Publications by authors named "Lynn D Cornell"

94 Publications

Automated Identification of Glomeruli and Synchronized Review of Special Stains in Renal Biopsies by Machine Learning and Slide Registration: A Cross-Institutional Study.

Histopathology 2021 Apr 4. Epub 2021 Apr 4.

Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center.

Aims: Machine learning in digital pathology can improve efficiency and accuracy via prescreening with automated feature identification. Studies using uniform histologic material have shown promise. Generalized application requires validation on slides from multiple institutions. We used machine learning to identify glomeruli on renal biopsies and compared performance between single and multiple institutions.

Methods And Results: Randomly selected, adequately sampled renal core biopsy cases (71) consisting of 4 stains each (H&E, trichrome, silver, PAS) from 3 institutions were digitized at 40x. Glomeruli were manually annotated by 3 renal pathologists using a digital tool. Cases were divided into training/validation (n=52) and evaluation (n=19) cohorts. An algorithm was trained to develop 3 convolutional neural network (CNN) models which tested case cohorts intra- and inter-institutionally. Raw CNN search data from each of the 4 slides per case were merged into composite regions of interest (ROI) containing putative glomeruli. The sensitivity and modified specificity of glomerulus detection (versus annotated truth) were calculated for each model/cohort. Intrainstitutional (3) sensitivity ranged from 90 to 93%, with modified specificity from 86 to 98%. Interinstitutional (1) sensitivity was 77%, with modified specificity 97%. Combined intra- and interinstitutional (1) sensitivity was 86%, with modified specificity 92%.

Conclusion: Feature detection sensitivity degrades when training and test material originate from different sites. Training using a combined set of digital slides from 3 institutions improves performance. Differing histology methods likely account for algorithm performance contrasts. Our data highlight the need for diverse training sets for the development of generalizable machine learning histology algorithms.
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http://dx.doi.org/10.1111/his.14376DOI Listing
April 2021

Myeloid bodies in acute tubular injury.

Kidney Int 2021 04;99(4):1027

Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1016/j.kint.2020.08.018DOI Listing
April 2021

In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes.

J Am Soc Nephrol 2021 Mar 21;32(3):695-706. Epub 2021 Jan 21.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

Background: In patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.

Methods: We conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.

Results: Our study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (=0.01), had significantly lower serum creatinine levels (=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (=0.009), and had significantly less chronicity features (glomerulosclerosis, =0.001 or interstitial fibrosis and tubular atrophy, <0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; 0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; =0.003).

Conclusions: The prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.
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http://dx.doi.org/10.1681/ASN.2020081181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920177PMC
March 2021

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 Mar;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 2021

Using Image Registration and Machine Learning to Develop a Workstation Tool for Rapid Analysis of Glomeruli in Medical Renal Biopsies.

J Pathol Inform 2020 7;11:37. Epub 2020 Nov 7.

Corista LLC, Concord, MA, USA.

Background: Prescreening of biopsies has the potential to improve pathologists' workflow. Tools that identify features and display results in a visually thoughtful manner can enhance efficiency, accuracy, and reproducibility. Machine learning for detection of glomeruli ensures comprehensive assessment and registration of four different stains allows for simultaneous navigation and viewing.

Methods: Medical renal core biopsies (4 stains each) were digitized using a Leica SCN400 at ×40 and loaded into the Corista Quantum research platform. Glomeruli were manually annotated by pathologists. The tissue on the 4 stains was registered using a combination of keypoint- and intensity-based algorithms, and a 4-panel simultaneous viewing display was created. Using a training cohort, machine learning convolutional neural net (CNN) models were created to identify glomeruli in all stains, and merged into composite fields of views (FOVs). The sensitivity and specificity of glomerulus detection, and FOV area for each detection were calculated.

Results: Forty-one biopsies were used for training (28) and same-batch evaluation (6). Seven additional biopsies from a temporally different batch were also evaluated. A variant of AlexNet CNN, used for object recognition, showed the best result for the detection of glomeruli with same-batch and different-batch evaluation: Same-batch sensitivity 92%, "modified" specificity 89%, average FOV size represented 0.8% of the total slide area; different-batch sensitivity 90%, "modified" specificity 98% and average FOV size 1.6% of the total slide area.

Conclusions: Glomerulus detection in the best CNN model shows that machine learning algorithms may be accurate for this task. The added benefit of biopsy registration with simultaneous display and navigation allows reviewers to move from one machine-generated FOV to the next in all 4 stains. Together these features could increase both efficiency and accuracy in the review process.
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http://dx.doi.org/10.4103/jpi.jpi_49_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737496PMC
November 2020

Immunoglobulin-Negative DNAJB9-Associated Fibrillary Glomerulonephritis: A Report of 9 Cases.

Am J Kidney Dis 2021 03 23;77(3):454-458. Epub 2020 Jul 23.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

Fibrillary glomerulonephritis (FGN) was previously defined by glomerular deposition of haphazardly oriented fibrils that stain with antisera to immunoglobulins but do not stain with Congo red. We report what is to our knowledge the first series of immunoglobulin-negative FGN, consisting of 9 adults (7 women and 2 men) with a mean age at diagnosis of 66 years. Patients presented with proteinuria (100%; mean protein excretion, 3g/d), hematuria (100%), and elevated serum creatinine level (100%). Comorbid conditions included carcinoma in 3 and hepatitis C virus infection in 2; no patient had hypocomplementemia or monoclonal gammopathy. Histologically, glomeruli were positive for DNAJB9, showed mostly mild mesangial hypercellularity and/or sclerosis, and were negative for immunoglobulins by immunofluorescence on frozen and paraffin tissue. Ultrastructurally, randomly oriented fibrils measuring 13 to 20nm in diameter were seen intermingling with mesangial matrix in all and infiltrating glomerular basement membranes in 5. On follow-up (mean duration, 21 months), 2 had disease remission, 4 had persistently elevated serum creatinine levels and proteinuria, and 3 required kidney replacement therapy. Thus, rare cases of FGN are not associated with glomerular immunoglobulin deposition, and the diagnosis of FGN in these cases can be confirmed by DNAJB9 immunostaining. Pathogenesis remains to be elucidated.
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http://dx.doi.org/10.1053/j.ajkd.2020.04.015DOI Listing
March 2021

DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.

Kidney Int 2020 08 28;98(2):498-504. Epub 2020 Mar 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

The association of fibrillary glomerulonephritis (FGN) with monoclonal gammopathy has been controversial, although monotypic FGN is currently classified as a monoclonal gammopathy of renal significance (MGRS) lesion. To define this lesion, we correlated findings by immunofluorescence on frozen and paraffin tissue, IgG subtype staining and serum protein electrophoresis with immunofixation in patients with monotypic FGN. Immunofluorescence was performed on paraffin sections from 35 cases of DNAJB9-associated FGN that showed apparent light chain restriction of glomerular IgG deposits by standard immunofluorescence on frozen tissue. On paraffin immunofluorescence, 15 cases (14 lambda and one kappa restricted cases on frozen tissue immunofluorescence) showed no light chain restriction, 19 showed similar light chain restriction, and one was negative for both light chains. Seven of the 15 cases with masked polyclonal deposits also had IgG subclass restriction and these cases would have been diagnosed as a form of monoclonal protein-associated glomerulonephritis if paraffin immunofluorescence was not performed. Monotypic FGN (confirmed by paraffin immunofluorescence and IgG subclass restriction) accounted for only one of 151 (0.7%) patients with FGN encountered during the last two years. Only one of 11 of cases had a detectable circulating monoclonal protein on serum protein electrophoresis with immunofixation. We propose that paraffin immunofluorescence is required to make the diagnosis of lambda-restricted monotypic FGN as it unmasked polytypic deposits in over half of patients. When confirmed by paraffin immunofluorescence and IgG subclass staining, DNAJB9-positive monotypic FGN is very rare and is not associated with monoclonal gammopathy in the vast majority of patients. Thus, there is a question whether this lesion should be included in MGRS-related diseases.
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http://dx.doi.org/10.1016/j.kint.2020.02.025DOI Listing
August 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Recurrence of DNAJB9-Positive Fibrillary Glomerulonephritis After Kidney Transplantation: A Case Series.

Am J Kidney Dis 2020 10 12;76(4):500-510. Epub 2020 May 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

Rationale & Objective: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that often progresses to kidney failure requiring kidney replacement therapy. We have recently identified a novel biomarker of FGN, DnaJ homolog subfamily B member 9 (DNAJB9). In this study, we used sequential protocol allograft biopsies and DNAJB9 staining to help characterize a series of patients with native kidney FGN who underwent kidney transplantation.

Study Design: Case series.

Setting & Participants: Between 1996 and 2016, kidney transplantation was performed on 19 patients with a reported diagnosis of FGN in their native/transplant kidneys. Using standard diagnostic criteria and DNAJB9 staining, we excluded 5 patients (4 atypical cases diagnosed as possible FGN and 1 donor-derived FGN). Protocol allograft biopsies had been performed at 4, 12, 24, 60, and 120 months posttransplantation. DNAJB9 immunohistochemistry was performed using an anti-DNAJB9 rabbit polyclonal antibody. Pre- and posttransplantation demographic and clinical characteristics were collected. Summary statistical analysis was performed, including nonparametric statistical tests.

Observations: The 14 patients with FGN had a median posttransplantation follow-up of 5.7 (IQR, 2.9-13.8) years. 3 (21%) patients had recurrence of FGN, detected on the 5- (n=1) and 10-year (n=2) allograft biopsies. Median time to recurrence was 10.2 (IQR, 5-10.5) years. Median levels of proteinuria and iothalamate clearance at the time of recurrence were 243mg/d and 56mL/min. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplantation biopsy, although the median time of follow-up was significantly less at 4.4 (IQR, 2.9-14.4) years. 3 (21%) patients had a monoclonal protein detectable in serum obtained pretransplantation; none of these patients had recurrent FGN.

Limitations: Small study sample and shorter follow-up time in the nonrecurrent versus recurrent group.

Conclusions: In this series, FGN had an indolent course in the kidney allograft in that detectable histologic recurrence did not appear for at least 5 years posttransplantation.
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http://dx.doi.org/10.1053/j.ajkd.2020.01.018DOI Listing
October 2020

Banff Digital Pathology Working Group: Going digital in transplant pathology.

Am J Transplant 2020 09 19;20(9):2392-2399. Epub 2020 Apr 19.

University of Alberta, Edmonton, Canada.

The Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27, 2019, held in Pittsburgh, Pennsylvania. At the meeting, the 14th Banff Conference, presentations directly and peripherally related to the topic of "digital pathology" were presented; and discussions before, during, and after the meeting have resulted in a list of issues to address for the DPWG. Included are practice standardization, integrative approaches for study classification, scoring of histologic parameters (eg, interstitial fibrosis and tubular atrophy and inflammation), algorithm classification, and precision diagnosis (eg, molecular pathways and therapeutics). Since the meeting, a survey with international participation of mostly pathologists (81%) was conducted, showing that whole slide imaging is available at the majority of centers (71%) but that artificial intelligence (AI)/machine learning was only used in ≈12% of centers, with a wide variety of programs/algorithms employed. Digitalization is not just an end in itself. It also is a necessary precondition for AI and other approaches. Discussions at the meeting and the survey highlight the unmet need for a Banff DPWG and point the way toward future contributions that can be made.
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http://dx.doi.org/10.1111/ajt.15850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496838PMC
September 2020

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.

Kidney Int 2020 03 9;97(3):589-601. Epub 2019 Nov 9.

Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2019.10.025DOI Listing
March 2020

De novo pauci-immune glomerulonephritis in renal allografts.

Mod Pathol 2020 03 2;33(3):440-447. Epub 2019 Sep 2.

Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Pauci-immune glomerulonephritis in the native kidney presents with renal insufficiency, proteinuria, and hematuria, and is usually due to anti-neutrophil cytoplasmic antibodies. Rarely, kidney transplants can show this pattern as de novo disease. We performed a retrospective analysis in 10 cases of de novo pauci-immune glomerulonephritis. The mean time from transplant to diagnostic biopsy was 32 months (range, 4-96). All biopsies showed focal necrotizing or crescentic glomerulonephritis (mean 16% glomeruli, range 2-36%). Immunofluorescence and electron microscopy showed a pauci-immune pattern. No patients had evidence of systemic vasculitis. Anti-neutrophil cytoplasmic antibody results were available for 7 patients and were negative in all but one. Most patients had functioning grafts at one year after diagnosis. Two patients had repeat biopsies that showed continued active glomerulonephritis. We report the first clinicopathologic series of de novo pauci-immune glomerulonephritis which appears to be a unique pathologic entity that may occur early or late post-transplant and in our cohort is not associated with systemic vasculitis and usually not associated with anti-neutrophil cytoplasmic antibodies. The degree of crescent formation and renal impairment are milder than those of pauci-immune crescentic glomerulonephritis in the native kidney.
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http://dx.doi.org/10.1038/s41379-019-0355-0DOI Listing
March 2020

The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry.

Kidney Int 2019 10 25;96(4):1005-1009. Epub 2019 Jun 25.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Immunoglobulin light chain amyloidosis is the most frequent type of renal amyloidosis in the United States, accounting for 81% of cases. Accurate typing is crucial for early diagnosis and treatment of immunoglobulin-derived amyloidosis and to avoid treating other amyloidoses with potentially toxic chemotherapy. Immunofluorescence is the first step to type renal immunoglobulin-derived amyloidosis but the performance characteristics of this method are largely unknown. Here, we establish the sensitivity and specificity of immunofluorescence for diagnosing immunoglobulin-derived amyloidosis in patients whose amyloid typing was performed by the current gold standard of laser microdissection/mass spectrometry. Renal biopsy pathology reports originating from several institutions with a diagnosis of amyloidosis and which had amyloid typing by laser microdissection/mass spectrometry performed at our center were reviewed. Reported immunofluorescence staining for kappa or lambda of 2+ or more, with weak or no staining for the other light chain was considered positive for light chain amyloidosis by immunofluorescence. Based on microdissection/mass spectrometry results, of the 170 cases reviewed, 104 cases were typed as immunoglobulin-derived amyloidosis and 66 were typed as non-immunoglobulin-derived amyloidosis. Immunofluorescence sensitivity for diagnosing immunoglobulin-derived amyloidosis was 84.6%. The remaining 16 cases could not be diagnosed by immunofluorescence due to reported weak staining for all antigens or reported lack of preferential staining for one antigen. Immunofluorescence specificity was 92.4%. Five cases, all amyloid A amyloidosis, were misdiagnosed as immunoglobulin-derived amyloidosis by immunofluorescence. Immunofluorescence failed to accurately differentiate immunoglobulin-derived from non-immunoglobulin-derived amyloidosis in 12.3% of cases of renal amyloidosis. Relying on immunofluorescence alone for determining immunoglobulin-derived vs. non-immunoglobulin-derived amyloidosis may lead to misdiagnosis. Thus, immunofluorescence has inferior sensitivity and specificity compared with laser microdissection/mass spectrometry in the typing of immunoglobulin-derived amyloidosis.
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http://dx.doi.org/10.1016/j.kint.2019.05.027DOI Listing
October 2019

Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial.

Am J Transplant 2019 10 19;19(10):2876-2888. Epub 2019 Apr 19.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.

We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28).
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http://dx.doi.org/10.1111/ajt.15364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790671PMC
October 2019

Multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney: CT and MRI findings and clinical characteristic.

Eur Radiol 2019 Sep 26;29(9):4843-4850. Epub 2019 Feb 26.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

Purpose: The aim of this study was to clarify the radiologic and clinical characteristics of multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney.

Method: Fourteen patients with unique and characteristic multiple hemorrhagic subcapsular cortical cysts of the kidney, not categorized in any existing renal cystic diseases, were retrospectively reviewed. The clinical information including age, sex, symptom, family history of renal or renal cystic disease, and laboratory data were collected. CT and MRI findings including distribution, number and size of cysts, and CT attenuation and signal intensity on T1- and T2-weighted MRI of cysts were analyzed.

Results: All patients except one were young and none had a family history of renal or renal cystic disease. Common clinical symptoms were flank or abdominal pain and hematuria. In all cases, only the left kidney was involved at initial presentation. Cysts were small (median cyst size, 4-15 mm), numerous, and distributed mainly along the subcapsular cortex of the kidney. Cysts were hyper-attenuated on unenhanced CT, extremely hypointense on T2-weighted MRI, and mildly hyperintense on T1-weighted MRI. All patients except one had normal renal function. Imaging follow-up revealed stable or mildly progressive disease in seven patients. Two patients developed several hemorrhagic subcapsular cortical cysts in the right kidney at follow-up. Three of five patients with a renal pathology specimen showed concurrent IgA nephropathy.

Conclusion: We have identified a unique renal cystic disease with multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney that has a characteristic manifestation both radiologically and clinically.

Key Points: • Multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney is a unique non-familial renal cystic disease with a characteristic manifestation both radiologically and clinically. • Most cases of multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney are stable or slowly progressive, and do not require invasive intervention.
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http://dx.doi.org/10.1007/s00330-019-06057-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684360PMC
September 2019

Modeling graft loss in patients with donor-specific antibody at baseline using the Birmingham-Mayo (BirMay) predictor: Implications for clinical trials.

Am J Transplant 2019 08 13;19(8):2274-2283. Epub 2019 Mar 13.

William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota.

Predicting which renal allografts will fail and the likely cause of failure is important in clinical trial design to either enrich patient populations to be or as surrogate efficacy endpoints for trials aimed at improving long-term graft survival. This study tests our previous Birmingham-Mayo model (termed the BirMay Predictor) developed in a low-risk kidney transplant population in order to predict the outcome of patients with donor specific alloantibody (DSA) at the time of transplantation and identify new factors to improve graft loss prediction in DSA+ patients. We wanted define ways to enrich the population for future therapeutic intervention trials. The discovery set included 147 patients from Mayo Cohort and the validation set included 111 patients from the Paris Cohort-all of whom had DSA at the time of transplantation. The BirMay predictor performed well predicting 5-year outcome well in DSA+ patients (Mayo C statistic = 0.784 and Paris C statistic = 0.860). Developing a new model did not improve on this performance. A high negative predictive value of greater than 90% in both cohorts excluded allografts not destined to fail within 5 years. We conclude that graft-survival models including histology predict graft loss well, both in DSA+ cohorts as well as DSA- patients.
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http://dx.doi.org/10.1111/ajt.15312DOI Listing
August 2019

Long-term outcomes of eculizumab-treated positive crossmatch recipients: Allograft survival, histologic findings, and natural history of the donor-specific antibodies.

Am J Transplant 2019 06 15;19(6):1671-1683. Epub 2018 Dec 15.

William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.

We aimed to determine the long-term outcomes of eculizumab-treated, positive crossmatch (+XM) kidney transplant recipients compared with +XM and age-matched negative crossmatch (-XM) controls. We performed an observational retrospective study and examined allograft survival, histologic findings, long-term B-cell flow cytometric XM (BFXM), and allograft-loss-associated factors. The mean (SD) posttransplant follow-up was 6.3 (2.5) years in the eculizumab group; 7.6 (3.5), +XM control group; 7.9 (2.5), -XM control group. The overall and death-censored allograft survival rates were similar in +XM groups (P = .73, P = .48) but reduced compared with -XM control patients (P < .001, P < .001). In the eculizumab-treated group, 57.9% (11/19) of the allografts had chronic antibody-mediated rejection, but death-censored allograft survival was 76.6%, 5 years; 75.4%, 7 years. Baseline IgG3 positivity and BFXM ≥300 were associated with allograft loss. C1q positivity was also associated with allograft loss but did not reach statistical significance. Donor-specific antibodies appeared to decrease in eculizumab-treated patients. After excluding patients with posttransplant plasmapheresis, 42.3% (9/21) had negative BFXMs; 31.8% (7/22), completely negative single-antigen beads 1 year posttransplant. Eculizumab-treated +XM patients had reduced allograft survival compared with -XM controls but similar survival to +XM controls. BFXM and complement-activating donor-specific antibodies (by IgG3 and C1q testing) may be used for risk stratification in +XM transplantation.
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http://dx.doi.org/10.1111/ajt.15175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509017PMC
June 2019

A method to reduce variability in scoring antibody-mediated rejection in renal allografts: implications for clinical trials - a retrospective study.

Transpl Int 2019 02 2;32(2):173-183. Epub 2018 Oct 2.

The William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.

Poor reproducibility in scoring antibody-mediated rejection (ABMR) using the Banff criteria might limit the use of histology in clinical trials. We evaluated the reproducibility of Banff scoring of 67 biopsies by six renal pathologists at three institutions. Agreement by any two pathologists was poor: 44.8-65.7% for glomerulitis, 44.8-67.2% for peritubular capillaritis, and 53.7-80.6% for chronic glomerulopathy (cg). All pathologists agreed on cg0 (n = 20) and cg3 (n = 9) cases, however, many disagreed on scores of cg1 or cg2. The range for the incidence of composite diagnoses by individual pathologists was: 16.4-22.4% for no ABMR; 17.9-47.8% for active ABMR; and 35.8-59.7% for chronic, active antibody-mediated rejection (cABMR). A "majority rules" approach was then tested in which the scores of three pathologists were used to reach an agreement. This increased consensus both for individual scores (ex. 67.2-77.6% for cg) and for composite diagnoses (ex. 74.6-86.6% cABMR). Modeling using these results showed that differences in individual scoring could affect the outcome assessment in a mock study of cABMR. We conclude that the Banff schema has high variability and a majority rules approach could be used to adjudicate differences between pathologists and reduce variability in scoring in clinical trials.
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http://dx.doi.org/10.1111/tri.13340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328317PMC
February 2019

Gastrointestinal and Extra-Intestinal Manifestations of IgG4-Related Disease.

Gastroenterology 2018 10 12;155(4):990-1003.e1. Epub 2018 Sep 12.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro-inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4 cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4 plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis.
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http://dx.doi.org/10.1053/j.gastro.2018.06.082DOI Listing
October 2018

Congophilic Fibrillary Glomerulonephritis: A Case Series.

Am J Kidney Dis 2018 09 14;72(3):325-336. Epub 2018 Jun 14.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Rationale & Objective: Congo Red positivity with birefringence under polarized light has traditionally permitted classification of organized glomerular deposits as from amyloid or nonamyloid diseases. The absence of congophilia has been used to differentiate fibrillary glomerulonephritis (GN) from amyloidosis. We describe a series of fibrillary GN cases in which the deposits are Congo Red-positive (congophilic fibrillary GN) and discuss the role of DNAJB9 in distinguishing congophilic fibrillary GN from amyloidosis.

Study Design: Case series.

Setting & Participants: Analysis of the clinicopathologic characteristics of 18 cases of congophilic fibrillary GN. Mass spectrometry was performed and compared with 24 cases of Congo Red-negative fibrillary GN, 145 cases of amyloidosis, and 12 apparently healthy individuals. DNAJB9 immunohistochemistry was obtained for a subset of cases.

Results: The proteomic signature of amyloid was not detected using mass spectrometry among cases of congophilic fibrillary GN. DNAJB9, a recently discovered proteomic marker for fibrillary GN, was detected using mass spectrometry in all cases of fibrillary GN regardless of congophilia and was absent in cases of amyloidosis and in healthy individuals. DNAJB9 immunohistochemistry confirmed the mass spectrometry findings. The congophilic fibrillary GN cases included 11 men and 7 women with a mean age at diagnosis of 65 years. Concomitant monoclonal gammopathy, hepatitis C virus infection, malignancy, or autoimmune disease was present in 35%, 22%, 17%, and 11% of patients, respectively. No patient had evidence of extrarenal amyloidosis. Patients presented with proteinuria (100%), nephrotic syndrome (47%), hematuria (78%), and chronic kidney disease (83%). After a mean follow-up of 23 months, 31% of patients progressed to end-stage kidney disease and the remaining 69% had persistently reduced kidney function.

Limitations: Retrospective nature. Blinded pathology evaluations were not performed.

Conclusions: The congophilic properties of organized fibrillary deposits should not be solely relied on in differentiating fibrillary GN from renal amyloidosis. Mass spectrometry and DNAJB9 immunohistochemistry can be useful in making this distinction.
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http://dx.doi.org/10.1053/j.ajkd.2018.03.017DOI Listing
September 2018

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft.

Kidney Int 2018 07 30;94(1):159-169. Epub 2018 Apr 30.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

The characteristics of allograft proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) are not well defined. To better characterize this disease we retrospectively identified 26 patients with allograft PGNMID, including 16 followed with early protocol biopsies. PGNMID was found to be a recurrent disease in most (89%) patients. A diagnostic biopsy was done for proteinuria and/or increased creatinine in most patients. Median time from transplant to diagnostic biopsy was 5.5 months, with detection within three to four months post-transplant in 86% of patients. Mesangial proliferative glomerulonephritis was the most common pattern on the diagnostic biopsy with 89% of cases showing immunoglobulin G3 subtype restriction. A detectable serum paraprotein was present in 20% of patients. During a mean follow up of 87 months from implantation, 11 of 25 patients lost their allograft largely due to PGNMID within a mean of 36 months from diagnosis. Median graft survival was 92 months. Independent predictors of graft loss were a higher degree of peak proteinuria and longer time from implantation to diagnosis. Sixteen patients were treated with immunosuppressive therapy which resulted in over 50% reduction in proteinuria in 60%, and improvement of glomerular pathology in nine of 13 patients. However, 44% of responders subsequently relapsed. Thus, PGNMID has a high recurrence rate in renal allografts occurring early with detection enhanced by protocol biopsies. Graft outcome is guarded as nearly half of patients lose their graft within three years from diagnosis. Hence, there is a need for better treatment strategies for this disease.
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http://dx.doi.org/10.1016/j.kint.2018.01.028DOI Listing
July 2018

Recurrent IgG4-related tubulointerstitial nephritis concurrent with chronic active antibody mediated rejection: A case report.

Am J Transplant 2018 07 24;18(7):1799-1803. Epub 2018 Apr 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

IgG4-related disease is a relatively newly described entity that can affect nearly any organ, including the kidneys, where it usually manifests as tubulointerstitial nephritis (IgG4-TIN). The diagnosis can be suggested by characteristic histological features, including an inflammatory infiltrate with increased IgG4-positive plasma cells associated with "storiform" fibrosis. Serum IgG4 is usually elevated. In the native kidney and other organs, there is typically a brisk response to treatment with immunosuppression. Recurrence of IgG4-TIN after renal transplant has not been described in the literature. Here, we describe the first case of recurrent IgG4-TIN in a young patient concomitant with chronic active antibody mediated rejection five years after kidney transplant. Recurrent IgG4-TIN could be diagnosed by the characteristic histopathologic features and increased IgG4-positive plasma cells. Despite maintenance immunosuppression, this disease may recur in the kidney allograft.
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http://dx.doi.org/10.1111/ajt.14758DOI Listing
July 2018

DNAJB9 Is a Specific Immunohistochemical Marker for Fibrillary Glomerulonephritis.

Kidney Int Rep 2018 Jan 8;3(1):56-64. Epub 2017 Aug 8.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Fibrillary glomerulonephritis (FGN) is a rare disease with unknown pathogenesis and a poor prognosis. Until now, the diagnosis of this disease has required demonstration of glomerular deposition of randomly oriented fibrils by electron microscopy that are Congo red negative and stain with antisera to Igs. We recently discovered a novel proteomic tissue biomarker for FGN, namely, DNAJB9.

Methods: In this work, we developed DNAJB9 immunohistochemistry and tested its sensitivity and specificity for the diagnosis of FGN. This testing was performed on renal biopsy samples from patients with FGN (n = 84), amyloidosis (n = 21), a wide variety of non-FGN glomerular diseases (n = 98), and healthy subjects (n = 11). We also performed immunoelectron microscopy to determine whether DNAJB9 is localized to FGN fibrils.

Results: Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without κ or λ) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules.

Conclusion: DNAJB9 immunohistochemistry is sensitive and specific for FGN. Incorporation of this novel immunohistochemical biomarker into clinical practice will now allow more rapid and accurate diagnosis of this disease.
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http://dx.doi.org/10.1016/j.ekir.2017.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762944PMC
January 2018

Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment.

Kidney Int 2018 05 19;93(5):1175-1182. Epub 2017 Dec 19.

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age.
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http://dx.doi.org/10.1016/j.kint.2017.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911429PMC
May 2018

Histologic regression of fibrillary glomerulonephritis: the first report of biopsy-proven spontaneous resolution of disease.

Clin Kidney J 2017 Dec 5;10(6):738-741. Epub 2017 Jun 5.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Fibrillary glomerulonephritis (FGN) is a rare immune complex type glomerulonephritis characterized by glomerular deposition of randomly oriented fibrils measuring 10-30 nm in thickness, and typically presents with proteinuria with or without renal insufficiency and hematuria. We present a case in which a patient initially presented at age 41 years with nephrotic-range proteinuria and hypertension; a kidney biopsy showed FGN. The patient was treated with angiotensin receptor blockage only, without immunosuppression as per patient preference, and the level of protein in the urine improved. During the follow-up period of 17 years, the patient developed type 2 diabetes mellitus. The patient re-presented with nephrotic-range proteinuria 17 years later, at the age of 58 years. A kidney biopsy was performed and showed diffuse diabetic glomerulosclerosis with secondary focal segmental glomerulosclerosis and related vascular changes. There was no evidence of FGN by immunofluorescence or electron microscopy. Although FGN has been rarely reported to regress clinically, this is the first documented case of histologic regression of FGN. The potential for FGN fibrils to regress spontaneously is important in the management of FGN patients considering that currently available immunosuppressive agents have limited efficacy, and is an encouraging finding for future studies aiming to find a cure for the disease.
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http://dx.doi.org/10.1093/ckj/sfx045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716195PMC
December 2017

IgG4-Related Tubulointerstitial Nephritis.

Adv Chronic Kidney Dis 2017 03;24(2):94-100

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory disorder that can involve nearly any organ. The disorder has increasingly become known as a distinct clinical entity during the last decade. IgG4-related tubulointerstitial nephritis (IgG4-TIN) is the most common manifestation of IgG4-RD in the kidney. Many patients with IgG4-TIN are diagnosed after IgG4-RD has been recognized in other organ systems, but the kidney may also be the first or only site involved. The presenting clinical features of IgG4-TIN are most commonly kidney insufficiency, kidney mass lesion(s), or both. On biopsy, IgG4-TIN shows a dense lymphoplasmacytic infiltrate, increased IgG4+ plasma cells, storiform fibrosis, and often tubular basement membrane immune complex deposits. Elevation of serum IgG4 often accompanies IgG4-RD; however, it is not specific in reaching the diagnosis. Like IgG4-RD in other organs, IgG4-TIN characteristically responds promptly to steroids, although there is a high relapse rate on discontinuation of immunosuppression. The pathogenesis of IgG4-RD is not understood.
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http://dx.doi.org/10.1053/j.ackd.2016.12.001DOI Listing
March 2017

Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome.

Kidney Int Rep 2017 Jan 29;2(1):44-52. Epub 2016 Sep 29.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children.

Methods: To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood).

Results: All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse.

Discussion: Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.
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http://dx.doi.org/10.1016/j.ekir.2016.09.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678677PMC
January 2017

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Kidney Int 2016 09 7;90(3):638-47. Epub 2016 Jun 7.

Divison of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.
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http://dx.doi.org/10.1016/j.kint.2016.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983464PMC
September 2016

Early subclinical inflammation correlates with outcomes in positive crossmatch kidney allografts.

Clin Transplant 2016 08 22;30(8):925-33. Epub 2016 Jun 22.

Division of Transplantation Surgery, Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.

The aim of this study was to investigate correlations between early subclinical findings (10- and 90-day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). We compared 34 +XMKTx (19 receiving eculizumab and 15 receiving standard of care without eculizumab) to 13 -XMKTx (between August 2001 and August 2011). At 10 days, light microscopy identified subclinical inflammation in only 18% of +XMKTx, while intragraft gene expression identified inflammation in 79% (gene sets for activated macrophages, dendritic cells, NK cells or T cells). Inflammation persisted at 90 days and was associated with the development of transplant glomerulopathy by 2 years and graft loss. In contrast, endothelial cell (EC) changes present at 90 days by either electron microscopy or gene expression were not associated with transplant glomerulopathy or graft loss in this cohort. Eculizumab treatment did not appear to alter inflammation or EC changes. Therefore, intragraft inflammation might be an appropriate surrogate marker of progression and also a target of therapy to prevent chronic antibody-mediated rejection.
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http://dx.doi.org/10.1111/ctr.12766DOI Listing
August 2016