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- 2011 USCAP Meeting Abstracts (4)
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Histopathologic Characteristic of Pediatric Anti-Neutrophil Cytoplasmic Antibody-Associated Glomerulonephritis (ANCA-GN).
Xu Zeng. Wayne State University, Detroit, MI
Background: ANCA-GN is the most common cause of rapidly progressive glomerulonephritis (GN) and the diagnosis is made by renal biopsy. Most ANCA-GN patients are adults. The recently published “histopathologic classification of ANCA-GN” by Annelies et al (J Am Soc Nephrol 21, 2010 e-publish) divides ANCA-GN into four categories (focal, crescentic, mixed and sclerotic ANCA-GN) corresponding to the severity of renal function impairment and outcome. Based on this classification, the majority of adult ANCA-GN belongs to the crescentic group, which has highly active renal disease and severely reduced renal function. There is paucity of reports regarding pediatric ANCA-GN, especialy those corrlating histopathologic changes and outcome. The objective of this study is to charaterize histopathologic changes and outcome in pediatric ANCA-GN.
Design: Renal biopsy cases with a diagnosis of ANCA-GN from pathologic database of Children's Hospital of Michigan between 2004-2009 were reviewed. Based on the predominance of normal glomeruli, cellular crescents and globally sclerotic glomeruli, ANCA-GN case was classified into one of the four categories listed above. In addition, the activity index and chronicity index for each ANCA-GN, including percentage of cellular crescent, segmental necrosis, global sclerotic glomeruli and tubular atrophy and interstitial fibrosis (TA/IF) were recorded.
Results: During the study time frame we identified 7 ANCA-GNs (F:M=4:3). The children ranges from 8-17 year-old (mean age 13.4). Five of 7 cases were focal ANCA-GN (71%) and two were crescentic (29%). None was mixed or sclerotic. Four of 7 ANCA-GN patients carried the diagnosis of Wegener's granulomatosis. The average percentage of crescent, necrosis, global sclerotic and TA/IF was 3.5%, 1.7%, 1.3% and 20, respectively.
Conclusions: The majority of pediatric ANCA-GN have focal disease, and therefore has a favorable renal outcome compared to adult ANCA-GN. The pediatric ANCA-GN has mild activity index including small percentage of cellular crescents and segmental necrosis. The chronicity index is also low in pediatric ANCA-GN with lower number of global sclerotic glomeruli and lower TA/IF.
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Hematologic Malignancies in Native Renal Biopsies: Report of 35 Cases.
Christine A VanBeek, Cynthia C Nast, Arthur H Cohen, Jerry Hussong, Mark Haas. Cedars-Sinai Medical Center, Los Angeles, CA
Background: Primary renal hematologic malignancies are rare, while secondary renal involvement is a known complication of lymphomas and leukemias. As they seldom cause renal failure, leukemic/lymphomatous infiltrates of the kidney are rarely biopsied and their frequency in native kidney biopsies is not well documented.
Design: Of 13,828 non-transplant medical renal biopsies examined from 2004-2010, 35 with hematologic malignancies were identified. Light, immunofluorescence, and electron microscopies, immunohistochemistry, and clinical information were reviewed.
Results: There were 29 males and 5 females, ages 18 – 89 (mean 62). In 12 cases (34%) the renal biopsy provided the first diagnosis of malignancy including intravascular large B-cell (2), T-cell (2), diffuse large B cell (DLBCL) (4), chronic lymphocytic leukemia (CLL) and other low grade B-cell (4) lymphomas. Cases with prior neoplastic history included CLL and other low grade B-cell lymphomas (18), myeloid leukemia (2), DLBCL (1), and B-(1) and T-(1) acute lymphoblastic leukemia. The intravascular lymphomas involved glomerular capillaries causing hematuria and proteinuria, whereas the other 9 high grade lymphomas produced acute renal failure (ARF) with interstitial infiltration, often involving >80% of the parenchyma. One case of DLBCL also presented with nephrotic syndrome (membranous glomerulopathy). In contrast, low grade neoplasms typically involved <30% of the parenchyma and in 20/24 (83%) co-existing pathology was the cause of renal symptoms. In one case of CLL, atypical lymphocytes in glomeruli produced a membranoproliferative pattern without immune complexes, with hematuria and proteinuria. Ten cases of low-grade B cell lymphoma showed paraprotein-associated lesions, including 4 cases of immunotactoid glomerulonephritis (GN). Other concurrent lesions were minimal change nephropathy, immune complex GN, diabetic nephropathy, nodular glomerulosclerosis, pauci-immune crescentic GN and tubulo-interstitial diseases. Of the 2 myeloid leukemias, one showed neoplastic cells in 90% of the parenchyma with ARF, and in the other immature myeloid cells intermixed with inflammation of interstitial nephritis.
Conclusions: Hematologic malignancies were found in 0.25% of native renal biopsies performed to evaluate non-neoplastic diseases. In 1/3 of cases, the renal biopsy provided the first diagnosis of lymphoid neoplasm. High grade malignancies cause a variety of renal symptoms depending on histologic distribution. Low grade malignancies are typically incidental findings. Recognition of these neoplasms is important for appropriate clinical management.
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Acute Renal Failure in Cocaine Users: Pathology Correlates.
Guillermo A Herrera, Elba A Turbat-Herrera. Nephrocor, Tempe, AZ
Background: A subset of patients using cocaine develop acute renal failure. Most of these patients do not volunteer the information that they have used cocaine in the immediate period prior to the development of renal failure. The mechanisms involved appear to be multifactorial and involve vasoconstriction with tubular injury and direct effect of the cocaine on proximal tubules where it is normally metabolized, as well as a possible hypersensitivy reaction to either cocaine itself or to other products admixed with it.
Design: A review of 2376 renal biopsies over a 4 year period revealed 12 cases with cocaine-related acute renal failure. The study is carried out to identify the histopathological, ultrastructural, and immunohistochemical findings associated with this entity.
Results: An antibody to cocaine metabolites identified the presence of these in proximal tubular cells in all cases. The pathology identified included acute tubular injury and a generally subdued interstitial inflammatory process associated with tubulitis and tubular damage. The inflammatory cells were predominantly lymphocytes and plasma cells, but eosinophils were present in most cases, albeit in variable numbers. By immunohistochemistry cocaine metabolites are identified in the cytoplasm of proximal tubular cells. Ultrastructurally, the damaged proximal tubules reveal large secondary lysosomes with particulate matter inside, a rather typical marker.
Conclusions: Identifying cases of cocaine-related acute renal failure requires a high index of suspicion as the pathologic findings are rather non-specific and often, quite focal and unimpressive. Ultrastructural evaluation is helpful to detect specific changes in damaged proximal tubular cells suggestive of recent cocaine use. This is very helpful to suggest a possible cocaine etiology for the tubular damage and may lead to the request for immunohistochemistry for cocaine metabolites. Immunohistochemistry stain for cocaine metabolites may provide a reliable marker to identify these cases.
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Acquired Glomerular Lesions in Patients with Down Syndrome.
Samar Said, Lynn Cornell, Sanjeev Sethi, Mary Fidler, Omar Al Masri, Jeffrey Marple, Samih Nasr. Mayo Clinic, Rochester; Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates; Lincoln Nephrology & Hypertension, Lincoln
Background: The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years, largely due to improvement in medical care. Renal disease is thought to be infrequent in these patients (pts) and data regarding renal biopsy are very limited. The aim of this study was to examine the clinicopathologic spectrum of pts with Down syndrome who underwent renal biopsy.
Design: We reviewed the characteristics of 16 pts with Down syndrome who underwent native renal biopsies that were processed at our laboratory from 1997 to 2010.
Results: The mean age at biopsy was 28 yrs (range 13-45). Eleven pts were Caucasian and 5 were African Americans. The male:female ratio was 1.6:1. History of hypothyroidism was present in 6 pts, congenital heart disease in 2, and congential urologic abnormalities in 1. Clinical presentations included renal insufficiency (15 pts, mean S. creatinine 3.4 mg/dl (range 0.7-15)), proteinuria (all pts, including 2 with nephrotic syndrome, mean 24h urine protein 3.6 g (range 0.4-24)), and hematuria (14 pts, including 3 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (IgAN)(n=5 pts), focal segmental glomerulosclerosis (FSGS) (n=3), membranoproliferative GN (MPGN) (n=2), acute post-infectious GN (APIGN) (n=2), ANCA-associated pauci-immune crescentic GN (PICGN)(n=2), membranous GN (n=1) and lupus nephritis (LN) class III (n=1). Mild dilatation of the urinary space was seen in 7 pts. Follow up (mean 47 mos, range 2-141) was available on 15 pts (94%). Two pts had complete remission; 1 of whom had nephrotic syndrome due to membranous GN that was treated with immunosuppressive agents (IS) (steroids and cyclophosphamide) and the other one had nephritic syndrome due to APIGN that was treated with IS (steroids). Eight pts (4 with IgAN, 2 with FSGS, 1 with LN III, and 1 with APIGN) had persistent renal dysfunction. Three of these pts (1 with IgAN, 1 with FSGS, and 1 with LN III) were treated with IS. The remaining 5 pts (2 with PICGN, 2 with MPGN, and 1 with FSGS) progressed to ESRD, 2 of whom died. Three of these 5 pts (2 with PICGN and 1 with MPGN) were treated with IS. One pt with MPGN received a succesful kidney transplant without histologic evidence of recurrence.
Conclusions: With prolonged survival, a growing number of pts with Down syndrome is expected to develop renal disease. A wide spectrum of acquired glomerular diseases can be seen in these pts. Renal biopsy is necessary to determine the type of glomerular lesion, appropriate treatment, and prognosis.
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Renal Amyloidosis and Clinicopathological Prognostic Factors: A Study of 196 Cases.
Kemal Kosemehmetoglu, Dilek Baydar. Hacettepe University Hospital, Ankara, Turkey
Background: In this study, we aimed to analyze our cases of renal amyloidosis diagnosed by needle biopsy and document their clinical and morphological features.
Design: Biopsy slides were retrieved from the archives and reviewed. Intensity and relative distribution of amyloid deposition in renal compartments were noted. Glomerular deposits were classified as hilar, mesangial segmental, mesangial nodular and mesangiocapillary. Chronic tubulointerstitial damage was graded from 1 to 3 according to its extent (<25%, 25-75% and >75%). Amyloid typing was performed by immunohistochemistry using anti-AA, lambda, kappa, apolipoprotein A, prealbumin (transthyretin), fibrinogen and lysosyme antibodies. Clinical information and follow-up data were gathered from hospital records and computer-based patient data system.
Results: Between years from 1981 to 2006, we found 196 needle biopsies with renal amyloidosis. Immunohistochemical studies could be achieved in 178 cases. Among them 168 were AA type, 3 were AL type and 1 was AFib, AApoA1 and ALys for each; 4 cases were unable to be categorized immunohistochemically. Within AA amyloidosis group, the most common preamyloidotic disease was Familial Mediterranean Fever (FMF) (29%), followed by chronic infectious diseases (tuberculosis-%16, bronchiectasis-%8) and chronic inflammatory conditions (rheumatoid arthritis-%9, Behcet's disease-%7). Patients almost always presented with edema due to proteinuria. 18% of patients had disturbed renal fuction at the time of diagnosis. Hypertension was recorded in 32% and hematuria in 45%. Glomerular amyloid deposition was noted to fall into 4 distinct patterns: Mesangial segmental (15.5%), mesangial nodular (11.3%), hilar (30.4%) and mesangiocapillary (42.8%). Regarding the compartment of dominant amyloid deposition, cases were further classified as glomerular-dominant (28.1%), vascular-dominant (15.8%) and co-dominant (51.5%) forms. Glomerular-dominant form closely correlated with level of proteinuria (p=0.008) and presence of hypertension (p=0.009). 5- and 10-year survivals were 37% and 30%, respectively. In multivariant analysis, the poor prognostic factors determining renal survival were low glomerular filtration rate and high 24-hr urine protein, mesangiocapillary type glomerular amyloid deposition and high renal injury score at the time of biopsy.
Conclusions: AA is the most common amiloid type seen in renal biopsies in our country in which FMF is endemic. Renal amyloidosis has a diverse pathology in terms of preferential location of amyloid deposition and its intensity. Patients follow variable clinical courses accordingly.
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Immunohistochemical (IHC) Staining with Kappa and Lambda
Confirms Monoclonality Detected by Immunofluorescence Studies (IF) and
Reveals a High Percentage of “Hybrid” Proximal Tubulopathy in Light
Chain Associated Monoclonal Nephropathy (LCAMN).
Wendy Wiesend, Michele Rooney, Thomas Fennell, Sharon Hicks, Ping Zhang. William Beaumont Hospital, Royal Oak, MI
Background: Basic research studies have shown that monoclonal light chains, uptaken by megalin-cubilin receptors in proximal tubules, stimulate cellular production of hydrogen peroxide and induce an inflammatory process causing tubular injury. Monoclonal proximal tubulopathy, however, is a relatively rare variant of LCAMN, based on current EM diagnostic criteria in human renal biopsies. The purpose of this study was to 1) confirm IF findings by IHC method and 2) determine whether IHC method could reveal monoclonal light chain staining in proximal tubules of LCAMN cases.
Design: The study included 18 control cases (8 FSGS and 10 immune complex mediated glomerulopathy) and 23 LCAMN cases (9 cast nephropathy, 7 light chain deposition disease, 6 AL amyloidosis and 1 “pure” proximal tubulopathy). Staining pattern for kappa and lambda by IHC method was evaluated as polyclonal (equivalent kappa and lambda stains) and monoclonal (dominant kappa or lambda staining). The monoclonal staining in proximal tubules was also recorded. PAS staining of proximal tubular brush borders was graded from 0 (intact) to 3+ (total loss of brush border) in each case.
Results: All cases in the control group showed equivalent kappa and lambda stains indicating polyclonal pattern. All cases in the LCAMN group showed either kappa or lambda dominant staining, indicating monoclonal pattern, which was 100% correspondent with the monoclonal record by IF method. Monoclonal proximal tubular staining was seen in 8/9 cases of cast nephropathy, 7/7 cases of light chain deposition disease and one “pure” proximal tubulopathy, but in only 1/6 AL amyloidosis cases. The PAS scores of all LCAMN cases ranged from 2+ to 3+, except for the 5 AL amyloidosis cases without monoclonal staining in proximal tubules, which showed 0 to 1+ PAS scores. The mean value of serum creatinine in the LCAMN group was 4.89 ± 0.73 mg/dl, which significantly correlated with the PAS scores (R value: 0.496 and p = 0.0136).
Conclusions: IHC studies confirmed the monoclonal data identified on previous IF studies. In addition, IHC revealed a high percentage of “hybrid” monoclonal proximal tubulopathy (16/22 cases, 73%, not counting the “pure” proximal tubulopathy case), defined by monoclonal staining in proximal tubules and moderate to severe loss of brush borders. We conclude that monoclonal proximal tubulopathy, “pure” or “hybrid” type, may significantly contribute to acute renal failure in patients with LCAMN.
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Isolated Light Chain Proximal Tubulopathy without Crystal Formation – An Under-Recognized and Critically Important Entity.
Christopher P Larsen, Patrick D Walker. Nephropathology Associates, Little Rock, AR
Background: The renal diseases most frequently associated with myeloma include light chain deposition disease, cast nephropathy, and amyloidosis. Less frequently reported is light chain proximal tubulopathy (LCPT) characterized by kappa-restricted crystal deposits in the proximal tubule cytoplasm. These patients classically present with Fanconi syndrome in the setting of smoldering myeloma. LCPT without crystal deposition is only loosely related to the typical LCPT. Little is known about this entity as only 3 cases have previously been reported compared with over 50 cases of LCPT with crystals. We describe 10 cases of LCPT without intra-cytoplasmic crystals and detail the pathologic and clinical significance of this not so uncommon condition.
Design: A search was performed of the 10081 native kidney biopsies processed by our laboratory over the past 2 years for cases that had light chain restriction limited to the proximal tubule cytoplasm by immunofluorescence without evidence of other concurrent paraproteinemic renal diseases on biopsy. All cases were evaluated by light, immunofluorescence, and electron microscopy.
Results: 13 cases of isolated LCPT were found representing 4.0% of light chain-related diseases. 10/13 cases of LCPT did not have intracytoplasmic crystals and 9 of these 10 showed lambda restriction. In the cases with crystals, 2 were kappa subtype. Only 3/10 patients with LCPT without crystals had a diagnosis of a plasma cell dyscrasia at the time of renal biopsy. After the biopsy was reported, follow-up was available on 9/10 patients with 9/9 showing a plasma cell dyscrasia. 8/9 had multiple myeloma, only one of which was classified as smoldering myeloma. Six of the patients without crystals were tested for Fanconi'syndrome and none were positive.
Conclusions: LCPT without crystal formation is a diagnostic entity on renal biopsy that has several distinctions from the more commonly described LCPT with crystals. Whereas, over 90% of cases with crystals in the literature are of the kappa subtype, our series shows that 90% without crystals are of the lambda subtype. Additionally, PLCT without crystals is more likely to be associated with multiple myeloma than PLCT with crystals and less likely to be associated with a Fanconi syndrome. The fact that LCPT without crystals is so rarely described in the medical literature despite being more than 3 times as prevalent in our series leads us to believe that it is an under recognized entity. And given that it is often associated with previously unrecognized myeloma, it is a critically important diagnosis.
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Significance of IgG4 Immunostaining in Plasma Cell-Rich Tubulointerstitial Nephritis (TIN).
Yassaman Raissian, Samih H Nasr, Christopher P Larsen, Mary E Fidler, Sanjeev Sethi, Ami Bhalodia, Lynn D Cornell. Mayo Clinic, Rochester, MN; Nephropath, Little Rock, AR; Univ of Louisiana, Shreveport
Background: A number of conditions may cause TIN. IgG4 staining has been proposed as a tool to identify TIN as part of IgG4-related systemic disease(IgG4-RSD), but the sensitivity and specificity of IgG4 staining has not been established.
Design: A database search was performed for all cases within one year(2007) with a final diagnosis of TIN, including cases with glomerular disease; causes of TIN were based on clinical and laboratory data. Light microscopy slides of TIN cases were reviewed for increased plasma cells, defined as >5 cells/40x field in ≥3 fields. Cases with increased plasma cells were stained for IgG4 by immunohistochemistry. For comparison, IgG4 staining was also done on TIN cases in patients with clinical features suspicious for IgG4-RSD(n=23), TIN in patients with a history of pancreatitis(n=17), pauci-immune crescentic glomerulonephritis(GN)(n=14), Sjogren TIN(n=14), drug-related(n=5), chronic pyelonephritis(n=2), and unknown or autoimmune cases(n=4). IgG4 stains were graded in the most concentrated area per 40x field as: no increase <5 cells, mild 5-10, moderate 11-30 and marked >30.
Results: Within the given year, 414 cases of TIN were found including 167 cases with associated non-diabetic glomerular disease. Of these, 83/414(20%) had at least moderate increase in plasma cells, with etiology as follows: 25% drug effect, 21% unknown, 20% associated with pauci-immune GN, 14% with other glomerular disease(immune-mediated crescentic GN,FSGS,diabetes), 10% autoimmune disease, 2% pyelonephritis, 2% IgG4-RSD, 1% oxalate nephropathy. 15/83(18%) showed moderate or marked increase in IgG4+ plasma cells; these cases were pauci-immune GN(n=7), TIN due to drug(n=3), other glomerular disease(n=2), pyelonephritis(n=1), and IgG4-RSD(n=1).
In the comparison groups, 23/23(100%) of the IgG4-RSD showed moderate to marked increase in IgG4+ cells, 6/24(25%) cases of pauci-immune GN, 1/14(7%) Sjogren TIN, and 0/17(0%) TIN in patients with a history of pancreatitis, 1/2(50%) with pyelonephritis, and 0/4(0%) TIN of unknown etiology showed increased IgG4+ cells.
In total, excluding IgG4-RSD and pauci-immune GN, 9/107(8%) of TIN studied showed at least moderate increase in IgG4+ plasma cells. If pauci-immune GN is excluded, the IgG4 stain has a sensitivity of 100% and a specificity of 92% for TIN as part of IgG4-RSD.
Conclusions: IgG4 is a sensitive and specific marker for diagnosis of TIN as part of IgG4-RSD. Increased IgG4+ cells may also be seen in pauci-immune crescentic GN; rare other TIN cases may show increased IgG4+ cells.
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Exogenous Ac-SDKP Administration Regulates Profibrotic Molecules in Obstructed Kidneys.
Yiqin Zuo, Sebastian A Potthoff, Hai-Chun Yang, Li-Jun Ma, Agnes B Fogo. Vanderbilt University, Nashville, TN
Background: Our previous studies showed that thymosin β4 (Tβ4), a G-actin sequestering protein, is remarkably increased in the obstructed kidney in the unilateral ureteral obstruction (UUO) model of tubulointerstitial fibrosis. Ac-SDKP, the degradation product of Tβ4 by prolyl oligopeptidase (POP), is postulated to have anti-fibrotic effects. Moreover, we found that inhibition of POP shifted the balance of Tβ4 and Ac-SDKP and exacerbated fibrosis in obstructed kidneys. We have now investigated profibrotic molecular gene expression in the UUO kidneys.
Design: Male C57BL/6 mice were sacrificed at day 5 after UUO and treatments: UUO without treatment, UUO+POP inhibitor (S17092, 40mg/kg per day, by gavage), UUO+Tβ4 (150µg/d, i.p.), UUO+combination (POP inhibitor and Tβ4), and UUO+Ac-SDKP (1.6 mg/kg/d, delivered by minipump).
Results: POP activity was significantly decreased in the obstructed kidneys of mice treated with either POP inhibitor or the combination (8% and 21% of levels in untreated UUO, respectively, both p<0.05). Ac-SDKP concentration was significantly reduced by both the POP inhibitor and combination treatment but dramatically increased by Ac-SDKP administration vs. untreated UUO (POP inhibitor, 47%; combination, 61%; Ac-SDKP, 172% of untreated UUO, respectively, all p<0.05). Neither POP activity nor Ac-SDKP was affected by Tβ4 treatment (77% and 78% of untreated UUO, respectively). Ac-SDKP treatment dramatically decreased plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-β1, Tβ4, collagen I and III expression assessed by real time PCR vs. untreated UUO. By contrast, PAI-1, TGF-β1 and collagen III expressions were significantly increased by POP inhibitor. Ku80, a potential receptor for Tβ4, was abundantly present in glomerular endothelial cells and peritubular capillary endothelium in UUO kidneys and increased vs. non-obstructed kidneys. Ku80 mRNA in the UUO kidney assessed by real time PCR was dramatically increased by POP inhibitor and Tβ4 treatment vs. untreated UUO.
Conclusions: Our study suggests that exogenous administration of Ac-SDKP inhibits profibrotic factors. We propose that the balance of thymosin β4 and Ac-SDKP is crucial in determining tubulointerstitial fibrosis, and Ku80, a potential receptor for Tβ4, may modulate these processes.
