[Hereditary fibrinogen Aα-chain amyloidosis caused by the E526V mutation: a case report and literature review].

Mutations in the fibrinogen Aα-chain genes are the most common cause of hereditary renal amyloidosis. The renal histologic appearance in the patient is characteristic and shows striking glomerular enlargement with almost complete obliteration of the normal glomerular architecture by extensive amyloid deposition. In contrast, the vessels and renal tubular interstitium of such patient contains almost no amyloid at all. Here, we described a patient with hereditary fibrinogen amyloidosis, who presented with proteinuria, hypertension and renal failure. He was shown to be heterozygous for the relevant mutation encoding the E526V fibrinogen variant.

Acquired Fanconi syndrome with proximal tubular cytoplasmic fibrillary inclusions of λ light chain restriction.

Light chain proximal tubulopathy is a rarely reported entity associated with plasma cell dyscrasia that classically manifests as acquired Fanconi syndrome and is characterized by the presence of κ-restricted crystals in the proximal tubular cytoplasm. We herein present a case of multiple myeloma with Fanconi syndrome and acute kidney injury due to light chain proximal tubulopathy with light chain cast nephropathy. Prominent phagolysosomes and numerous irregularly shaped inclusions with a fibrillary matrix in the cytoplasm of the proximal tubules were identified on electron microscopy. A monotypic light chain of the λ type was detected in the distal tubular casts, proximal tubular cytoplasmic lysosomes and fibrillary inclusions on immunofluorescence and immune electron microscopy. This case underscores the importance of conducting careful ultrastructural investigations and immunocytologic examinations of light chains for detecting and diagnosing light chain proximal tubulopathy.

A clinicopathological analysis in a large cohort of Chinese patients with renal amyloid light-chain amyloidosis.

BACKGROUND: The aim of the study is to investigate the association between clinical and pathological features in a large cohort of Chinese patients with renal immunoglobulin light-chain amyloidosis (AL). METHODS: A series of 186 patients with renal AL amyloidosis diagnosed between 1990 and 2011 were retrospectively reviewed. The extent of amyloid deposition in glomeruli, blood vessels and tubulointerstitium were evaluated semiquantitatively. The renal amyloid load was defined by the sum of glomerular, vascular and interstitial deposits. The associations between the clinical manifestations and pathological features were analyzed. RESULTS: The extent of glomerular amyloid deposition was positively correlated with the level of proteinuria. Patients with codeposition of amyloid and immune complexes (ICs) in glomeruli had higher levels of proteinuria than those without ICs. Advanced glomerular amyloid deposition was an independent pathological factor associated with renal insufficiency at diagnosis. The degree of vascular amyloid (VA) deposition was positively correlated with cardiac involvement and hepatic involvement. Patients with AL-κ showed a higher prevalence of hepatic involvement and more severe VA deposition than patients with AL-λ. High renal amyloid load independently predicted the increased risk for overall death after adjusting for recognized confounders. CONCLUSIONS: The degree and localization of amyloid deposits in the kidney of AL patients were associated with the degree of proteinuria and renal insufficiency, as well as extrarenal organs involvement. There were some differences between AL-κ and AL -λ in clinical and pathological characteristics. The renal amyloid load was an independent predictor for overall mortality.

Diffuse thin glomerular basement membrane in association with Fabry disease in a Chinese female patient.

We report a 41-year-old Chinese female with Fabry disease and diffuse thinning of the glomerular basement membrane (GBM). The patient presented with peripheral edema, mild proteinuria, microscopic hematuria, normal renal function, hypertension and tinnitus. Family screening showed that her daughter had microscopic hematuria, tinnitus and neuropathic pain. Renal biopsy of the proband showed focal segmental glomerulosclerosis with cytoplasmic vacuolization of the glomerular visceral epithelial cells by light microscopy. Laminated myelin inclusions in some of the glomerular podocytes, parietal epithelia, distal tubular epithelial cells and vascular endothelial cells along with diffuse thinning of the GBM (mean thickness of GBM: 216 ± 31 nm) were identified by electron microscopy. Genetic analysis detected a de novo novel GLA mutation, 1208 ins 21 bp, while a new variant of COL4A3 SNP M1209I was carried by mother and daughter as well as the proband's father (I-1) and one sister (II-4). The coexistence of thinned GBM should be considered in patients with Fabry disease-manifested familial hematuria.

Ultrastructural features and expression of cytoskeleton proteins of podocyte from patients with minimal change disease and focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) have been suggested for the category of podocytopathies. An ultrastructural observation and immunogold labeling for cytoskeleton proteins of podocytes on 11 cases each of FSGS and MCD were performed. Compared to MCD, more severe ultrastructural alterations of podocyte were identified in FSGS, which were characterized by higher frequency of mat-like condensation of microfilaments in the foot process and the detachment of the foot process from glomerular basement membrane. The labeling of alpha-actinin of podocytes in FSGS was significantly higher than MCD, which suggested an abnormal expression of cytoskeleton protein of podocyte in FSGS. The present study demonstrated a much more severe podocyte injury at the ultrastructural level in FSGS than in MCD.

[Clinicopathologic study of different variants of focal segmental glomerulosclerosis].

OBJECTIVE: To study the clinicopathologic features of different variants of primary focal segmental glomerulosclerosis (FSGS). METHODS: One hundred and two cases of FSGS were retrieved from the archival files of Peking University First Hospital during the past 6-year period. The pathologic findings were reviewed and the degrees of active and chronic changes were assessed by morphometric analysis. The histopathologic patterns were then correlated with clinical manifestations. RESULTS: Amongst the 102 cases of primary FSGS studied, 55.9% belonged to the NOS (not other specified) variant, while the perihilar, cellular, tip and collapsing variants accounted for 6.9%, 25.5%, 4.8% and 6.9% respectively. The level of proteinuria in the cellular and tip variants were much higher than that in the NOS variant; and the incidence of nephrotic syndrome in the tip and collapsing variants was higher than that in the other three variants (chi(2) = 12.23, P < 0.05). The activity score of the cellular and collapsing variants was also higher than that of the other three variants (P < 0.05). The interval between disease onset and renal biopsy diagnosis in the perihilar variant was longer than that in the other variants. The chronicity score of this variant was higher than that of the tip and NOS variants (P < 0.05). On the other hand, the total scores of active and chronic changes of the tip variant was lower than that of the cellular and collapsing variants (P < 0.05); and its chronic score was lower than that of the NOS and perihilar variants (P < 0.05). CONCLUSIONS: The NOS variant is the commonest morphologic pattern seen in primary FSGS. The cellular and collapsing variants are the patterns associated with active lesions, while perihilar variant is the pattern associated with chronic lesions. The tip variant shows mild pathological changes compared with the other patterns.

Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69 kDa target antigen of neutrophil granules.

OBJECTIVE: Antineutrophil cytoplasmic autoantibodies (ANCA) were found in patients with systemic lupus erythematosus (SLE). Cathepsin G and lactoferrin were the major target antigens. However, some ANCA-positive sera did not recognize either of them. The present study was to investigate the unknown target antigens of ANCA in patients with SLE and their clinical significance. METHODS: Sera were collected from 72 patients with SLE. ANCA were detected in both indirect immunofluorescence and antigen-specific enzyme-linked immunosorbent assay (ELISA). Mixed neutrophil granules were separated from normal human peripheral neutrophils; soluble acid extracts in non-reducing conditions were used as antigens in western blot analysis to detect ANCA. RESULTS: SLE sera could blot a few bands. Interestingly, 14/72 (19.4%) sera recognized a novel 69 kDa protein band and 10/72 (13.9%) sera recognized the 55 kDa protein band, which might be bactericidal/permeability-increasing protein (BPI). The 69 kDa target antigen was different from the known target ANCA antigens such as cathepsin G and lactoferrin. Further study revealed that the percentages of patients with photosensitivity and oral ulcer in the anti-69 kDa autoantibodies-positive group were significantly higher than those in the anti-69 kDa autoantibodies-negative group (57.1%vs 10.3%, P < 0.005 and 50.0%vs 12.1%, P < 0.05, respectively). CONCLUSIONS: A 69 kDa protein in human neutrophil granules was identified as a novel target antigen of ANCA in patients with SLE. The anti-69 kDa autoantibodies might be associated with photosensitivity and oral ulcer in patients with SLE.

Autoantibodies against glomerular mesangial cells and their target antigens in lupus nephritis.

UNLABELLED: Mesangial proliferation and deposition of immunoglobulins and complement components within glomerular mesangium was one of the important pathological features of lupus nephritis. Autoantibodies against human mesangial cells could be detected in the sera of patients with IgA nephropathy (IgAN) and Henoch-Schöenlein nephritis. We speculated that autoantibodies against human glomerular mesangial cells might play a role in the development of lupus nephritis. OBJECTIVE: To screen autoantibodies against human glomerular mesangial cells in sera from patients with lupus nephritis and to identify their target antigens. METHODS: Sera were collected from 96 patients with lupus nephritis as well as 25 patients with IgAN and 20 patients with idiopathic membranous nephropathy (IMN). Cell lysates of in vitro cultured human glomerular mesangial cells were used as antigens in Western-blot analysis to detect autoantibodies against human mesangial cells in sera from patients with lupus nephritis as well as IgAN and IMN. The clinical and pathological significance of the autoantibodies were further investigated. RESULTS: Autoantibodies against human mesangial cells could be detected in 94/96 (97.9%) of the sera from patients with lupus nephritis in Western-blot analysis. Twelve protein bands could be blotted by the sera from patients with lupus nephritis. The prevalence of autoantibodies against human mesangial cells in IgAN was 14/25 (56.0%) and only seven protein bands could be blotted. Five autoantibodies (anti-18, 24, 36, 46, and 91 kD) could be detected only in sera from patients with lupus nephritis. In patients with lupus nephritis, some autoantibodies might have some relationship with gender, hematuria, ANA, anti-dsDNA or anti-ENA antibodies. CONCLUSIONS: There are autoantibodies directly against heterogeneous antigens of human glomerular mesangial cells in sera from patients with lupus nephritis, and some of them might be associated with different clinical manifestations.

[Anti-endothelial cell antibodies(AECA) are associated with disease activity of propylthiouracil induced antineutrophil cytoplasmic antibody (ANCA) positive vasculitis].

OBJECTIVE: To investigate the prevalence of anti-endothelial cell antibodies(AECA) and its possible role in the pathogenesis of propylthiouracil (PTU) induced ANCA positive vasculitis. METHODS: Sera from 11 patients with PTU induced ANCA positive vasculitis and 10 patients with PTU induced ANCA but without clinical vasculitis were studied. Soluble proteins from in vitro cultured human umbilical vein endothelial cells were used as antigens and immunoblotting technique was performed to identify the specific target antigens. RESULTS: In patients with PTU induced ANCA positive vasculitis group, 10 of the 11 patients in active phase were AECA positive and 7 of the 10 patients turned to negative in remission. AECA consisted of a group of heterogeneous antibodies. In patients with ANCA positive but without vasculitis, none was AECA positive. CONCLUSION: AECAs recognizing a variety of antigens could be found in sera from patients with PTU induced ANCA positive vasculitis and they had a much closer association with vasculitic disease activity compared with ANCA.

The clinical and pathological characteristics of Chinese elderly patients with anti-neutrophil cytoplasmic autoantibodies associated small vessel vasculitis.

BACKGROUND: Anti-neutrophil cytoplasmic autoantibodies (ANCA) are serological markers of ANCA-associated small vessel vasculitis (AASV) which is one of common autoimmune diseases in Caucasian elderly population. OBJECTIVE: To analyze the clinical and pathological characteristics of Chinese elderly patients with AASV. METHODS: One-hundred forty one Chinese patients with AASV over 65 years old, diagnosed between 1997 and 2001 in the Institute of Nephrology of Peking University First Hospital, were retrospectively studied and their clinical and pathological data were analyzed. RESULTS: Patients diagnosed with AASV patient increased chronologically with the yearly ratio in 2000 and 2001 significantly (P < 0.05) higher than that in 1998 and before. Of the 141 patients, 72 were male and 69 were female with an average age of 68.2 years. 13 of the 141 were cytoplasmic ANCA (cANCA) positive and all recognized proteinase 3 (PR3). The other 128 were perinuclear ANCA (pANCA) positive and 120/128 recognized MPO, 8/128 recognized both PR3 and MPO. Less than 50% of the patients were correctly diagnosed within 3 months. Clinically, 78% of the patients had fever and fatigue, 52.5% had body weight loss, 96.4% had kidney involvement, of which 75% had elevated serum creatinine and 30.8% had acute renal failure. 76.6% had lung involvement, over half of them had hemoptysis or lung infiltrates. Other clinical manifestations included arthralgia (48.2%), muscle pain (39.7%), gastrointestinal symptoms (39.7%), eye involvement (28.3%) and ENT involvement (31.2%). In laboratory examinations, 94.4% of the patients had anemia, 62.4% had increased WBC count, 93.6% had increased ESR and 55.1% had increased CRP. CONCLUSIONS: More and more patients with AASV were diagnosed in Chinese elderly. Kidney was the most vulnerable organ to be involved and lung was the most important extra-renal organ to be affected. For elderly patients with multi-organ damage, an ANCA test should be performed in order to make an early diagnosis and start therapy in time.

[The clinic significance of urinary podocytes in patients with focal segmental glomerulosclerosis].

OBJECTIVE: To address the significance of urinary podocytes in the diagnosis of human focal segmental glomerulosclerosis(FSGS). METHODS: Twelve patients with FSGS and 20 patients with minimal change disease (MCD) were diagnosed by routine renal biopsy, and 8 healthy persons as controls. Morning urinary sediments was collected and centrifuged onto glass slides. Urinary podocytes were identified by immunofluorescent staining of podocyte specific protein Podocalyxin(PCX). The state of podocytes in glomeruli was observed using immunofluorescence. RESULTS: Urinary podocytes were found in 8 out of 12 FSGS patients(66.67%), whereas none of 20 patients with MCD and control had podocytes in their urine. FSGS patients with positives urinary podocytes had prominent manifestation of nephropathy syndrome, whereas no nephrotic syndrome in patients with negative urinary podocytes. Focal absence of the expression of PCX, a marker protein of podocytes in glomeruli was found in FSGS patients, and the locations of absence were consistent with the lesions of focal sclerosis in glomeruli. In contrast, PCX was expressed integrally in MCD patients. CONCLUSION: Appearances of podocytes in urine of patients with nephropathy may be used as one of the reliable, convenient and unharmful accessorial methods for distinguished diagnosis of FSGS and MCD.

[The relationship between subclassification of anti-myeloperoxidase IgG by enzyme-linked immuno-sorbent assay analysis and vasculitis activity].

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA) is an important serological diagnostic tool for certain vasculitides, such as Wegener's granulomatosis and microscopic polyangiitis. Several studies suggested that ANCA titers correlated with disease activity. However, in some patients, ANCA still remained positive when patients were in clinical remission. The major isotype of ANCA is IgG, which has four subclasses. This study is to investigate the relationship between anti-MPO IgG subclasses and vasculitis activity. METHODS: Serum samples, taken from 30 anti-myeloperoxidase (MPO) antibody positive patients both in active phase and in remission, were analysed by ELISA for their anti-MPO IgG subclass distribution and the change of anti-MPO IgG subclasses was compared with the change of anti-MPO IgG antibodies. RESULTS: All four anti-MPO IgG subclasses were positive in active phase, IgG(4) being the highest. In remission, the level of anti-MPO IgG(1) and IgG(3) subclasses decreased the most and the percentage of negative change of IgG(3) was the highest, even more significant than that of the total IgG. CONCLUSION: anti-MPO IgG(3) antibody is more closely related with clinical disease activity than the total IgG. Higher ratio of IgG(4) may suggest that chronic repeated antigen stimuli may play a role in the production of ANCA.

[Clinical and pathological features of anti-neutrophil cytoplasm antibody associated systemic vasculitis in children].

OBJECTIVE: Anti-neutrophil cytoplasmic antibodies (ANCA) are serological diagnostic markers for certain types small vessel vasculitis including Wegener's granulomatosis and microscopic polyangiitis, which are also termed ANCA associated systemic vasculitis (AASV). The majority of patients with primary AASV reported are adults and predominantly elderly. Data on pediatric patients with primary AASV in China are lacking. This study aimed to analyze the clinical and pathological features of primary AASV in children. METHODS: Patients with primary AASV, admitted to the hospital within the past 7 years, were retrospectively studied. The clinical and pathological features were compared between pediatric and adult patients. In pediatric group, there were 20 cases with an average age of (12.1 +/- 4.1) years (aged from 5 to 17 years); in adult group, there were 38 cases with an average age of (55.3 +/- 14.1) years (aged from 20 to 78 years). RESULTS: The data of this study showed that pediatric patients accounted for 7.87% (20/254) of the whole primary AASV patients. Compared with 38 adult hospitalized patients, pediatric patients were predominantly female (80% vs 50%, P = 0.047). Patients from both groups were microscopic polyangiitis predominantly (95% vs 74%, P > 0.05) and the majority of the sera were P-ANCA/anti-MPO antibody positive in both groups (95% vs 74%, P > 0.05). The prevalence of hypertension in pediatric patients was significantly lower than that in adults (20% vs 61%, P = 0.005). There was no significant difference in clinical manifestations and clinical remission rates between the two groups. CONCLUSION: Pediatric patients with AASV were not rare in China. The clinical and pathological features of patients with AASV in childhood were similar to adult patients, but there was a female predominance in children.