Publications by authors named "Serena Bagnasco"

62 Publications

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

Pediatr Nephrol 2021 Mar 1. Epub 2021 Mar 1.

Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging.

Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes.

Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features.

Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
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http://dx.doi.org/10.1007/s00467-021-04990-4DOI Listing
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

Low-Level Proteinuria in Systemic Lupus Erythematosus.

Kidney Int Rep 2020 Dec 18;5(12):2333-2340. Epub 2020 Sep 18.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: In patients with systemic lupus erythematosus (SLE) without concurrent active urinary sediment or unexplained acute kidney injury (AKI), current guidelines recommend performing a kidney biopsy in those with at least 500 mg/24-hour (European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA]) or 1000 mg/24-hour (American College of Rheumatology [ACR]) proteinuria. To evaluate the relevance of these indications, we studied histopathologic findings in patients with SLE with proteinuria below these cutoffs.

Methods: We retrospectively reviewed the clinical, laboratory and histological characteristics of patients with SLE with <1000 mg/24-hour proteinuria (or mg/g urinary protein-to-creatinine ratio [UPCR]) who underwent their first kidney biopsy between 2003 and 2018.

Results: We identified 87 patients with SLE with proteinuria less than 1000 mg/24-hour (or mg/g UPCR); 52 of 87 (60%) with isolated proteinuria, that is, without AKI or active urinary sediment (hematuria). Histologic evidence of lupus nephritis (LN) was present in 40 of 52 (76%). Of the 40 patients with LN, 12 had class I or II, 14 had class III or IV, 8 had class V, 6 had a combined proliferative and membranous LN. Non-lupus diagnoses included focal segmental glomerulosclerosis, acute interstitial nephritis, and others. Patient's age, low C3, low C4, and positivity for anti-double-stranded DNA (anti-dsDNA) antibodies predicted the histological diagnosis of LN on univariate logistic regression; however, a multivariate model including these parameters as independent covariates failed to predict LN.

Conclusions: Patients with SLE with low-level proteinuria may have significant lupus- or non-lupus-related kidney disease with management implications. There was a significant burden of severe forms of LN. The presence of LN was not predicted by laboratory abnormalities. Based on our findings, we suggest current guidelines be revised to expand kidney biopsy indications to include isolated proteinuria of any grade.
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http://dx.doi.org/10.1016/j.ekir.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710831PMC
December 2020

A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action.

Am J Transplant 2020 Jul 23. Epub 2020 Jul 23.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

HIV-positive donor to HIV-positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV-negative donor to HIV+ recipient (HIV D-/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D- (22 recipients from D- with false positive HIV tests). Median follow-up was 1.7 years. There were no deaths nor differences in 1-year graft survival (91% D+ vs 92% D-, P = .9), 1-year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D-, P = .31), HIV breakthrough (4% D+ vs 6% D-, P > .99), infectious hospitalizations (28% vs 26%, P = .85), or opportunistic infections (16% vs 12%, P = .72). One-year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84-3.95, P = .13) but did not reach statistical significance; rejection was lower with lymphocyte-depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21-0.87, P = .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D-/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation.
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http://dx.doi.org/10.1111/ajt.16205DOI Listing
July 2020

ANCA-associated pauci-immune necrotizing glomerulonephritis during the treatment with pembrolizumab.

Virchows Arch 2020 Jul 21. Epub 2020 Jul 21.

Renal Pathology Department, Faculty of Medicine, Medical School of Johns Hopkins University, Baltimore, MD, USA.

Cancer immunotherapy is rapidly changing the treatment paradigm in oncology, and immune checkpoint inhibitors (ICPIs) have been used successfully in a variety of cancer types. Specific side effects termed immune-related adverse events (irAEs) have now been described in various organ systems, including the kidney. Renal complications have rarely been reported compared with other irAEs and mostly consist of acute interstitial nephritis. Only rare cases of ICPI-related glomerulonephritis have been described. Herein, we report the case of an adult patient treated with pembrolizumab (anti-PD-1) for squamous cell carcinoma (SCC), who developed infectious enterocolitis, and ANCA-related with diffuse necrotizing crescentic glomerulonephritis, both conditions potentially linked to treatment with pembrolizumab.
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http://dx.doi.org/10.1007/s00428-020-02882-wDOI Listing
July 2020

Kidney Involvement in COVID-19: Need for Better Definitions.

J Am Soc Nephrol 2020 09 9;31(9):2224-2225. Epub 2020 Jul 9.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1681/ASN.2020050630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461668PMC
September 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

BK Virus RNA in Renal Allograft Biopsies.

J Histochem Cytochem 2020 05 30;68(5):319-325. Epub 2020 Apr 30.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC ( = 0.65, 0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.
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http://dx.doi.org/10.1369/0022155420922604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226623PMC
May 2020

Renal crystal-storing histiocytosis involving glomeruli - A comprehensive clinicopathologic analysis.

Ann Diagn Pathol 2019 Dec 29;43:151403. Epub 2019 Aug 29.

Renal Pathology, Department of Pathology, Johns Hopkins University and Johns Hopkins Hospital, Baltimore, MD 21287, USA. Electronic address:

Crystal-storing histiocytosis (CSH) is a rare manifestation of monoclonal gammopathy in which histiocytes containing monoclonal proteins in their cytoplasm are found in various organs of the body including the kidney. Within the kidney, these monoclonal crystal-laden histiocytes have been described to occur in the interstitium (most commonly) or in the glomerular mesangium. CSH within glomerular capillary loops has rarely been reported. We describe three cases of CSH primarily affecting the glomerular capillaries and review the literature of CSH in general. Twenty cases of CSH involving the kidney are present in the literature; three describe CSH in glomeruli, only one of which showed histiocytes predominantly in glomerular capillary loops, while 15 had predominantly or solely interstitial CSH. Most cases involve IgG kappa crystals with only one case involving lambda light chain. Patients with CSH predominantly involving the glomerular capillaries showed a trend toward lower serum creatinine and proteinuria at presentation, and several patients with CSH lacked a definitive diagnosis of a monoclonal gammopathy at the time of diagnosis, emphasizing the role that kidney biopsy and particularly electron microscopy play in diagnosis of this entity.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.151403DOI Listing
December 2019

Biomarkers of Chronic Renal Tubulointerstitial Injury.

J Histochem Cytochem 2019 09 26;67(9):633-641. Epub 2019 Jun 26.

Department of Pathology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.

Progression of renal parenchyma injury is characterized by increasing interstitial fibrosis and tubular atrophy, irrespective of the cause. Histopathologic assessment of renal tissue obtained by biopsy remains the gold standard for determining the presence and extent of tubulointerstitial scarring. Discovery of robust non-invasive means for capturing a snapshot and for longitudinal monitoring of parenchymal deterioration has been the focus of intense multimodal effort by investigators within the renal community and beyond. Research in this field has included the use of in vitro and in vivo experimental models and has fostered the development and evaluation of tissue and biofluid assays for novel analytes with potential translation to the diagnosis and prognosis of kidney disease. Here, we examine recent advances in the search of "biomarkers" for detection of renal tubulointerstitial scarring and prediction of renal outcome in human renal disease.
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http://dx.doi.org/10.1369/0022155419861092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713977PMC
September 2019

Microvascular inflammation in renal allograft biopsies assessed by endothelial and leukocyte co-immunostain: a retrospective study on reproducibility and clinical/prognostic correlates.

Transpl Int 2019 03 11;32(3):300-312. Epub 2018 Dec 11.

Renal Pathology Service, Johns Hopkins University, Baltimore, MD, USA.

The most prominent histologic lesion in antibody-mediated rejection is microvascular inflammation (MVI); however, its recognition and scoring can be challenging and poorly reproducible between pathologists. We developed a dual immunohistochemical (IHC)-stain (anti-CD34/anti-CD45 for endothelium/leukocytes) as ancillary tool to improve on the semi-quantitative Banff scores and allow quantification of MVI. We examined the relationship between CD34-CD45 IHC-based quantitative MVI score (the inflamed peritubular capillary ratio, iptcr) and renal-graft failure or donor-specific antibodies (DSA) strength at the time of biopsy. Quantitative iptcr score was significantly associated with renal graft failure (hazard ratio 1.81, per 1 SD-unit [0.13 points] of iptcr-increase; P = 0.026) and predicted the presence and strength of DSA (ordinal odds ratio: 2.42; P = 0.005; 75 biopsies/60 kidney transplant recipients; 30 HLA- and/or ABO-incompatible). Next, we assessed inter-pathologist agreement for ptc score and ptc extent (focal/diffuse) using CD34-CD45 IHC as compared to conventional stain. Compared to conventional stain, CD34-CD45 IHC significantly increased inter-pathologist agreement on ptc score severity and extent (κ-coefficient from 0.52-0.80 and 0.46-0.68, respectively, P < 0.001). Our findings show that CD34-CD45 IHC improves reproducibility of MVI scoring and facilitates MVI quantification and introduction of a dual anti-CD34/CD45 has the potential to improve recognition of MVI ahead of DSA results.
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http://dx.doi.org/10.1111/tri.13371DOI Listing
March 2019

Beyond the microscope: interpreting renal biopsy findings in the era of precision medicine.

Am J Physiol Renal Physiol 2018 12 3;315(6):F1652-F1655. Epub 2018 Oct 3.

Department of Pathology, Johns Hopkins School of Medicine , Baltimore, Maryland.

As rapid progress in science and biotechnology is affecting the practice of renal medicine, increasingly precise diagnostic assessment is needed to select the most effective therapeutic approach for individual patients. The kidney biopsy remains the gold standard for the diagnosis of renal disease, but the field of renal pathology is evolving, classification of renal parenchyma lesions and histopathological diagnostic criteria are undergoing more validation and updates, and new technologies and assays are sought to improve efficiency and accuracy of the diagnostic process. How new knowledge and scientific advances may potentially affect renal pathology is discussed.
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http://dx.doi.org/10.1152/ajprenal.00407.2018DOI Listing
December 2018

Transfusion of leukoreduced blood products and risk of antibody-mediated rejection of renal allografts.

Transfusion 2018 08 1;58(8):1951-1957. Epub 2018 Sep 1.

Department of Pathology.

Background: Antibody-mediated rejection (AMR) is a major barrier to the long-term function of renal allografts. White blood cells, which may be present in red blood cell (RBC) units, and platelets (PLTs) express HLA antigens that may increase the risk of AMR by inducing or increasing humoral sensitization to HLA.

Study Design And Methods: A retrospective cohort study of HLA-incompatible (HLAi) renal transplant recipients between 2004 and 2015 was conducted. Data on apheresis PLT and leukoreduced RBC transfusions within 4 weeks of transplantation, demographic information, and biopsy-proven AMR were collected from medical records and the Scientific Registry of Transplant Recipients. Patients were evaluated until they showed evidence of AMR or until 1 year posttransplant, whichever came first. Multivariable analysis with Cox modeling was performed.

Results: Of 244 individuals, 182 (74.6%) received RBCs and 20 (8.2%) of those also received PLTs. During the first year posttransplant, 97 (39.8%) had AMR. RBC-alone or RBC and PLT transfusions were not associated with increased risk of AMR after adjustment for panel-reactive antibody, years on dialysis, HLA antibody strength, and number of therapeutic plasma exchange treatments (adjusted hazard ratio [adjHR] 1.00, 95% confidence interval [95% CI] 0.59-1.69; and adjHR 0.68, 95% CI 0.28-1.68, respectively). For each 1-unit increase in RBC transfusions, there was no association with AMR (adjHR 0.94, 95% CI 0.85-1.05). Only HLA antibody strength before transplantation was associated with AMR (adjHR 2.23, 95% CI 1.10-4.52; cytotoxic crossmatch compared to crossmatch negative but detectable donor-specific HLA antibodies).

Conclusions: Patients who receive an HLAi transplant who are transfused with leukoreduced RBCs or PLTs in the peritransplant period are at no higher risk of AMR than nontransfused patients.
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http://dx.doi.org/10.1111/trf.14800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131050PMC
August 2018

Raman Spectroscopy for the Diagnosis of Intratubular Triamterene Crystallization.

Kidney Int Rep 2018 Jul 23;3(4):997-1003. Epub 2018 Mar 23.

Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1016/j.ekir.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035282PMC
July 2018

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

Am J Transplant 2019 01 19;19(1):123-131. Epub 2018 Jul 19.

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

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.
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http://dx.doi.org/10.1111/ajt.14979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309659PMC
January 2019

Reproducibility and Feasibility of Strategies for Morphologic Assessment of Renal Biopsies Using the Nephrotic Syndrome Study Network Digital Pathology Scoring System.

Arch Pathol Lab Med 2018 May 19;142(5):613-625. Epub 2018 Feb 19.

From Biostatistics, Arbor Research Collaborative for Health, Ann Arbor, Michigan (Dr Zee); the Departments of Pathology (Dr Hodgin), Internal Medicine (Dr Mariani), and Biostatistics (Dr Gillespie), University of Michigan, Ann Arbor; Arbor Research Collaborative for Health, Ann Arbor, Michigan (Dr Mariani); the Department of Pathology & Immunology, Washington University, St Louis, Missouri (Dr Gaut); the Departments of Pathology and Laboratory Medicine (Dr Palmer) and Medicine (Dr. Holzman), University of Pennsylvania, Philadelphia; the Department of Pathology, Johns Hopkins University, Baltimore, Maryland (Drs Bagnasco and Rosenberg); the Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (Dr Rosenberg); the Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland (Dr Hewitt); and the Department of Pathology, University of Miami, Miami, Florida (Dr Barisoni).

Context Testing reproducibility is critical for the development of methodologies for morphologic assessment. Our previous study using the descriptor-based Nephrotic Syndrome Study Network Digital Pathology Scoring System (NDPSS) on glomerular images revealed variable reproducibility. Objective To test reproducibility and feasibility of alternative scoring strategies for digital morphologic assessment of glomeruli and explore use of alternative agreement statistics. Design The original NDPSS was modified (NDPSS1 and NDPSS2) to evaluate (1) independent scoring of each individual biopsy level, (2) use of continuous measures, (3) groupings of individual descriptors into classes and subclasses prior to scoring, and (4) indication of pathologists' confidence/uncertainty for any given score. Three and 5 pathologists scored 157 and 79 glomeruli using the NDPSS1 and NDPSS2, respectively. Agreement was tested using conventional (Cohen κ) and alternative (Gwet agreement coefficient 1 [AC]) agreement statistics and compared with previously published data (original NDPSS). Results Overall, pathologists' uncertainty was low, favoring application of the Gwet AC. Greater agreement was achieved using the Gwet AC compared with the Cohen κ across all scoring methodologies. Mean (standard deviation) differences in agreement estimates using the NDPSS1 and NDPSS2 compared with the single-level original NDPSS were -0.09 (0.17) and -0.17 (0.17), respectively. Using the Gwet AC, 79% of the original NDPSS descriptors had good or excellent agreement. Pathologist feedback indicated the NDPSS1 and NDPSS2 were time-consuming. Conclusions The NDPSS1 and NDPSS2 increased pathologists' scoring burden without improving reproducibility. Use of alternative agreement statistics was strongly supported. We suggest using the original NDPSS on whole slide images for glomerular morphology assessment and for guiding future automated technologies.
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http://dx.doi.org/10.5858/arpa.2017-0181-OADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946059PMC
May 2018

Pre-transplant Screening for Non-HLA Antibodies: Who should be Tested?

Hum Immunol 2018 Apr 8;79(4):195-202. Epub 2018 Feb 8.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009-2013 criteria. AT1R-Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p < 0.0001), males (p = 0.008) and those with FSGS (p = 0.04) and younger (p = 0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p < 0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126 days versus 368 days respectively; p = 0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community.
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http://dx.doi.org/10.1016/j.humimm.2018.02.001DOI Listing
April 2018

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

J Am Soc Nephrol 2018 02 17;29(2):620-635. Epub 2017 Oct 17.

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

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (, , , , and ) indicative of endothelial activation, IFN response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; =0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.
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http://dx.doi.org/10.1681/ASN.2017050589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791056PMC
February 2018

Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies.

Nephrol Dial Transplant 2018 02;33(2):310-318

Johns Hopkins University, Baltimore, MD, USA.

Background: Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies.

Methods: We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria.

Results: IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis.

Conclusions: The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.
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http://dx.doi.org/10.1093/ndt/gfw443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837529PMC
February 2018

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies.

PLoS One 2016 16;11(6):e0156441. Epub 2016 Jun 16.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

Background: In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment.

Design: We reviewed 277 biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository, enumerating 9,379 glomeruli by means of whole slide imaging. Glomerular number and the percentage of globally sclerotic glomeruli are values routinely recorded in the official renal biopsy pathology report from the 25 participating centers. Two general trends in reporting were noted: total number per biopsy or average number per level/section. Both of these approaches were assessed for their accuracy in comparison to the analogous numbers of annotated glomeruli on WSI.

Results: The number of glomeruli annotated was consistently higher than those reported (p<0.001); this difference was proportional to the number of glomeruli. In contrast, percent globally sclerotic were similar when calculated on total glomeruli, but greater in FSGS when calculated on average number of glomeruli (p<0.01). The difference in percent globally sclerotic between annotated and those recorded in pathology reports was significant when global sclerosis is greater than 40%.

Conclusions: Although glass slides were not available for direct comparison to whole slide image annotation, this study indicates that routine manual light microscopy assessment of number of glomeruli is inaccurate, and the magnitude of this error is proportional to the total number of glomeruli.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911144PMC
July 2017

Morphometry Predicts Early GFR Change in Primary Proteinuric Glomerulopathies: A Longitudinal Cohort Study Using Generalized Estimating Equations.

PLoS One 2016 10;11(6):e0157148. Epub 2016 Jun 10.

Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.

Objective: Most predictive models of kidney disease progression have not incorporated structural data. If structural variables have been used in models, they have generally been only semi-quantitative.

Methods: We examined the predictive utility of quantitative structural parameters measured on the digital images of baseline kidney biopsies from the NEPTUNE study of primary proteinuric glomerulopathies. These variables were included in longitudinal statistical models predicting the change in estimated glomerular filtration rate (eGFR) over up to 55 months of follow-up.

Results: The participants were fifty-six pediatric and adult subjects from the NEPTUNE longitudinal cohort study who had measurements made on their digital biopsy images; 25% were African-American, 70% were male and 39% were children; 25 had focal segmental glomerular sclerosis, 19 had minimal change disease, and 12 had membranous nephropathy. We considered four different sets of candidate predictors, each including four quantitative structural variables (for example, mean glomerular tuft area, cortical density of patent glomeruli and two of the principal components from the correlation matrix of six fractional cortical areas-interstitium, atrophic tubule, intact tubule, blood vessel, sclerotic glomerulus, and patent glomerulus) along with 13 potentially confounding demographic and clinical variables (such as race, age, diagnosis, and baseline eGFR, quantitative proteinuria and BMI). We used longitudinal linear models based on these 17 variables to predict the change in eGFR over up to 55 months. All 4 models had a leave-one-out cross-validated R2 of about 62%.

Conclusions: Several combinations of quantitative structural variables were significantly and strongly associated with changes in eGFR. The structural variables were generally stronger than any of the confounding variables, other than baseline eGFR. Our findings suggest that quantitative assessment of diagnostic renal biopsies may play a role in estimating the baseline risk of succeeding loss of renal function in future clinical studies, and possibly in clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157148PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902229PMC
July 2017

Anti-Angiotensin II Type 1 Receptor and Anti-Endothelial Cell Antibodies: A Cross-Sectional Analysis of Pathological Findings in Allograft Biopsies.

Transplantation 2017 03;101(3):608-615

1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. 3 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. 4 Clinic of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charite, Berlin, Germany.

Background: This is a cross-sectional study designed to evaluate the histologic characteristics of graft injury in the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA).

Methods: Non-HLA antibody testing was included in the posttransplant evaluation for 70 kidney recipients. Biopsies were performed for cause for 47 patients and as protocol for the remaining 23 patients. Biopsy-proven rejection was defined according to the Banff 2009-2013 criteria. AT1R-Ab was measured on an ELISA platform. Patients were divided into 3 groups based on AT1R-Ab levels (>17, 10-17, and <10 U/ml). AECA was evaluated using an endothelial cell crossmatch (ECXM) in patients whose HLA antibody level was insufficient to cause a positive flow cytometric crossmatch.

Results: AT1R-Ab levels were higher in patients diagnosed with antibody mediated rejection compared to those with no rejection (P = 0.004). Glomerulitis (g) and peritubular capillaritis (ptc) scores were independently correlated with increased AT1R-Ab concentrations in the presence or absence of HLA-DSA (P = 0.007 and 0.03 for g scores; p = 0.005 and 0.03 for ptc scores). Patients with a positive ECXM had higher AT1R-Ab levels compared to those with a negative ECXM (P = 0.005). Microcirculation inflammation (MCI = g + ptc score) was higher in patients with a positive ECXM and with AT1R-Ab >17 U/ml, although this did not reach statistical significance (P = 0.07).

Conclusions: The data show an association between non-HLA antibodies detected in the ECXM and AT1R ELISA and microvascular injury observed in antibody mediated rejection.
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http://dx.doi.org/10.1097/TP.0000000000001231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319389PMC
March 2017

Renal Thrombotic Microangiopathy, Podocytopathy, and Chylous Ascites: A Hard-Nosed Diagnosis.

Am J Med 2016 Oct 3;129(10):e227-31. Epub 2016 May 3.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Md.

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http://dx.doi.org/10.1016/j.amjmed.2016.04.011DOI Listing
October 2016

Long-term Renal Function in Living Kidney Donors Who Had Histological Abnormalities at Donation.

Transplantation 2016 06;100(6):1294-8

1 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD. 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors.

Methods: We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor.

Results: Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P < 0.01).

Conclusions: In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.
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http://dx.doi.org/10.1097/TP.0000000000001236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820762PMC
June 2016

Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images.

Mod Pathol 2016 07 22;29(7):671-84. Epub 2016 Apr 22.

Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.

The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen's kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40
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http://dx.doi.org/10.1038/modpathol.2016.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515468PMC
July 2016

Complete Remission in the Nephrotic Syndrome Study Network.

Clin J Am Soc Nephrol 2016 Jan 10;11(1):81-9. Epub 2015 Dec 10.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever).

Design, Setting, Participants, & Measurements: We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever.

Results: We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis.

Conclusions: In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.
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http://dx.doi.org/10.2215/CJN.02560315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702222PMC
January 2016

Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.

Sci Transl Med 2015 Dec;7(316):316ra193

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.
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http://dx.doi.org/10.1126/scitranslmed.aac7071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861144PMC
December 2015

Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature.

Medicine (Baltimore) 2015 Aug;94(32):e1366

From the Division of Nephrology (BAM, PJS, MGA); Osler Medical Residency Program (TN); and Division of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (SB).

Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported.We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size.This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis.
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http://dx.doi.org/10.1097/MD.0000000000001366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616672PMC
August 2015

Peritubular capillaritis in the renal allograft takes center stage.

Kidney Int 2015 Aug;88(2):218-20

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Capillaritis in the renal allograft is important for diagnosis and prognosis. Although glomerulitis has been well studied, peritubular capillaritis has been defined only relatively recently. The finding that peritubular capillaritis severity score and extent may correlate independently with graft outcome mandates further prospective studies to confirm this finding, and to enhance recognition and quantitation of this important lesion.
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http://dx.doi.org/10.1038/ki.2015.99DOI Listing
August 2015