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- 2011 USCAP Meeting Abstracts (3)
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Membranoproliferative Glomerulonephritis Secondary to Dysfunction of the Alternative Pathway of Complement.
Sanjeev Sethi, Fernando Fervenza, Yuzhou Zhang, Samih Nasr, Julie Vrana, Richard JH Smith. Mayo Clinic, Rochester, MN; Carver College of Medicine, Iowa City, IA; Mayo Clinic, Rochester
Background: Dense Deposit Disease (DDD) is the prototypical membranoproliferative glomerulonpehritis (MPGN) in which dysregulation of the alternative pathway (AP) of complement results in accumulation of complement debris in glomeruli. MPGN with C3 deposition (GN-C3) is a recently recognized entity that bears many similarities to DDD. The aim of this study was to evaluate AP in cases of MPGN with C3 deposition.
Design: Five cases of MPGN with extensive C3 deposition were studied. IF was negative for immunoglobulins, C1q, kappa and lambda light chains, but showed extensive C3 deposition in the mesangium and along the GBM. EM showed electron dense deposits in the mesangium and along GBM (Case 1-3) but lacked the classic sausage shaped dense deposits of DDD, and were diagnosed as GN-C3. EM in case 5 exhibited the classic findings of DDD. Case 4 showed features of both DDD and GN-C3, with some loops showing electron dense deposits, and other loops showing sausage shaped deposits of DDD.
Results: Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (sMAC, all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a missence factor H mutation (one case).
| Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | |
| CFH | 1 copy H402 | 1 copy H402 | 2 copies of H402 | 2 copies of H402; c.2867 C>T p. Thr956Met | 1 copy H402 |
| CFI | No mutation | No mutation | No mutation | No mutation | No mutation |
| MCP | No mutation | No mutation | No mutation | No mutation | No mutation |
| CFB | ND | No mutation | No mutation | ND | No mutation |
| CFHR5 | ND | No mutation | No mutation | ND | No mutation |
| AP functional assay | 6.6% very low | 109.0% normal | 1.0% very low | 5.5% very low | 1.0% very low |
| Hemolytic Assay | Normal | 1+ | Normal | Normal | Normal |
| FH antibody | 1:200 | Negative | Negative | Negative | Negative |
| C3NeF | Negative | 1:200 | Negative | Negative | 1:800 |
| sMAC (Normal <0.30 mg/dL | 0.46 | 0.41 | 1.23 | 0.93 | 0.31 |
Laser microdissection and mass spectrometry of glomeruli of GN-C3 showed a proteomic profile very similar to DDD.
Conclusions: Dysregulation of AP results in a spectrum of renal diseases that includes GN-C3 and DDD.
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Membranoproliferative Glomerulonephritis and Less Characterized Etiological Factors.
Shashank Cheemalavaagu, Sang H Woo, Ajit Mahapatra, Neeraja Kambham. Stanford University, CA; Kaiser Permanente, Santa Clara
Background: Membranoproliferative glomerulonephritis (MPGN types I, III) is an uncommon cause of nephrotic syndrome (NS) in adults, is often associated with immune complex deposits and characterized by mesangial proliferation and reduplication of glomerular basement membranes. Majority of MPGN cases are secondary to autoimmune diseases, cryoglobulins, Hepatitis C infection, and dysproteinemias. Other causes of MPGN are less well studied and many are categorized as idiopathic.
Design: Pathology database was searched (2000-09) for renal biopsies with a diagnosis of MPGN in adults. Patients with clinical or serological evidence of systemic lupus erythematosus (ANA), cryoglobulinemia, Heptitis C/B infection, dysproteinemia (SPEP, UPEP) or lymphoproliferative disorders were excluded. Clinical data including presentation, laboratory investigations and follow up were obtained and all biopsies were reviewed for histological parameters. In addition to routine immunofluorescence staining (including K, L light chains), IgG subtyping was studied (IgG1-4).
Results: A total of 30 patients met our inclusion criteria and the mean age at presentation was 57 years (range 20-85). Two thirds of the patients presented with full NS while most others had non-nephrotic proteinuria. Renal insufficiency was common and one patient presented with acute renal failure. The amount of 24 hour proteinuria had a significant correlation with poor renal function (serum creatinine) (R=0.65, P= 0.001) while crescents, % glomerulosclerosis and interstitial fibrosis did not correlate with renal function. Except in one, immune deposits were evident in all patients either by immunofluorescence or ultrastructural examination. C3 deposits were common followed by IgG and IgM. K/L light chain restriction was detected in 12 patients (9K; 3L) and IgG subclass was monoclonal in nine patients (IgG3: 8; IgG2:1) and oligoglonal in 4 others. The possible etiological factors based on clinical history and follow up include cirrhosis, portocaval shunts, autoimmune hemolytic anemia, drugs and familial forms.
Conclusions: MPGN secondary to less characterized etiologies includes a broad spectrum and the cause may often be elusive. The light chain and IgG subtype restriction may be observed despite lack of monoclonal gammopathy and may result from chronic antigenic/immune stimulation. Histologic parameters were not strongly correlated with renal function.
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The Expression of Apoptotic Related Proteins and Apoptosis in Human Renal Tissues of Class II and IV Lupus Nephritis.
Jing Zhang, Jihong Cui, YaQing Zhang, Qing Qiao. Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
Background: Apoptosis is involved in glomerular injuries leading to glomerulonephritis. The role of renal cell apoptosis in the pathogenesis and progress of human lupus nephritis (LN) is still controversial. Furthermore, in different types of LN renal tissues, the expression of apoptotic related proteins, such as FasL, Bax and caspase-3, is still unknown. We therefore investigated these apoptotic related proteins and apoptosis index (AI) in human renal tissues of class II and IV LN.
Design: The expressions of FasL, Bax and caspase-3 were assessed in forty-two cases of human LN renal tissues (twenty cases of class II, twenty-two cases of class IV) and ten cases of human normal renal tissues by immunocytochemistry. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to assess AI.
Results: In class II and IV LN renal tissues, the increased expressions of FasL, Bax, caspase-3, and AI were detected in glomerular cells, tubular epithelial cells compared with controls (P<0.05). The expression of Bax, caspase-3 and AI in glomerular cells of class IV LN was significantly higher than class II LN (P<0.05). However, there was no difference in FasL expression between class II LN and class IV LN (P>0.05).
Conclusions: Apoptosis might be induced to LN pathogenesis by FasL, Bax and caspase-3. There might be other pathways except Fas/FasL signaling to initiate apoptosis during LN progress.
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Quantitation of IgG4+ Plasma Cells in Tubulointerstitial Nephritis.
Donald C Houghton, Megan L Troxell. Oregon Health and Sciences University, Portland
Background: IgG4-related tubulointerstitial nephritis (IRTIN) is a sclerosing lymphoplasmacytic inflammatory disorder that may affect the kidney alone, or may be part of the multi-system disorder, IgG4-related systemic disease (IRSD). Auto-immune pancreatitis (AIP) is the most common lesion of IRSD. The active inflammatory lesion in IRTIN is characterized by the presence of numerous IgG4+ plasma cells (IgG4+PC), but the specificity of this finding has not been determined. In this study we investigated the prevalence of IgG4+PC in renal interstitial infiltrates.
Design: We examined all renal biopsy samples with active interstitial inflammation, regardless of principal diagnosis, from 1/1/09 through 6/1/10, to determine the presence and extent of IgG4+PC in the infiltrates (N=100). Two observers independently scored each case for the density and extent of infiltrates, the apparent proportion of plasma cells, the extent and density of CD138+ plasma cells, and the distribution and numbers of IgG4+PC in the infiltrate.
Results: 29 cases were negative for IgG4+PC and 63 had fewer than 2 per high power field (hpf). The highest numbers of IgG4+PC were seen in some cases of diabetic nephropathy (DN), idiopathic interstitial nephritis (IISN), diffuse lupus nephritis (DLN), membranous glomerulonephritis (MGN), and necrotizing glomerulonephritis (NGN), including pauci-immune lesions, and those with granular and linear immune deposits:
| Diagnosis | # of IgG4+PC/hpf | |||||
| 0-2 | 3-5 | 6-10 | 11-20 | 20-120 | ||
| DN | 3 | 3 | 2 | |||
| IISN | 3 | 2 | 1 | 1 | ||
| DLN | 5 | 1 | ||||
| MGN | 4 | 3 | 1 | |||
| NGN | 8 | 3 | 1 | 1 | 4 | |
Three biopsies from patients with Sjogren's syndrome demonstrated 0.7, 2.5 and 3.0 IgG4+PC/hpf, and a biopsy in the setting of tubulointerstitial nephritis-uveitis syndrome (TINU) was negative for IgG4+PC. PC were prominent in all cases with more than 20 IgG4+PC. The numbers of IgG4+PC did not correlate with severity of fibrosis, or the presence or absence of eosinophils. By comparison, infiltrates in a 2005 biopsy of IRTIN demonstrated dense sclerosis and numerous eosinophils, and contained more than 200 IgG4+PC/hpf.
Conclusions: Infiltrates of numerous IgG4+PC's are rare in renal biopsies, regardless of the density and activity of the inflammation, but they may be seen in some non-IRTIN cases, particularly in NGN. It may be instructive to further investigate our cases with this finding: in MGN because of it's known association with IRTIN; in DN because it may develop as a complication of AIP; and in IISN to rule out previously unsuspected IRTIN.
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Validation Study of Oxford Classification of IgA Nephropathy in a Chinese Cohort.
Shaoshan Liang, Caihong Zeng, Sharon Phillips, Yu Shyr, Stephan Troyanov, Zhi-Hong Liu, Agnes B Fogo. Nanjing Research Institute of Nephrology, Jiangsu, China; Vanderbilt Unversity, Nashville, TN; Hôpital du Sacré-Coeur de Montréal, University of Montreal, QC, Canada
Background: The Oxford Classification of IgA Nephropathy (IgAN) identified four renal biopsy lesions of prognostic significance, namely mesangial hypercellularity, segmental glomerulosclerosis/adhesion, endocapillary proliferation and significant tubular atrophy/interstitial fibrosis. We now sought to validate whether these results were applicable in a Chinese cohort of patients.
Design: 213 adult Chinese patients from a single center, Nanjing Research Institute of Nephrology were studied. Inclusion criteria were as in the original Oxford cohort, with eGFR ≥ 30 ml/min and minimum of one year follow up, excluding patients with rapid progression in less than a year, or with no or minimal proteinuria, diabetes or other glomerulonephritis. Renal biopsies included at least 10 glomeruli.
Results: Patients were on average age 34 years (range 18-65), 46.5% female. MAP was higher than in the Oxford cohort (102 ± 22 mm Hg) at time of biopsy. RAS blockade at time of biopsy, and during followup were similar to the Oxford cohort. Follow up was on average 81 months (range 30-157 months). 21.1% received immunosuppression, 14.6% prednisone and 7.5% cyclophosphamide, all slightly less than the Oxford cohort. Rate of renal function decline was -2.2 ± 4.2 ml/min per 1.73 m2 per year, with 20.2% reaching 50% decline in renal function and 14.1% reaching ESRD, all similar to the original Oxford cohort. On average, 22.7 ± 8.8 (range 8-61) glomeruli were available. All Oxford classification variables were scored independently by two pathologists. Global sclerosis/advanced segmental sclerosis was present in 19.8% of glomeruli. Segmental sclerosis was present in 85% of biopsies. Significant mesangial hypercellularity, endocapillary proliferation, segmental sclerosis were present in, on average, 65, 22 and 85% of biopsies. Significant tubulointerstitial fibrosis (T1 or T2), >25%, was present in 33%. Tubulointerstitial fibrosis correlated with proteinuria and loss of eGFR over time, and endocapillary proliferation (E1) correlated with proteinuria over followup. Mesangial proliferation (M1) and segmental sclerosis/adhesion (S1) did not predict changes in eGFR or proteinuria in this cohort.
Conclusions: In conclusion, application of the Oxford IgAN classification to Chinese patients shows similar trends for prediction of clinical outcome in some, but not all variables, as the previous data set.
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Henoch-Schölein purpura Nephritis (HSPN) and IgA Nephropathy
(IgAN) in Children: A Comparison of Pathological Features Using Oxford
Classification of IgA Nephropathy.
Xu Zeng. Wayne State University, Detroit, MI
Background: HSPN and IgAN are common in the pediatric population with overlapping clinical, genetic and immunological features causing HSPN to be considered as a systemic form of IgAN. Both entities are characterized by immunofluorescent IgA staining with variable degrees of mesangial proliferation and by IgA deposits on electron microscopy (EM). HSPN has been reported to show more severe glomerular lesions than IgAN however, systemic approach to quantitatively compare both diseases is lacking. The objective of this study was to assess the benefit of applying the newly described semi-quantitative, Oxford classification of IgA nephropathy (OXC-IGA), to distinguishing these two entities.
Design: All consecutive renal biopsy performed at the Children's Hospital of Michigan between 2004-2010 with a diagnosis of IgAN and HSPN were reviewed. The scoring system of OXC-IGA was applied to all biopsies to measure mesangial cellularity (MC, M score), segmental glomerulosclerosis (SG, S score), endocapillary hypercellularity (EC, E score) and tubular atrophy and interstitial fibrosis (TA/IF, T score). In addition, the highest number of MC, percentage of glomeruli with EC, cellular crescent (CC) and segmental necrosis (SN) were also recorded and compared between HSPN and IgAN using student t-test and basing statistical significance of P<0.05.
Results: A total of 23 HSPN (F:M=12:11) and 26 IgAN (F:M=11:15) were diagnosis during the study period. The HSPN patients were significantly younger than IgAN (7.8+/-3.3 vs 12.4+/-3.2, years, p<0.05). Patients with HSPN had significantly higher MC (11 3.2 vs 8.3 2.4), percentage of EC (14.9 2.2 vs 4.9 8.2), CC (10.4 1.2 vs 4.3 2.8) and SN (6.6 1.3 vs 0.7 1.1, all with a P<0.05). There was no significant difference between IgAN and HSPN in M, S, E and T score (p>0.05).
Conclusions: While our data showing IgAN and HSPN to share histopathological features of mesangial/endocapillary proliferation, we demonstrated that HSPN has more extensive mesangial/endcapillary proliferation, high percentage of glomeruli with cellular crescent and segmental necrosis, thus more severe glomerular damage. These findings further characterize pediatric HSPN, therefore benefit to the clinical management.
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Glomerular Endothelial Injury in Patients with Non-Renal Transplants: Are We Missing Subclinical Thrombotic Microangiopathy?
Yael B Kushner, Fahim A Malik, A Bernard Collins, Robert K Holmes, R Neal Smith, Robert B Colvin. Massachusetts General Hospital, Boston
Background: Approximately 20% of recipients of heart, liver, lung or bone marrow transplants develop chronic renal failure. This study aimed to elucidate the value of the renal biopsy, the contribution of thrombotic microangiopathy (TMA) and a novel means to assess glomerular endothelial damage.
Design: An institutional database containing 9,729 renal biopsies identified 32 patients with non-renal transplants (heart, lung, liver, and bone marrow). Clinicopathologic parameters were extracted and biopsies were reviewed by a pathologist. Ultrastructural signs of glomerular endothelial damage were assessed using a novel scoring system. The degree of endothelial fenestration was measured in 5-10 glomerular capillary loops; 10 patients with minimal change disease (MCD) were scored for comparison.
Results: The median patient age was 49 (range 20-74). Median time from transplant to renal biopsy was 42 months (range 1-168). The renal diagnoses were: 19 focal segmental glomerulosclerosis (FSGS), including 5 with features of collapsing FSGS; 9 TMA; 4 immune complex glomerulonephritis, including 2 with HCV-related disease and one with IgA nephropathy; 25 with arteriolar hyalinosis; and 20 with more than 25% interstitial fibrosis (many had more than one diagnosis). The mean serum creatinine at the time of biopsy was 3.7 (+/-1.9). Median platelet count was 169,000/mm2 (+/-70,000). Glomeruli had fewer endothelial fenestrations compared with controls with MCD (45 +/-31% vs 89 +/-7%, respectively; p<0.001). Loss of endothelial fenestrations was present in 77% of the biopsies, including 75% of the patients with collapsing FSGS. The percent of endothelial area with fenestrations was correlated with the platelet count (p<0.05), even though most of the patients did not have diagnostic signs of TMA. 18 patients progressed to end-stage renal disease (ESRD) and/or required renal transplantation.
Conclusions: Patients with non-renal transplants frequently develop renal failure, which in this series was biopsied late in the course. TMA, likely related to calcineurin inhibitors, has been associated with poor renal survival in these patients. Glomerular endothelial injury is known to be a feature of TMA, and, as assessed by our novel scoring system using ultrastructural findings, may allow detection of subclinical TMA in the absence of typical clinical or light microscopic features. Patients with subclinical TMA may benefit from modified treatment modalities to reduce their risk of progression to ESRD.
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Distinct Histopathologic Changes Elicited in Baboon Kidneys
after Challenge with Shiga Toxin Type 1 or 2 from Enterohemorrhagic E.
coli.
Joel M Henderson, Shinichiro Kurosawa, Deborah J Stearns-Kurosawa. Boston University Medical Center, MA
Background: Shiga toxin-producing E. coli (STEC) are an important cause of regional outbreaks of acute hemorrhagic enteritis and hemolytic uremic syndrome. Long-term renal impairment is often a consequence of STEC infection. STEC may produce either or both of two virulent toxins, Stx1 and Stx2, which share similar structure and cell receptors. Despite similarities, STEC producing primarily Stx2 is more often associated with kidney injury in patients, and the mechanism is not known. We investigated effects of each Shiga-like toxin on kidneys in a baboon model.
Design: Anesthetized juvenile baboons (Papio) were challenged with an i.v. toxin dose (Stx1:10, 50, 100 ng/kg; Stx2: 10, 50 ng/kg), and followed until euthanasia was performed up to seven days post challenge. Necropsy kidney tissue was processed for standard renal histopathologic examination.
Results: Kidneys from Stx2-challenged animals showed the most severe changes. High dose Stx2 (n=6; 50 ng/kg, euthanasia <128hrs) elicited severe changes including interstitial hemorrhage (most prominent in the medulla), prominent tubulointerstitial injury and polymorphonuclear inflammation, and striking apoptotic changes in glomerular mesangial cells. Glomerular capillary wall changes (thickening, double contours) were overall mild and focal with high-dose Stx2. In contrast, higher dose Stx1 (n=10; 50, 100ng/kg; euthanasia <74hrs) resulted in more substantial glomerular capillary wall changes (moderate thickening and double contouring) along with moderate tubular injury. Mesangial apoptotic changes were not seen in Stx1-challenged animals. Low dose Stx2 (n=4; 10ng/kg) and low dose Stx1 (n=3; 10ng/kg) showed minor or no significant changes, respectively.
Conclusions: Overall kidney injury was more severe after Stx2 challenge, although euthanasia was required earlier in Stx1 animals, possibly obscuring further Stx1-mediated damage with time. The pattern of glomerular injury with Stx1 challenge featured prominent “HUS-like" capillary wall changes, whereas that with Stx2 challenge was predominantly characterized by mesangial cell apoptotic changes. Thus, Stx1 and Stx2 had distinct effects on the glomerulus, with endothelial injury predominating with Stx1 and mesangial injury predominating with Stx2. The novel finding of Stx2-induced mesangial cell injury raises new avenues of investigation into mechanisms of renal damage after STEC infection.
