LITTLE ROCK, AR, United States
LITTLE ROCK, AR, United States

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Larsen C.P.,Nephropathology Associates | Walker P.D.,Nephropathology Associates | Weiss D.T.,University of Tennessee at Knoxville | Solomon A.,University of Tennessee at Knoxville
Kidney International | Year: 2010

Renal pathologists identify the protein component of renal amyloid deposits by immunohistochemistry using antibodies against known amyloidogenic proteins. The majority of amyloid cases can be categorized by a simple antibody panel that includes immunoglobulin light chains lambda and kappa, and serum amyloid A. In some instances, however, these reagents do not recognize materials that stain with Congo red or yield ambiguous staining results, thus creating a diagnostic dilemma. Chemical analysis of fibrils extracted from such a nonreactive renal biopsy led to the discovery of a previously unknown amyloid formed from leukocyte chemotactic factor 2 (LECT2). Over the past 8 years, we received 285 renal amyloid samples, of which 31 remained unclassified. In an effort to determine whether any of the latter samples were LECT2 related, tandem mass spectrometry was performed. In all, 7 of the 31 cases were identified as an amyloid LECT2 (ALECT2), a finding confirmed immunohistochemically using a LECT2-specific antibody. The deposits strongly stained for Congo red and, in most cases, had distinctive morphological features with diffuse involvement of the interstitium, arteries, and glomeruli. Hence, we believe that ALECT2 represents the third common form of renal amyloidosis. © 2010 International Society of Nephrology.


Cossey L.N.,University of Arkansas for Medical Sciences | Cossey L.N.,Nephropathology Associates | Rahim F.,Idaho Kidney Institute | Larsen C.P.,University of Arkansas for Medical Sciences | Larsen C.P.,Nephropathology Associates
American Journal of Kidney Diseases | Year: 2013

Oxalate nephropathy is a rare condition characterized by extensive calcium oxalate deposition in the renal tubules, resulting in kidney injury. There are primary forms of the disease that arise from genetic mutation causing overproduction of oxalate. More commonly, this condition is seen as a secondary phenomenon. The clinical presentation is nonspecific, with acute kidney injury and normal serologic study results. The characteristic finding on kidney biopsy is the presence of acute tubular injury associated with polarizable crystals in the tubular lumen and epithelial cytoplasm. We present a case of acute oxalate nephropathy in a patient with underlying systemic lupus erythematosus who recently received intravenous vitamin C. © 2013 National Kidney Foundation, Inc.


Raissian Y.,Mayo Medical School | Nasr S.H.,Mayo Medical School | Larsen C.P.,Nephropathology Associates | Colvin R.B.,Massachusetts General Hospital | And 9 more authors.
Journal of the American Society of Nephrology | Year: 2011

IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell - rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell - rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90-100%) and a specificity of 92% (95% CI 86-95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN. Copyright © 2011 by the American Society of Nephrology.


Larsen C.P.,Nephropathology Associates | Walker P.D.,Nephropathology Associates | Thoene J.G.,University of Michigan
Molecular Genetics and Metabolism | Year: 2010

Nephropathic cystinosis results from lysosomal cystine storage and, if untreated with cysteamine, results in end-stage renal disease by 10. years of age. The renal Fanconi syndrome occurs in the first year of life and is accompanied by a characteristic "swan neck" deformity of the proximal renal tubule. The linkage between cystine storage, Fanconi syndrome, and renal failure has not been understood. This study reports the presence of substantial numbers of atubular glomeruli (ATG) in end-stage cystinotic renal tissue. Compared to normal renal tissue, cystinotic kidneys at end stage had 69% atubular glomeruli and 30% atrophic glomeruli. Normal renal tissue had 4% ATG and 0% atrophic glomeruli (p< 0.0001 for both comparisons). These nonfunctioning nephrons may be the end result of cell loss from the tubules and represent the final stage of the swan neck deformity. The process is consistent with the previously reported increased apoptosis in renal tubule cells due to lysosomal cystine storage. © 2010 Elsevier Inc.


Alexander M.P.,Mayo Medical School | Larsen C.P.,Nephropathology Associates | Gibson I.W.,University of Manitoba | Nasr S.H.,Mayo Medical School | And 7 more authors.
Kidney International | Year: 2013

IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Renal involvement by IgG4-RD usually takes the form of IgG4-related tubulointerstitial nephritis, but cases of membranous glomerulonephritis (MGN) have also been described. Here we present a series of 9 patients (mean age at diagnosis 58 years) with MGN associated with IgG4-RD. All patients showed MGN on biopsy, presented with proteinuria (mean 8.3 g/day), and most had elevated serum creatinine (mean 2.2 mg/dl). Seven patients had known extrarenal involvement by IgG4-RD, with 5 patients having concurrent IgG4-related tubulointerstitial nephritis. Immunohistochemical analysis for the phospholipase A2 receptor, a marker of primary MGN, was negative in all 8 biopsies so examined. Six of 7 patients with available follow-up (mean 39 months) were treated with immunosuppressive agents; one untreated patient developed end-stage renal disease and underwent transplantation, without recurrence at 12 years after transplant. All 6 treated patients showed decreased proteinuria (mean 1.2 g/day), and most showed decreased serum creatinine (mean 1.4 mg/dl). Thus, MGN should be included in the spectrum of IgG4-RD and should be suspected in proteinuric IgG4-RD patients. Conversely, patients with MGN and an appropriate clinical history should be evaluated for IgG4-RD. © 2012 International Society of Nephrology.


Gaut J.P.,Nephropathology Associates
Surgical Pathology Clinics | Year: 2014

This review discusses the pathology of non-neoplastic kidney disease that pathologists may encounter as nephrectomy specimens. The spectrum of pediatric disease is emphasized. Histopathologic assessment of non-neoplastic nephrectomy specimens must be interpreted in the clinical context for accurate diagnosis. Although molecular pathology is not the primary focus of this review, the genetics underlying several of these diseases are also touched on. © 2014 Elsevier Inc.


Larsen C.P.,Nephropathology Associates | Larsen C.P.,University of Arkansas for Medical Sciences | Messias N.C.,Nephropathology Associates | Silva F.G.,Nephropathology Associates | And 4 more authors.
Modern Pathology | Year: 2013

Autoantibody formation directed against phospholipase A2 receptor (PLA2R)1 is the underlying etiology in most cases of primary membranous glomerulopathy. This new understanding of the pathogenesis of primary membranous is in the process of transforming the way the disease is diagnosed. We validated an indirect immunofluorescence assay to examine PLA2R1 in renal biopsies utilizing a commercially available antibody and standard indirect immunofluorescence. Using this assay, we examined a total of 165 cases of membranous glomerulopathy including 85 primary and 80 secondary. We found tissue staining for PLA2R1 to have a sensitivity of 75% (95% CI 65-84%) and a specificity of 83% (95% CI 72-90%) for primary membranous glomerulopathy. Hepatitis C virus was the secondary etiology with the most number of cases staining positive for PLA2R1 (7/11, 64%) followed by sarcoidosis (3/4, 75%) and neoplasm (3/12, 25%). Autoimmune etiologies showed rare PLA2R1-positive staining (1/46, 2%). All cases of secondary membranous glomerulopathy with positive PLA2R1 showed IgG4-predominant staining, which is typically associated with primary membranous glomerulopathy. This IgG4 predominance raises the possibility that these cases are more pathogenically related to primary membranous glomerulopathy than secondary. We present the largest case series to date examining PLA2R1 involvement in membranous glomerulopathy utilizing a technique that is readily adoptable by most renal pathology laboratories. © 2013 USCAP, Inc.


Larsen C.P.,Nephropathology Associates | Bell J.M.,Nephropathology Associates | Harris A.A.,Nephropathology Associates | Messias N.C.,Nephropathology Associates | And 2 more authors.
Modern Pathology | Year: 2011

The renal diseases most frequently associated with myeloma include amyloidosis, monoclonal immunoglobulin deposition disease, and cast nephropathy. Less frequently reported is light chain proximal tubulopathy, a disease characterized by-restricted crystal deposits in the proximal tubule cytoplasm. Light chain proximal tubulopathy without crystal deposition is only loosely related to the typical light chain proximal tubulopathy, and little is known about this entity. A search was performed of the 10 081 native kidney biopsy samples processed by our laboratory over the past 2 years for cases that had light chain restriction limited to the proximal tubule cytoplasm. A total of 10 cases of light chain proximal tubulopathy without crystal deposition were found representing 3.1% of light chain-related diseases. Nine of these 10 showed-light chain restriction. Only three cases of light chain proximal tubulopathy with crystals were found accounting for 0.9% of light chain-related diseases. Two of these three were subtype. Plasma cell dyscrasia was unsuspected in seven of the 10 patients with light chain proximal tubulopathy without crystals 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 including 8/9 with multiple myeloma. We found that light chain proximal tubulopathy without crystal formation, despite being rarely described in the literature, is over three times more common than light chain proximal tubulopathy with crystal formation in our series. And given that it is often associated with previously unrecognized myeloma, it is a critically important diagnosis. © 2011 USCAP, Inc. All rights reserved.


Rodriguez E.F.,Mayo Medical School | Nasr S.H.,Mayo Medical School | Larsen C.P.,Nephropathology Associates | Sethi S.,Mayo Medical School | And 2 more authors.
American Journal of Kidney Diseases | Year: 2014

Background Membranous nephropathy (MN) with crescents is rare and, in the absence of lupus, usually is associated with anti-glomerular basement membrane (anti-GBM) nephritis or antineutrophil cytoplasmic antibody (ANCA)-positive glomerulonephritis. Only rare cases of crescentic MN without ANCA or anti-GBM have been reported. Study Design Case series. Setting & Participants 19 patients with ANCA- and anti-GBM-negative crescentic MN and no clinical evidence of systemic lupus. Outcomes Clinical features, kidney biopsy findings, laboratory results, treatment, and follow-up of patients with crescentic MN. Results Mean age was 55 (range, 5-86) years. All patients presented with proteinuria (mean protein excretion, 11.5 [range, 3.3-29] g/d) and nearly all had hematuria; 16 of 19 (84%) patients had decreased estimated glomerular filtration rates (eGFRs; mean serum creatinine, 2.9 [range, 0.4-10] mg/dL; mean eGFR, 39.7 [range, 4 to >100] mL/min/1.73 m2). Glomeruli showed on average 25% (range, 2%-73%) involvement by crescents. All showed a membranous pattern; 7 showed mesangial and 2 showed segmental endocapillary proliferation. By immunofluorescence, all cases showed granular subepithelial immunoglobulin G (IgG) and κ and λ light chains, and all but one showed C3; 5 showed C1q or IgA. Electron microscopy revealed stages I-III MN; 38% of cases were M-type phospholipase A2 receptor (PLA2R) associated, indicating that at least some were primary MN. Follow-up clinical data were available for all patients (mean, 22 [range, 1.5-138] months). 14 patients received immunosuppressive therapy, and 2, only angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy. 4 patients (21%) progressed to end-stage renal disease, at 0-9 months postbiopsy. Mean serum creatinine level of those without end-stage renal disease at follow-up was 1.7 (range, 0.5-4.1) mg/dL; mean eGFR was 53.3 (range, 16-103) mL/min/1.73 m2. 67% of patients had proteinuria with protein excretion ≥ 1 (mean, 3.2) g/d at follow-up. Limitations Retrospective study. Conclusions Crescentic MN is a rare variant of MN that usually presents with heavy proteinuria, hematuria, and decline in GFR. The prognosis is variable and the disease may respond to therapy, but most patients develop a long-term decline in GFR. © 2014 by the National Kidney Foundation, Inc.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 143.38K | Year: 2014

DESCRIPTION (provided by applicant): There are currently mutations in over 200 genes that have been described to cause kidney disease. Current strategies for diagnosis of genetic kidney disease are extremely costly and time consuming. We aim to develop a comprehensive next generation sequencing panel that can simultaneously test for all currently described kidney- associated gene mutations at a low price within approximately 2 weeks. There are currently no comprehensive gene panels commercially available inthe field of nephrology. We believe this assay will greatly decrease turnaround time and cost for the diagnosis of disease. Once the nephrology gene panel is developed, we will use it to describe genotypic-phenotypic correlations in a large cohort of patients with unexplained chronic kidney disease. We will isolate DNA from de-identified renal biopsy samples and use these samples for target enrichment, amplification and labeling of the exons of genes in our panel followed by sequencing on a MiSeq. We

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