Publications by authors named "Lorraine Racusen"

86 Publications

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

A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.

Transplantation 2018 11;102(11):1795-1814

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
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http://dx.doi.org/10.1097/TP.0000000000002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597974PMC
November 2018

Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

Physiol Rep 2017 Nov;5(20)

Department of Physiology, The Women's Health Research Center University of Mississippi Medical Center, Jackson, Mississippi

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22-25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT-treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule-1 (KIM-1), than did age-matched controls. In addition, DHT-treated-old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT-treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age.
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http://dx.doi.org/10.14814/phy2.13461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661229PMC
November 2017

A proposal for standardized grading of chronic changes in native kidney biopsy specimens.

Kidney Int 2017 04;91(4):787-789

Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade.
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http://dx.doi.org/10.1016/j.kint.2017.01.002DOI Listing
April 2017

Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.

Clin J Am Soc Nephrol 2016 Feb 14;11(2):262-70. Epub 2015 Dec 14.

Departments of Medicine and.

Background And Objectives: Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors.

Design, Setting, Participants, & Measurements: In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation.

Results: The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology.

Conclusions: APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.
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http://dx.doi.org/10.2215/CJN.07490715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741048PMC
February 2016

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.

J Am Soc Nephrol 2016 May 13;27(5):1278-87. Epub 2015 Nov 13.

Mayo Clinic, Rochester, Minnesota.

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN.
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http://dx.doi.org/10.1681/ASN.2015060612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849835PMC
May 2016

T Lymphocyte-Specific Activation of Nrf2 Protects from AKI.

J Am Soc Nephrol 2015 Dec 20;26(12):2989-3000. Epub 2015 Aug 20.

Division of Nephrology, Department of Medicine and

T lymphocytes are established mediators of ischemia reperfusion (IR)-induced AKI, but traditional immune principles do not explain their mechanism of early action in the absence of alloantigen. Nrf2 is a transcription factor that is crucial for cytoprotective gene expression and is generally thought to have a key role in dampening IR-induced AKI through protective effects on epithelial cells. We proposed an alternative hypothesis that augmentation of Nrf2 in T cells is essential to mitigate oxidative stress during IR-induced AKI. We therefore generated mice with genetically amplified levels of Nrf2 specifically in T cells and examined the effect on antioxidant gene expression, T cell activation, cytokine production, and IR-induced AKI. T cell-specific augmentation of Nrf2 significantly increased baseline antioxidant gene expression. These mice had a high frequency of intrarenal CD25(+)Foxp3(+) regulatory T cells and decreased frequencies of CD11b(+)CD11c(+) and F4/80(+) cells. Intracellular levels of TNF-α, IFN-γ, and IL-17 were significantly lower in CD4(+) T cells with high Nrf2 expression. Mice with increased T cell expression of Nrf2 were significantly protected from functional and histologic consequences of AKI. Furthermore, adoptive transfer of high-Nrf2 T cells protected wild-type mice from IR injury and significantly improved their survival. These data demonstrate that T cell-specific activation of Nrf2 protects from IR-induced AKI, revealing a novel mechanism of tissue protection during acute injury responses.
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http://dx.doi.org/10.1681/ASN.2014100978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657838PMC
December 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

Renal allograft rejection: pieces of the puzzle.

J Am Soc Nephrol 2015 May 7;26(5):1004-5. Epub 2014 Nov 7.

Department of Nephrology and Transplantation, Saint-Louis Hospital, Paris, France.

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http://dx.doi.org/10.1681/ASN.2014090932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413772PMC
May 2015

Sarcoidosis in native and transplanted kidneys: incidence, pathologic findings, and clinical course.

PLoS One 2014 20;9(10):e110778. Epub 2014 Oct 20.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.

Unlabelled: Renal involvement by sarcoidosis in native and transplanted kidneys classically presents as non caseating granulomatous interstitial nephritis. However, the incidence of sarcoidosis in native and transplant kidney biopsies, its frequency as a cause of end stage renal disease and its recurrence in renal allograft are not well defined, which prompted this study. The electronic medical records and the pathology findings in native and transplant kidney biopsies reviewed at the Johns Hopkins Hospital from 1/1/2000 to 6/30/2011 were searched. A total of 51 patients with a diagnosis of sarcoidosis and renal abnormalities requiring a native kidney biopsy were identified. Granulomatous interstitial nephritis, consistent with renal sarcoidosis was identified in kidney biopsies from 19 of these subjects (37%). This is equivalent to a frequency of 0.18% of this diagnosis in a total of 10,023 biopsies from native kidney reviewed at our institution. Follow-up information was available in 10 patients with biopsy-proven renal sarcoidosis: 6 responded to treatment with prednisone, one progressed to end stage renal disease. Renal sarcoidosis was the primary cause of end stage renal disease in only 2 out of 2,331 transplants performed. Only one biopsy-proven recurrence of sarcoidosis granulomatous interstitial nephritis was identified.

Conclusions: Renal involvement by sarcoidosis in the form of granulomatous interstitial nephritis was a rare finding in biopsies from native kidneys reviewed at our center, and was found to be a rare cause of end stage renal disease. However, our observations indicate that recurrence of sarcoid granulomatous inflammation may occur in the transplanted kidney of patients with sarcoidosis as the original kidney disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110778PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203836PMC
June 2015

Eculizumab and splenectomy as salvage therapy for severe antibody-mediated rejection after HLA-incompatible kidney transplantation.

Transplantation 2014 Oct;98(8):857-63

1 Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD. 2 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD. 3 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD. 4 Department of Surgery, University of Alabama, Birmingham, AL. 5 Address correspondence to: Robert Montgomery, M.D., DPhil, 720 Rutland Avenue, Ross 765, Baltimore, MD 21205.

Background: Incompatible live donor kidney transplantation is associated with an increased rate of antibody-mediated rejection (AMR) and subsequent transplant glomerulopathy. For patients with severe, oliguric AMR, graft loss is inevitable without timely intervention.

Methods: We reviewed our experience rescuing kidney allografts with this severe AMR phenotype by using splenectomy alone (n=14), eculizumab alone (n=5), or splenectomy plus eculizumab (n=5), in addition to plasmapheresis.

Results: The study population was 267 consecutive patients with donor-specific antibody undergoing desensitization. In the first 3 weeks after transplantation (median=6 days), 24 patients developed sudden onset oliguria and rapidly rising serum creatinine with marked rebound of donor-specific antibody, and a biopsy that showed features of AMR. At a median follow-up of 533 days, 4 of 14 splenectomy-alone patients experienced graft loss (median=320 days), compared to four of five eculizumab-alone patients with graft failure (median=95 days). No patients treated with splenectomy plus eculizumab experienced graft loss. There was more chronic glomerulopathy in the splenectomy-alone and eculizumab-alone groups at 1 year, whereas splenectomy plus eculizumab patients had almost no transplant glomerulopathy.

Conclusion: These data suggest that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.
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http://dx.doi.org/10.1097/TP.0000000000000298DOI Listing
October 2014

Risk for BK viremia and nephropathy after desensitization.

Transplantation 2014 Jul;98(2):e7-8

1 Department of Nephrology and Transplantation Queen Elizabeth Hospital Birmingham, United Kingdom 2 Department of Pathology Johns Hopkins School of MedicineBaltimore, MD 3 Department of SurgeryJohns Hopkins School of MedicineBaltimore, MD 4 Department of MedicineJohns Hopkins School of MedicineBaltimore, MD.

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http://dx.doi.org/10.1097/TP.0000000000000241DOI Listing
July 2014

Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies.

Transplantation 2014 Jun;97(12):1240-6

1 Department of Medicine, Virginia Commonwealth University, Richmond, VA. 2 Department of Medicine, University of Cincinnati, Cincinnati, OH. 3 Department of Pathology, Johns Hopkins University, Baltimore, MD. 4 Department of Medicine, Johns Hopkins University, Baltimore, MD. 5 Department of Pharmacy, Johns Hopkins Hospital, Baltimore, MD. 6 Department of Surgery, Johns Hopkins University, Baltimore, MD. 7 Address correspondence to: Nada Alachkar, MD, Johns Hopkins University School of Medicine, 600 Wolfe Street, Brady 502, Baltimore, MD 21287.

Background: Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR.

Methods: Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength.

Results: Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06).

Conclusions: A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.
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http://dx.doi.org/10.1097/01.TP.0000442503.85766.91DOI Listing
June 2014

Atypical hemolytic uremic syndrome recurrence after kidney transplantation.

Transplantation 2014 Dec;98(11):1205-12

1 Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD. 3 Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD. 4 Address correspondence to: Nada Alachkar, M.D., Johns Hopkins University School of Medicine, 600 Wolfe Street. Brady 502, Baltimore, MD 21287.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation.

Methods: In this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab.

Results: Overall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far.

Conclusion: Genetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.
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http://dx.doi.org/10.1097/TP.0000000000000200DOI Listing
December 2014

Solid organ transplant pathology: updates for a complex specialty.

Curr Opin Organ Transplant 2014 Jun;19(3):281-2

The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1097/MOT.0000000000000080DOI Listing
June 2014

Time course of pathologic changes in kidney allografts of positive crossmatch HLA-incompatible transplant recipients.

Transplantation 2014 Feb;97(4):440-5

1 Department of Pathology, Johns Hopkins University, Baltimore, MD. 2 Department of Medicine, Johns Hopkins University, Baltimore, MD. 3 Department of Surgery, Johns Hopkins University, Baltimore, MD. 4 Address correspondence to: Serena M. Bagnasco, M.D., Department of Pathology, Johns Hopkins University, Ross 632, 720 Rutland Avenue, Baltimore, MD 21205.

Background: Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression.

Methods: We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years).

Results: Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg≥1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P<0.0001 and P<0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g≥1 and ptc≥1) with detectable donor-specific antibodies was observed in some recipients (<20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P<0.001).

Conclusions: Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.
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http://dx.doi.org/10.1097/01.TP.0000437177.40551.f4DOI Listing
February 2014

Histologic phenotype on 1-year posttransplantation biopsy and allograft survival in HLA-incompatible kidney transplants.

Transplantation 2014 Mar;97(5):541-7

1 Renal Institute of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom. 2 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD. 3 Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD. 4 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD. 5 Address correspondence to: Robert Montgomery, Ph.D., Department of Surgery, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Ross Research 765, Baltimore, MD 21205.

Background: The correlation between histopathologic phenotypes and allograft outcomes among patients desensitized for donor-specific antibody (HLA-incompatible) is unknown.

Methods: We analyzed 1-year biopsies from desensitized recipients transplanted between 1999 and 2010 and estimated graft survival for each histologic phenotype identified. Median time posttransplant for the 1-year biopsy was 367 days (interquartile range 357-388 days) and median follow-up of all patients post-1-year biopsy was 42 months (interquartile range 19.5-65 months).

Results: Transplant glomerulopathy was present in 25.0% of biopsies and resulted in worse graft survival (66.7% vs. 96.7%, P<0.001). C4d positivity and transplant glomerulopathy together portended exceptionally poor graft survival (33.3% vs. 97.2%, P<0.001). Microcirculation inflammation was prevalent, with glomerulitis and peritubular capillaritis found in 60.0% and 47.6% of 1-year biopsies, respectively. Glomerulitis was associated with worse graft survival (82.1% vs. 98.1%, P=0.004), whereas capillaritis was not (88.1% vs. 97.7% respectively, P=0.091). Among C4d-negative HLA-incompatible recipients (82.6% of biopsies), no difference in graft survival was observed between patients with or without microcirculation inflammation in contrast to previous reports by other investigators. Patients who had no C4d deposition, transplant glomerulopathy, or microcirculation inflammation had a 100.0% graft survival. On Cox regression analysis, no independent histopathological parameter was associated with graft survival.

Conclusions: We have identified several histopathologic phenotypes in HLA-incompatible kidney recipients that correlate with allograft outcomes. Characterization of these phenotypes is the first step towards better understanding the pathophysiologic basis of chronic antibody-mediated allograft injury and individualizing therapeutic intervention.
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http://dx.doi.org/10.1097/01.TP.0000442513.27641.7eDOI Listing
March 2014

Validation of the new classification of pauci-immune glomerulonephritis in a United States cohort and its correlation with renal outcome.

BMC Nephrol 2013 Oct 4;14:210. Epub 2013 Oct 4.

Medicine, The Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland, USA.

Background: Renal biopsies provide important diagnostic and prognostic information in ANCA associated glomerulonephritis. A new classification for prognostication of pauci-immune glomerulonephritis (GN) based on four categories (Mixed, Crescentic, Sclerotic and Focal) was proposed by an international working group of renal pathologists (IWGRP). The goal of our study was to apply the proposed classification system to a United States cohort of vasculitis patients and determine the association of IWGRP class with estimated glomerular filtration rate (eGFR) at one year.

Methods: Seventy-six cases of pauci-immune glomerulonephritis diagnosed from 1995 to 2011 from a single center were identified for this retrospective study. Clinical data were collected by abstraction from medical records. Histology was reviewed by a pathologist and classified according to the new classification. MDRD formula was used to calculate eGFR. We correlated IWGRP class to renal function at presentation and at one year. ×2, ANOVA, and linear regression analysis were performed as appropriate.

Results: Renal biopsies were categorized as focal: n = 20, crescentic: n = 18, mixed: n = 27, sclerotic: n = 11. The baseline e-GFR was lowest in the crescentic class and highest in the focal class. In linear regression analysis investigating e-GFR at 1 year; age and baseline e-GFR were independent predictors of e-GFR at 1 year.

Conclusions: The e-GFR at diagnosis and age were predictors of e-GFR at 1 year. Pathologic class at diagnosis may also be a helpful tool in risk stratification at diagnosis.
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http://dx.doi.org/10.1186/1471-2369-14-210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819021PMC
October 2013

The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.

Kidney Int 2014 Jan 2;85(1):134-41. Epub 2013 Oct 2.

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

Acute kidney injury (AKI) caused by ischemia-reperfusion is a major clinical problem in both native and transplanted kidneys. We had previously shown that deficiency of Nrf2, a potent bZIP transcription factor that binds to the antioxidant response element, enhances susceptibility to experimental ischemic AKI. Here we further explored the role of Nrf2 in AKI by amplifying Nrf2 activation in vivo and in vitro with the synthetic triterpenoid CDDO-imidazolide. Mice treated with CDDO-imidazolide and undergoing experimental bilateral ischemic AKI had improved survival and renal function. Treated mice had improved renal histology with a decrease in tubular injury, as well as a decrease in proinflammatory cytokine and chemokine production compared with vehicle-treated mice. In an exploration of protective mechanisms, we found an upregulation of Nrf2 target antioxidant genes in CDDO-imidazolide-treated mouse kidneys. Furthermore, Nrf2-deficient mice treated with CDDO-imidazolide had no significant improvement in mortality, renal function or histology, proinflammatory cytokine gene expression, and no significant increase in antioxidant gene expression. In vitro studies demonstrated that the renal epithelial cells were likely an important target of CDDO-imidazolide. Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition.
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http://dx.doi.org/10.1038/ki.2013.357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282962PMC
January 2014

C1q-binding antibodies in kidney transplantation.

N Engl J Med 2013 Sep;369(13):1266-7

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http://dx.doi.org/10.1056/NEJMe1309686DOI Listing
September 2013

Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy.

Transplantation 2013 Oct;96(7):649-56

1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Medicine, Rush University Medical Center, Chicago, IL. 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. 4 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL. 5 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL. 6 Department of Medicine, Union Memorial Hospital, Baltimore, MD. 7 Address correspondence to: Nada Alachkar, M.D., Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 971, Baltimore, MD 21205 and Jochen Reiser, M.D., Ph.D., Department of Medicine, Rush University Medical Center, Cohn Research Building, Suite 724, 1735 W. Harrison Street, Chicago, IL 60612.

Background: Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30% of cases and can lead to allograft loss. Serum soluble urokinase-type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS.

Methods: We conducted a retrospective study of 25 adults with posttransplantation FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function, and resolution of histologic changes.

Results: A median (interquartile range) of 15 (10-23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pretreatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4806 pg/mL; P=0.02). Overall, mean±SD of proteinuria improved from 5.1±3.8 to 2.1±2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57%±33% to 22%±22% (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6-44.2) to 39.3 (28.8-63.4; P<0.0001), and suPAR levels decreased from a median of 6.781 to 4.129 pg/mL (P=0.02) with therapy.

Conclusions: Podocyte effacement is the first pathologic manifestation of FSGS after transplantation. The degree of podocyte effacement correlates with suPAR levels at time of diagnosis. Response to therapy results in significant reduction of suPAR levels and complete or significant improvement of podocyte effacement.
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http://dx.doi.org/10.1097/TP.0b013e31829eda4fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026282PMC
October 2013

The Banff classification revisited.

Kidney Int 2013 Feb 12;83(2):201-6. Epub 2012 Dec 12.

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

From small beginnings in 1991, the Banff working classification of renal allograft pathology has grown to be a major force for setting standards in renal transplant pathology, and is widely used in international clinical trials of new antirejection agents. The meeting, classification, and consensus process have unique history, and look poised to continue for another several decades as the embodiment of the process for setting global standards in pathology. The Banff meetings have expanded from renal allograft pathology to most other areas of solid organ transplantation, and increasingly incorporate international working groups, so that productive collaborative activity is ongoing, creating an important dynamic process enhancing clinical success in transplantation. On the other hand, despite the successes of the working classifications and ongoing collaborative efforts, there are limitations in this and other pathological classifications, related to potential for sampling error, issues of reproducibility when implemented globally, and lack of formal incorporation of morphometry and molecular and genomics approaches. Some of these problems cannot be overcome within the realm of traditional histopathology, and will only be solved when the classification is able to confidently embrace genomics and molecular medicine parameters for all common diagnoses. The smooth integration of these newer technologies with traditional histopathology is one of the great challenges for the future.
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http://dx.doi.org/10.1038/ki.2012.395DOI Listing
February 2013

Incidence and outcomes of BK virus allograft nephropathy among ABO- and HLA-incompatible kidney transplant recipients.

Clin J Am Soc Nephrol 2012 Aug 24;7(8):1320-7. Epub 2012 May 24.

Renal Institute of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.

Background And Objectives: ABO-incompatible kidney transplant recipients may have a higher incidence of BK virus allograft nephropathy (BKVAN) compared with ABO-compatible recipients. It is unclear whether HLA-incompatible recipients share this risk or whether this phenomenon is unique to ABO-incompatible recipients. DESIGN, SETTING, PARTICIPATION, MEASUREMENTS: This study analyzed adult incompatible kidney transplant recipients from 1998 to 2010 (62 ABO-incompatible and 221 HLA-incompatible) and identified patients in whom BKVAN was diagnosed by biopsy (per protocol or for cause). This was a retrospective analysis of a prospectively maintained database that compared BKVAN incidence and outcomes between ABO- and HLA-incompatible recipients, respectively. BKVAN link to rejection and graft accommodation phenotype were also explored. The Johns Hopkins Institutional Review Board approved this study.

Results: Risk for BKVAN was greater among ABO-incompatible than HLA-incompatible patients (17.7% versus 5.9%; P=0.008). Of BKVAN cases, 42% were subclinical, diagnosed by protocol biopsy. ABO-incompatibility and age were independent predictors for BKVAN on logistic regression. C4d deposition without histologic features of glomerulitis and capillaritis (graft accommodation-like phenotype) on 1-year biopsies of ABO-incompatible patients with and without BKVAN was 40% and 75.8%, respectively (P=0.04). Death-censored graft survival (91%) and serum creatinine level among surviving kidneys (1.8 mg/dl) were identical in ABO- and HLA-incompatible patients with BKVAN (median, 1399 and 1017 days after transplantation, respectively).

Conclusions: ABO-incompatible kidney recipients are at greater risk for BKVAN than HLA-incompatible kidney recipients. ABO-incompatible recipients not showing the typical graft accommodation-like phenotype may be at heightened risk for BKVAN, but this observation requires replication among other groups.
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http://dx.doi.org/10.2215/CJN.00770112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408120PMC
August 2012

HIV-associated nephropathy patients with and without apolipoprotein L1 gene variants have similar clinical and pathological characteristics.

Kidney Int 2012 Aug 11;82(3):338-43. Epub 2012 Apr 11.

Department of Medicine, Johns Hopkins Medical Center, Baltimore, MD 21205, USA.

Recently, an association was found between nondiabetic kidney disease in African Americans and two independent sequence variants in the APOL1 gene, encoding apolipoprotein L1. In this study we determined the frequency of APOL1 risk variants in patients with biopsy-proven HIV-associated nephropathy (HIVAN) and distinctive pathological characteristics potentially driven by those risk variants. Among 76 patients with HIVAN, 60 were successfully genotyped for APOL1 G1 and G2 polymorphisms. In this cohort, 37 had two risk alleles, 18 were heterozygous, and 5 had neither risk variant. There were no differences in the pathological findings of HIVAN and the number of APOL1 risk alleles. Further, the progression to end-stage kidney disease or death did not differ by the number of risk alleles. Median renal survival was 9.3 months in patients with zero or one risk allele compared to 11.7 months in patients with two APOL1 risk alleles. Thus, our study suggests that although the majority of African-American patients with HIVAN have two APOL1 risk alleles other as yet unknown factors in the host, including genetic risk variants and environmental or viral factors, may influence the development of this disorder in those with zero or one APOL1 risk allele.
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http://dx.doi.org/10.1038/ki.2012.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463138PMC
August 2012

Fibrillary glomerulonephritis presenting as rapidly progressive glomerulonephritis.

Am J Kidney Dis 2012 Jul 6;60(1):157-9. Epub 2012 Mar 6.

Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Fibrillary glomerulonephritis (GN) is an uncommon cause of rapidly progressive kidney failure. We report a case of rapidly progressive kidney failure with kidney biopsy showing crescentic GN on light microscopy and immunofluorescence showing linear/globular glomerular basement membrane (GBM) staining for immunoglobulin G and C3, consistent with anti-GBM disease. However, electron microscopy showed fibrillary deposits in the GBM, suggesting a diagnosis of fibrillary GN. As exemplified by this case, it is important to consider fibrillary GN in the differential diagnosis of crescentic GN with linear immunoglobulin G deposits within the GBM. Electron microscopy is crucial to make this diagnosis.
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http://dx.doi.org/10.1053/j.ajkd.2011.12.024DOI Listing
July 2012

Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure.

Hypertension 2012 Mar 23;59(3):726-31. Epub 2012 Jan 23.

Women's Health Research Center, Department of Physiology, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.

Androgen levels are lower in obese men as compared with normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats, starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10-fold in both obese Zucker rats and lean Zucker rats. In obese Zucker rats, testosterone supplements reduced body weight, plasma insulin, and cholesterol levels and improved the oral glucose tolerance test. None of these parameters were affected in lean Zucker rats. Mean arterial pressure was significantly increased in obese Zucker rats but not lean Zucker rats. Testosterone supplements increased proteinuria and accelerated renal injury in lean Zucker rats only. Thus, treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.180943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319027PMC
March 2012

Transcriptional analysis of infiltrating T cells in kidney ischemia-reperfusion injury reveals a pathophysiological role for CCR5.

Am J Physiol Renal Physiol 2012 Mar 7;302(6):F762-73. Epub 2011 Dec 7.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Bldg., Rm. 965, 720 Rutland Ave., Baltimore, MD 21205, USA.

Although T cells have been shown to play a direct role in kidney ischemia-reperfusion injury (IRI), little is known about the underlying mechanisms. We hypothesized that studying the transcriptional responses in kidney-infiltrating T cells would help elucidate novel therapeutic targets for kidney IRI. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6 mice, and CD3(+) T cells were isolated from the kidney and purified. Transcriptional activities of T cell were measured by array-based PCR compared between ischemic kidneys and contralateral nonischemic kidneys. Among total of 89 genes analyzed, 24, 22, 24, and 37 genes were significantly changed at 6 h, day 3, day 10, and day 28 after IRI. Genes associated with cytokines, chemokines, and costimulatory molecules were upregulated. Pathway analysis identified CC motif chemokine receptor 5 (CCR5) as a candidate pathophysiological pathway. CCR5 upregulation was validated at the protein level, and CCR5 blockade improved renal function after kidney IRI. Using discovery techniques to identify transcriptional responses in purified kidney-infiltrating cells enabled the elucidation of novel mechanisms and therapeutic targets for IRI.
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http://dx.doi.org/10.1152/ajprenal.00335.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311318PMC
March 2012

APOL1 risk variants predict histopathology and progression to ESRD in HIV-related kidney disease.

J Am Soc Nephrol 2012 Feb 1;23(2):343-50. Epub 2011 Dec 1.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

With earlier institution of antiretroviral therapy, kidney diseases other than HIV-associated nephropathy (HIVAN) predominate in HIV-infected persons. Outcomes for these diseases are typically worse among those infected with HIV, but the reasons for this are not clear. Here, we examined the role of APOL1 risk variants in predicting renal histopathology and progression to ESRD in 98 HIV-infected African Americans with non-HIVAN kidney disease on biopsy. We used survival analysis to determine time to ESRD associated with APOL1 genotype. Among the 29 patients with two APOL1 risk alleles, the majority (76%) had FSGS and 10% had hypertensive nephrosclerosis. In contrast, among the 54 patients with one APOL1 risk allele, 47% had immune-complex GN as the predominant lesion and only 23% had FSGS. Among the 25 patients with no APOL1 risk allele, 40% had immune-complex GN and 12% had FSGS. In 310 person-years of observation, 29 patients progressed to ESRD. In adjusted analyses, individuals with two APOL1 risk alleles had a nearly three-fold higher risk for ESRD compared with those with one or zero risk alleles (P=0.03). In summary, these data demonstrate an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients.
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http://dx.doi.org/10.1681/ASN.2011060562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269183PMC
February 2012

Acute renal venous obstruction is more detrimental to the kidney than arterial occlusion: implication for murine models of acute kidney injury.

Am J Physiol Renal Physiol 2012 Mar 23;302(5):F519-25. Epub 2011 Nov 23.

Div. of Nephrology, Johns Hopkins Univ. School of Medicine, MD 21205, USA.

In this study, we compared the traditional murine model with renal pedicle clamp with models that clamped the renal artery or vein alone as well as to a whole body ischemia-reperfusion injury (WBIRI) model. Male C57BL/6J mice underwent either clamping of the renal artery, vein, or both (whole pedicle) for 30 or 45 min followed by reperfusion, or 10 min of cardiac arrest followed by resuscitation up to 24 h. After 30 min of ischemia, the mice with renal vein clamping showed the mostly increased serum creatinine and the most severe renal tubule injury. After 45 min of ischemia, all mice with renal vasculature clamping had a comparable increase in serum creatinine but the renal tubule injury was most severe in renal artery-clamped mice. Renal arterial blood flow was most decreased in mice with a renal vein clamp compared with a renal artery or pedicle clamp. A 30-or 45-min renal ischemia time led to a significant increase in the protein level of interleukin-6, keratinocyte-derived chemokine (KC), and granular colony-stimulating factor in the ischemic kidney, but the KC was the highest in the renal pedicle-clamped kidney and the lowest in the renal vein-clamped kidney. Of note, 10 min of WBIRI led to kidney dysfunction and structural injury, although less than longer time clamping of isolated renal vasculature. Our data demonstrate important differences in ischemic AKI models. Understanding these differences is important in designing future experimental studies in mice as well as clinical trials in humans.
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http://dx.doi.org/10.1152/ajprenal.00011.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353642PMC
March 2012

ASN clinicopathologic conference.

Clin J Am Soc Nephrol 2011 Nov 1;6(11):2722-8. Epub 2011 Sep 1.

Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

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http://dx.doi.org/10.2215/CJN.05300611DOI Listing
November 2011