Glomerulopathy associated with glomerular microtubular deposits: a report of a case]

A male aged 58 was admitted to our hospital because of proteinuria, hematuria and bilateral pretibial edema. Laboratory tests showed normocytic, normochromic anemia and moderately impaired renal function. Antinuclear antibodies were negative. Neither M-protein nor Bence-Jones protein were detected. Light microscopic study on the biopsied renal specimen indicated a moderate mesangial proliferation accompanying with the deposition of PAS-positive and Congo red-negative materials in the subendothelial area. C3 accumulated segmentally along the capillary walls, which was clarified by immunofluorescence microscopy. Staining for IgG, IgA, IgM and light chains were negative. Electron microscopy demonstrated the deposition of microtubules in the mesangial, subepithelial and subendothelial areas. The diameter of these microtubules ranged from 40 to 80 nm. Such type of the microtubules have been reported to exist in the glomeruli in the patients with systemic diseases such as amyloidosis, systemic lupus erythematosus, cryoglobulinemia and light chain disease. In our patient, however, any clinical or serological findings suggestive of these systemic diseases were not obtained. On the other hand previous report pointed out that microtubules deposited in the glomeruli in the patients with immunotactoid glomerulopathy or other glomerulopathies. Our patient had the clinical features consistent with these glomerulopathies. However, no depositions of immunoglobulins were observed. This case is an atypical glomerulopathy accompanying with the glomerular microtubular deposits.     

Immunotactoid (microtubular) glomerulopathy: an entity distinct from fibrillary glomerulonephritis?

Immunotactoid glomerulopathy (IT), or alternatively, microtubular glomerulopathy, is a term that has been used by some investigators to encompass those glomerulopathies characterized by the presence of fibrillar or microtubular deposits which are distinguished from amyloid principally by their larger size and lack of reactivity with the Congo red reagent. A case is presented here of IT as it was initially described. The present case, and a review of the literature, suggest that the diagnosis of IT be restricted to those glomerulopathies associated with large, at times organized, microtubular deposits. Terms such as fibrillary glomerulonephritis, or alternatively Congo red-negative amyloidosis-like glomerulopathy, could then be used to describe those patients with smaller, fibrillar glomerular deposits having an appearance closely resembling amyloid. We believe it is possible to separate the entities fibrillary glomerulonephritis and IT on morphological grounds. This is a potentially useful distinction that identifies patients who are likely to have or develop clinical evidence of a lymphoplasmacytic disorder or dysproteinemia, which are associated with deposits of IT, and distinguishes them from patients with fibrillary glomerulonephritis, of whom only a single case has been linked to such clinical findings.     

Immunotactoid glomerulopathy

During the past 10 years, immunotactoid glomerulopathy has become recognized with increasing frequency. The lesion is characterized histologically by highly organized ultrastructural deposits that appear to be composed of immunoglobulin and complement and are negative for amyloid by Congo red stain. Clinically and/or serologically, patients have no evidence of cryoglobulinemia, amyloidosis, systemic lupus erythematosus, or a paraproteinemia, disorders associated with glomerular deposits, which also have a highly organized tactoidal or fibrillar characteristic. Immunotactoid glomerulopathy does not appear to be a multisystemic disease process and thus may represent a primary glomerulopathy. Patients with immunotactoid glomerulopathy present with proteinuria (nephrotic range in more than 60%) and over half of the patients have hypertension, hematuria, and renal insufficiency. Progression to end stage renal disease has occurred in more than 40% of patients reported to date. The experience in treating this disorder using prednisone and/or immunosuppression is limited and has not been impressive. Four patients have successfully undergone renal transplantation, but proteinuria recurred in two and was associated with the recurrence of immunotactoid glomerulopathy in the renal allograft. Although we have gained insight into the clinical course and histopathology of this disorder over the past few years, we still know little about its pathogenesis, an area for further research.     

Glomerular mesangial fibrillary deposits in a patient with diabetes mellitus

Various systemic or primary glomerular diseases can result in deposition of fibrillary material in the glomerular tuft and may cause an important diagnostic challenge for the pathologists. Biopsy findings of a patient with type 2 diabetes is presented here in which striking fibrillary structures were identified in the mesangium by ultrastructural examination. The distinction between diabetic fibrillosis and fibrillary glomerulonephritis accompanying diabetic nephropathy is discussed in the setting of a literature review.     

Fibrillary glomerulonephritis in siblings

Fibrillary/immunotactoid glomerulopathy is characterized by organized glomerular deposition of extracellular, nonbranching, immunoglobulin- derived microfibrils, which is not associated with systemic diseases such as amyloidosis, cryoglobulinemia, or monoclonal gammopathy. This is an uncommon condition with an obscure etiology and accounts for approximately 1% of primary glomerular diseases in white populations. We report the first case of familial fibrillary/immunotactoid glomerulopathy affecting a brother and a sister in a Chinese family. Both patients presented with heavy proteinuria, which improved transiently on treatment with prednisolone and cyclophosphamide. Human lymphocyte antigen typing for the siblings showed no haplotype association. Despite the generally poor renal prognosis reported in the literature, with 50% of patients reaching end-stage renal failure within 2 to 4 years, both patients had relative preservation of renal function (creatinine clearance from 79 to 76 mL/min/1.73 m2 after 2 years in one patient and from 111 to 99 mL/min/1.73 m2 after 3 years in the other). Our observations show that fibrillary/immunotactoid glomerulopathy can present as a familial condition. Compared with sporadic cases, patients with familial fibrillary/immunotactoid glomerulopathy may have a more favorable renal prognosis. (Am J Kidney Dis 1998 May;31(5):E4)     

Fibrillary (immunotactoid) glomerulopathy. A possible role for kappa light chain in its etiology and/or pathogenesis

The initial clinical manifestations, course, and immunopathologic findings of renal biopsies of nine patients with fibrillary glomerulopathy are reported. Their first symptoms and courses were variable, but proteinuria and renal failure were common. While some patients required hemodialysis soon after coming for treatment, others progressed to renal failure over several years. Three patients had monoclonal gammopathy; one of them had an isolated, transient, Bence-Jones proteinuria. The main pathologic features are glomerular enlargement, mesangial expansion, and mild hypercellularity. Congo red and thioflavin stains were negative. Kappa chain, either alone or with lambda chain and IgG, were the predominant immunoreactants. Ultrastructurally, the presence of coarse fibrils of 15-25 nm was characteristic, but there were also granular deposits in the capillary wall that occurred in a band-like pattern in the inner half of the glomerular basement membrane in a manner similar to the deposits seen in light chain deposit disease. The immunofluorescence and ultrastructural findings suggest that light chains (especially kappa) may be significant in the pathogenesis of fibrillary glomerulopathy and that there may be a relationship with light chain deposit disease.     

Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion

Membranoproliferative glomerulonephritis (MPGN) denotes a general pattern of glomerular injury that is easily recognized by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition that are classically referred to as MPGN type I (MPGN I), MPGN II, and MPGN III, while immunofluorescence typically detects immunoglobulins in MPGN I and MPGN III but not in MPGN II. All three MPGN types stain positive for complement component 3 (C3). Subgrouping has led to unnecessary confusion, primarily because immunoglobulin-negative MPGN I and MPGN III are more common than once recognized. Together with MPGN II, which is now called dense deposit disease, immunoglobulin-negative, C3-positive glomerular diseases fall under the umbrella of C3 glomerulopathies (C3G). The evaluation of immunoglobulin-positive MPGN should focus on identifying the underlying trigger driving the chronic antigenemia or circulating immune complexes in order to begin disease-specific treatment. The evaluation of C3G, in contrast, should focus on the complement cascade, as dysregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no disease-specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs.     

Occurrence of kidney diseases and patterns of glomerular disease based on a 10-year kidney biopsy material: A retrospective single-centre analysis in Estonia

Abstract Objective. Kidney biopsy is an important diagnostic tool in assessing glomerular damage. This study aimed to determine the occurrence of glomerular disease during the past decade at a single centre, to assess potential changes in the structure of primary glomerulopathies over time, and to define gender- and age-related differences. Material and methods. A total of 578 consecutive native kidney biopsies during the period 2000-2010 was retrospectively reviewed at Tartu University Hospital, Estonia. Biopsies were evaluated according to clinical data with standard histological methods. Results. The patients' mean age was 39.9 ± 17.9 (range 4-87) years. Less than half of informative kidney biopsies (n = 547) comprised primary glomerulopathies (45.4%), the patients' mean age was 38.7 ± 17.7 (4-79) years and the predominant group comprised male patients. Secondary glomerulopathies made up 22.3%, tubulointerstitial diseases 8.2% and other conditions 24.1%. Among primary glomerulopathies, inflammatory damage to glomeruli dominated (63.4%), whereas immunoglobulin A (IgA) nephropathy was the most common disease (35.5%). Non-inflammatory diseases of glomeruli made up 34.6%, among which the most common was focal and segmental glomerulosclerosis (16.1%), followed by minimal change disease (14.1%). Membranoproliferative glomerulonephritis was a rare form of glomerular damage among primary glomerulopathies (7.7%). Comparison between male and female cases in the primary glomerulopathies group revealed a statistically significant difference in their frequency (p = 0.01). Conclusions. Inflammatory glomerulopathies mostly prevailed in the spectrum of primary glomerulopathies. IgA nephropathy was the most common glomerulopathy. Comparing the data with those from a 15-year earlier period at the same centre, a change towards non-inflammatory glomerulopathies was noticed.     

五例免疫类晶团聚体性肾病的临床与病理

报告五例免疫类晶团聚性肾病，肾活检示肾小球中有特殊沉积物，其刚果红染色阴性，免疫荧光检查免疫球蛋白和补体成份阳性，电镜下呈序化原纤维或微管状结构，病人无冷凝蛋白血症，淀粉样变，系统性红斑狼疮，副蛋白血症等临床和血清学证据，主要临床表现为蛋白尿，其中四例为肾病综合征，半数以上病人有高血压，血尿和肾功能不全，本病的发病机理目前尚不祥。     

Fibrillary-immunotactoid glomerulopathy with renal deposits of IgAlambda: a rare cause of glomerulonephritis

We describe a 24-year-old patient who presented with a nephrotic syndrome. His renal biopsy revealed a diffuse mesangioproliferative glomerulonephritis with eosinophilic deposits. Electron microscopy showed organized, Congo-red negative deposits, forming microtubules of about 20 nm width in the capillary walls and in the mesangium, establishing a diagnosis of fibrillary-immunotactoid glomerulopathy. Fibrillary-immunotactoid glomerulopathy is a rare cause of glomerulonephritis, characterized by Congo-red-negative glomerular deposits of fibrils, sometimes organized in microtubules, predominantly containing IgG and C3. Patients clinically present with the nephrotic syndrome, hematuria and hypertension. The pathogenesis of this glomerulopathy has not been elucidated yet. In our patient, the renal deposits contained IgAlambda. This peculiar feature is suggestive of an underlying paraproteinemia. However, in the serum no paraproteins or cryoglobulins were found, and also microscopical examination and immunophenotyping of the bone marrow did not point to the presence of a monoclonal plasma cell dyscrasia. Our patient was not treated with immunosuppressive drugs and he is currently progressing to end-stage renal disease.     

Glomerular diseases associated with hematopoietic neoplasms: an expanding spectrum

Once thought to be limited mainly to lesions involving deposition of monoclonal paraproteins, glomerular diseases associated with hematologic neoplasms now include forms in which manifestations are probably mediated through cytokines or chemokines. Said et al. studied one such lesion, myeloproliferative neoplasm-related glomerulopathy, and found it to be a late complication of these neoplasms, with a generally poor renal outcome. Whether earlier recognition of glomerular diseases associated with hematopoietic neoplasms can result in more effective treatment remains an important question.     

Minimal-change nephropathy and chronic hepatitis C infection: coincidental or associated?

Sir, Hepatitis C virus (HCV) infection is among the known main causesof glomerulonephritis. Membranoproliferative glomerulonephritisassociated with cryoglobulinaemia is the predominant form inHCV-infected patients. Less common glomerular diseases, i.e.membranoproliferative glomerulonephritis without cryoglobulinaemia,membranous glomerulonephritis, focal segmental glomerular sclerosis,proliferative glomerulonephritis, renal thrombotic microangiopathyassociated with anti-cardiolipin antibodies and fibrillary andimmunotacoid glomerulopathies, have also occurred in these patients.We encountered a patient with chronic     

Nonamyloidotic fibrillary glomerulopathy

A 29-year-old man had oedema, proteinuria in nephrotic range, haematuria and cardiac arrhythmia (second grade atrioventricular block). The pathologic findings of kidney biopsy showed in light microscopy diffuse mesangial matrix increase with mild mesangial proliferation and variable thickening of the glomerular capillary walls. IgG, c₃ and c_1q were intensely fluorescent and exhibited a diffuse granular pattern in mesangial areas and along the capillary walls. Both kappa and lambda chains were weakly positive in the same pattern. Ultrastructurally, microfibrils of about 20 nm in width were seen to be deposited in mesangial areas and along the glomerular basement membranes. Congo red stain and metachromasia were negative. Neither cryoglobulinaemia nor paraproteinaemia including light chains were found. The aetiology of nonamyloidotic fibrillary glomerulopathy is unknown and no clear-cut clinical or pathologic pattern has emerged. It may represent more than one disease process with a common morphologic expression.     

Pattern of double glomerulopathy in children

Occasional case reports have been issued on children with double glomerulopathy, involving either the coexistence of two different glomerulopathies or superimposition of a second glomerulopathy onto a first. A retrospective clinicopathological review of 294 children who had received renal biopsies resulted in 9 (3.1%) being confirmed to have double glomerulopathy. Superimposed glomerulopathy was diagnosed by a second renal biopsy in two cases, and coexistence of two glomerulopathies was confirmed by single biopsy in seven. Original glomerulopathies were those with a chronic course, such as Alport syndrome, IgA nephropathy, relapsing minimal-change nephrotic syndrome, Frasier syndrome, and thin basement membrane nephropathy. The superimposing glomerulopathies were common types in children, such as postinfectious glomerulonephritis, IgA nephropathy, and Henoch-Schönlein nephritis. Thus, the pattern of double glomerulopathy was considered to be due to the chance occurrence of two different glomerulopathies without a common pathogenesis. Acute nephritic symptoms of superimposed glomerulopathies resolved almost completely during follow-up in most cases. Double glomerulopathies are not rare in children and may occur by chance alone in most cases. The possibility of superimposed glomerulopathy should be suspected if the clinical course of a glomerulopathy changes atypically. However, the long-term influence of a superimposed glomerulopathy on renal functional deterioration remains unclear.     

Expression of decorin, biglycan, and collagen type I in human renal fibrosing disease

BACKGROUND: The extracellular matrix proteoglycans decorin and biglycan may have a pathogenic role in renal fibrosing disease via regulation of the activity of growth factors, such as transforming growth factor-beta, and effects on collagen type I fibrillogenesis. The expression of decorin and biglycan in human glomerular diseases characterized by mesangial sclerosis is unknown. METHODS: Decorin, biglycan, and collagen type I were localized immunohistochemically in human renal biopsy cases of amyloidosis (N = 18), diabetic nephropathy (N = 11), fibrillary glomerulonephritis (N = 5), immunotactoid glomerulopathy (N = 5), light-chain deposition disease (N = 4), idiopathic mesangial sclerosis (N = 4), and nephrosclerosis (N = 6), and in morphologically normal tissues obtained from tumor nephrectomies (N = 8). Decorin and biglycan mRNA synthesis was evaluated by in situ hybridization. RESULTS: Decorin and biglycan protein were not identified in normal glomeruli. Decorin accumulated in amyloid deposits, but not in deposits of fibrillary glomerulonephritis or immunotactoid glomerulopathy. Biglycan weakly accumulated in amyloid deposits, and both decorin and biglycan weakly stained mesangial nodules in cases of morphologically advanced light-chain deposition disease and diabetic nephropathy. In all analyzed cases, irrespective of the underlying disease, decorin and biglycan accumulated in glomeruli in areas of fibrous organization of the urinary space and in areas of tubulointerstitial fibrosis. Biglycan, but not decorin, accumulated in the neointima of arteriosclerotic blood vessels. Decorin and biglycan mRNA synthesis was detected at sites of proteoglycan accumulation in glomeruli, interstitium, and neointima. Collagen type I colocalized with decorin and biglycan deposits. CONCLUSIONS: Differences in extracellular matrix proteoglycan composition may be diagnostically useful in distinguishing morphologically similar diseases. Distinct patterns of proteoglycan expression may be related to modulation of specific growth factor activity in different glomerular diseases.     

Glomerular lesions in the transplanted kidney in children

The glomerular pathology of 634 transplant specimens (526 biopsies and 108 transplantectomies) from 410 children was studied. Three types of glomerulopathies were observed: (1) recurrent glomerulonephritis (GN) (40 of 142 patients with glomerular nephropathy), (2) de novo GN (52 grafts), and (3) transplant glomerulopathy (29 grafts). The study of recurrent GN is considered of great interest because of the possible insight into the nature of the original disease and the opportunity to observe the evolution of the disease in sequential biopsies of the transplant. The two major forms of de novo GN were membranous GN and IgG linear deposits along glomerular and tubular basement membranes. Transplant glomerulopathy, although distinctive morphologically, may resemble membranoproliferative GN (MPGN) or thrombotic microangiopathy.     

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy: A Podocyte Perspective

The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation “reverse nephrectomy” is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10- to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting.     

A case of immunotactoid glomerulopathy with IgA2, kappa deposition ameliorated by steroid therapy

We report a case of idiopathic immunotactoid glomerulopathy with IgA2, kappa light chain deposition, ameliorated by steroid therapy. A 28-year-old male patient was admitted to our hospital due to exacerbation of nephrotic syndrome. The onset of his renal disease was at 24 years of age and the renal biopsy revealed membranoproliferative glomerulonephritis with moderate-degree deposition of IgA, IgG, IgM, C3 and C1q. Prednisolone therapy was started at the dose of 50 mg/day and effective for nephrotic syndrome and renal dysfunction. Two years later, the proteinuria and microscopic hematuria gradually exacerbated during reduction of prednisolone. The second renal biopsy showed mesangioproliferative glomerulonephritis with predominant deposition of IgA and C3. The glomerular proliferative changes were successfully suppressed by steroid treatment. On electron microscopy, a microtubular deposit with an average width of 40 nm and double-tracked appearance was observed in the mesangial and subendothelial areas. Immunohistochemical examination revealed that the deposit was predominantly composed of IgA2 subclass and kappa light chain. Selective deposition of IgA2 subclass and kappa light chain indicated that the glomerular lesion should be induced by monoclonal immunoglobulin, although it could not be detected in the serum and urine clinically. Immunoglobulin subclass staining of renal biopsy specimens provides an important clue for understanding the pathogenesis of immunotactoid glomerulopathy or fibrillary glomerulonephritis.     

Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy

C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice 2 hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies, and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was observed after daily administration of CR2-FH for 1 week. In a second mouse model with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data show that CR2-FH protects the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy.     

C3 glomerulopathy and current dilemmas

C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components. Because laboratory detection of complement dysregulation is still uncommon in practice, “dominant C3 deposition by two orders greater than that of immunoglobulins in the glomeruli by immunofluorescence”, as stated in the consensus report, defines C3G. However, this morphological definition possibly includes the cases with glomerular diseases of different mechanisms such as post-infectious glomerulonephritis. In addition, the differential diagnosis between DDD and C3GN is often difficult because the distinction between these two diseases is based solely on electron microscopic features. Recent molecular and genetic advances provide information to characterize C3G. Some C3G cases are found with genetic abnormalities in complement regulatory factors, but majority of cases seem to be associated with acquired factors that dysregulate the alternative complement pathway. Because clinical courses and prognoses among glomerular diseases with dominant C3 deposition differ, further understanding the background mechanism, particularly complement dysregulation in C3G, is needed. This may resolve current dilemmas in practice and shed light on novel targeted therapies to remedy the dysregulated alternative complement pathway in C3G.