with respect to neighboring membranoid material. These fibrillar deposits can coexist with osmophilic granular deposits. They consist mostly of polyclonal IgG 4.
IgG 4 is normally about 2% of the circulating IgG.
This subclass of IgG is produced under the effect of prolonged antigenic stimulation. IgG 4 are compact and rigid molecules, which can promote fibrillogenesis. The amyloid P component could be demonstrated in these fibrillar deposits as in amylose, but not glycosaminoglycans. Only the most recent observations have been studied with anti-Ig light chains. In our recent experiment on a series of nine cases, deposits are made up of polyclonal IgG in eight cases.If we exclude the case of Rosenmann et al, which for us is a microtubular glomerulonephritis with monotypic kappa IgG deposits, no lymphoplasmocytic proliferation has been demonstrated in the published observations even after extensive research in the bone marrow and with an average observation period of 56 months in our series.Spontaneous or undergoing treatment progresses to chronic renal insufficiency in 80% of cases and end-stage in more than 50% of cases. This glomerulopathy is likely to recur under immunosuppressive therapy after renal transplantation.
MICROTUBULAR DEPOSITION GLOMERULONÉPHRITE:
In optical microscopy, the deposits are not different from the pseudoamyloid fibrillar deposits. They are also Congo red negative. There may be pseudothrombi in the lumen of the glomerular capillaries, in relation to very large subendothelial deposits. Unlike the glomerular lesions of cryoglobulins, there is no true thrombus, no large influx of macrophages, no lesion of intra- or extrarenal associated vasculitis. In electron microscopy, the deposits consist of microtubules frequently rectilinear, with a visible central light. Their outer diameter varies from 10 to 50 nm and the internal diameter is from 6 to 20 nm. The deposits are mostly dense, osmiophilic, with clear limits in relation to the neighboring collagenous collagen material. In some places, the microtubules are arranged parallel to one another, forming bundles which are oriented in all directions.
Some authors have proposed to differentiate pseudoamyloid fibrils from microtubules on the external diameter of the substructures alone. If the microtubules can have a diameter greater than 30 nm, up to 50 nm (“megamicrotubule”), in some cases the external diameter is not different from that of the pseudoamyloid fibrils (“small microtubules”). In these cases where the external diameter of the substructures is less than 30 nm, the diagnosis is based on the parallel arrangement, the existence of a central lumen, and the well-defined and dense character of the deposits with respect to the neighboring collagen membrane material.
The term “immunotactoid” encountered in the Anglo-Saxon literature describes the crystalline organization of Ig deposits, in analogy to liquid crystals consisting of biopolymers. Schwartz and Korbet proposed to classify glomerulonephritis with Ig deposits organized in the form of fibrils and / or microtubules as immunotac- tis and occurring in the absence of any systemic disease, in particular of monoclonal gammopathy. It is currently established that highly-sensitive (Western blot) techniques can be used to identify monoclonal Ig whereas conventional techniques (immunoelectrophoresis and even immunofixation) remain negative. Moreover, in a large number of old observations, the monotypic character of the Ig deposits was not sought. We have shown that microtubular deposits are very often monotypic and that the circulating precursor is sometimes absent even using sensitive techniques. Careful examination of the bone marrow and circulating lymphoid cells in search of a minimal monoclonal lymphocyte population should be performed to eliminate incipial lymphoplasmocytic proliferation. Electron microscopy of circulating B lymphoid cells or bone marrow allowed us to identify the monoclonal IgG at the origin of the deposits and to demonstrate its property in forming microtubules in ergastoplasmic and perinuclear tanks, these microtubules being strictly identical to those found in glomerular deposits. In addition, lymphoplasmocytic proliferation may occur outside the bone marrow and is sometimes found in the renal interstitium. The monotypic character of the lymphoplasmocytic cells infiltrating the kidney is confirmed by the study with the light and heavy antigens of Ig, demonstrating intracytoplasmic inclusions in monoclonal Ig needles. Glomerulonephritis with Ig microtubular deposits may complicate various pathologies related to the stimulation and proliferation of the lymphocyte B line, as recently reported in an experimental model. Transgenic mice for B-cell growth factor, NNT-1 / BSF-3 / novel neurotrophin-1 / B cell stimulating factor-3 or cytokine-mediated cytokine belonging to the interleukin 6 family, exhibit B lymphocytic hyperplasia with splenic but also renal plasmocytosis, a high level of IgM, IgE, IgG 2b , IgG 3 (profile evoking an immune response Th2) and non-amyloid glutaminous Ig microtubular deposits, the monotypy and monoclonality of which not studied.
From a therapeutic standpoint, in our recent series, seven patients out of 13 had an associated lymphoproliferative syndrome and chemotherapy induced remission of the nephrotic syndrome in ten patients.
With a mean follow-up of 52 months, six patients had normal renal function, six had chronic renal failure, two were severe, and two patients had periodic hemodialysis. One of these patients died after 8 years of hemodialysis after developing diffuse lambda AL amylosis. One patient is in remission of lymphoma and glomerulopathy, after aplasing chemotherapy and bone marrow autograft.
Glomerulonephritis of cryoglobulins:
Renal clinical signs usually occur after extrarenal manifestations (purpura, arthralgias, fever, polyneuropathy or multiple mononeuritis, digestive disorders, myocarditis …). They consist most often of an acute or rapidly progressive glomerulonephritic syndrome, sometimes with impure nephrotic syndrome. Renal biopsy by optical microscopy reveals a membranoproliferative glomerulonephritis or segmental glomerular lesions with an influx of neutrophil and macrophage inflammatory cellular elements and thrombi fibrinoids in the glomerular capillary lumen at the time of disease outbreaks.
GLOMERULONÉPHRITES OF TYPE I CRYOGLOBULINS AND GLOMERULONEPHRITES WITH MICROTUBULAR ORGANIC DEPOSITS OF MONOCLONAL IMMUNOGLOBULIN:
In the absence of detectable cryoglobulinemia, these glomerular lesions may be labeled “glomerulonephritis with microtubular organized deposits of monoclonal Ig” (glomerulonephritis with organized microtubular monoclonal immunoglobulins deposits [GOMMID]). Microtubules under electron microscopy are the same. In both cases, there is often a detectable lymphoplasmic proliferation. The diagnosis of cryoglobulin is suggested by the existence of substructures in glomerular capillary lumens in deposits constituting true thrombi, by the influx of macrophages and neutrophils, the presence of dense organized inclusions, sometimes crystalline, in endothelial cells and macrophages, the subendothelial predominance of deposits and the more rare character of extramembrane deposits.
Thrombi and deposits are sometimes crystalline, evoking crystalcryoglobulin. Identical crystals are detected in serum cryoprecipitate and in the cytoplasm of lymphoid or plasma cell tumors and in macrophages. We have been able to show that the crystallization of a monoclonal Ig is linked in part to structural features of the V region of the light chain.
NATURE AND SEAT OF DEPOSITS IN TYPE II:
Glomerular deposits consist mostly of a kappa IgM and polyclonal IgG. They are demonstrated both with anti- c , anti-μ, anti- and anti- k antibodies. The ultrastructural organization of the deposits, when it exists, is very particular, with curvilinear annular and tubular structures of large diameter (from 50 to 60 nm). These structures are sometimes difficult to distinguish on a more or less dense osmiophilic granular background and the organization can be very focal.Chronic hepatopathy linked to the hepatitis C virus is the cause of type II cryoglobulinaemia in 90% of cases.
NATURE AND SEAT OF DEPOSITS IN TYPE III :
Glomerular deposits are mostly unorganized, and consist of polyclonal Ig and complement components. In the course of systemic lupus erythematosus, these deposits may present a crystalline organization carrying out fingerprints, consisting of lamellar, curvilinear structures with a periodic striation of 22 nm. These deposits consist of the three main classes of polyclonal Ig, deoxyribonucleic acid and complement components. Type III cryoglobulinemia is detected almost constantly.
Fibrillar structures and Randall syndrome:
RANDALL AND AMYLOSE AL SYNDROME:
Amyloid fibrillar AL deposits consisting of a light chain of the same type as that found in the dense osmiophilic granular deposits of the Randall syndrome were described in the same patient. It should be noted, however, that if the deposits can coexist in the kidney, they are often in different sites: arterioles for amyloid AL fibrillary deposits; glomerular membranes within the glomerular capillary basal membranes in the mesangium and on the periphery of tubular basal membranes and arteriolar myocytes for Randall granular deposits.
RANDALL SYNDROME AND NON-AMYLOID FIBRILLS:
Pseudoamyloid fibrils may also be mixed with the osmiophilic granular deposits characteristic of Randall syndrome.
These fibrils are short, straight, osmiophilic and about 14 nm in diameter. We have observed once these non-amyloid and amorphous fibrillar mixed deposits on a series of 51 cases of Randall syndrome. It was a 30-year-old woman whose disease began with respiratory manifestations and exhibited diffuse deposits of Kappa monoclonal light chains in the small vessels of all organs, mainly bronchi, liver, bone marrow, lymph nodes and secondary kidney. The study of the serum showed a kappa monoclonal IgM. In the bone marrow, there was a kappa IgM immunocytoma and Congo red negative, kappa positive arteriolar deposits, causing a foreign body granulomatous reaction. In the kidney, non-amyloid fibrillar structures and dense amorphous deposits coexisted in the mesangium, at the periphery of the capsular basal membrane and tubular basal membranes.
Glomerulopathies with organized Ig defects of glomerulopathies should be distinguished from non-immunoglobulin substructures, essentially collagen fibers.
Collagen fibrils are very often observed in the mesangium of glomeruli in the course of sclerosis, whatever the initial nephropathy. During diabetic glomerulopathy, a very marked mesangium fibrillosis, consisting of non-rectilinear microtubules with little osmiophilicity of 10 nm in diameter, can be observed. The CD2AP – / – mice exhibit congenital nephrotic syndrome and extensive fibrillar mesangial sclerosis consisting of fibronectin, collagen IV, perlecan and laminin 1, 2 and 10. The collagen fibrils are in fact made up of curvilinear microtubules of 10 nm diameter.
During osteo-onycho-dysplasia, periodically striated collagen fibers are present in the mesangium, in the subendothelial space and within the basal membrane itself.
The same type III collagen structures are described in the absence of any bone and nail malformation in type III collagenous glomerulopathy, often familial.
Finally, there are observations of familial glomerulonephritis with fibrillary deposits consisting of fibronectin, laminin and collagen IV.
There are glomerulonephritis with organized deposits that may be immunoglobulinic or collagenous in nature. The study in light microscopy, immunofluorescence and electron microscopy makes it possible to easily distinguish between immunoglobulin deposits and collagen deposits and amyloid deposits in non-amyloid deposits within immunoglobulin deposits. Organ Ig-deposited glomerulonephritis consists of pseudoamyloid fibrillar glomerulonephritis, glomerulonephritis with microtubular Ig deposits most commonly monoclonal, and glomerulonephritis of type I and II cryoglobulins. Particular pseudoamyloid fibrils are described in association with the amorphous deposits of monoclonal Ig of Randall syndrome. The existence of monoclonal gammopathy and of an immunoproliferative B syndrome is common in patients with glomerulonephritis with microtubular deposits of monoclonal Ig. The treatment of the immunoproliferative syndrome then allows the remission of the renal impairment at the same time as haematological signs. In contrast, in pseudoamyloid fibrillar glomerulonephritis, the deposits are polyclonal Ig, an associated immunoproliferative syndrome is exceptional and no treatment has been demonstrated.The progression towards chronic terminal renal failure is frequent. Recurrence is possible on the graft after renal transplantation.