Publications by authors named "Ivy A Rosales"

28 Publications

  • Page 1 of 1

Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib.

Nephrol Dial Transplant 2020 Dec 23. Epub 2020 Dec 23.

Division of Nephrology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.

Objectives: To characterize the incidence, risk factors, and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib.

Methods: We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI.

Results: 199 patients who received dabrafenib in our healthcare system from 2010-2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of total cohort, 24% of AKI) experienced AKI occurring during a dabrafenib/trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms, and elevated liver enzymes. Pre-existing liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids.

Conclusions: Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia.
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http://dx.doi.org/10.1093/ndt/gfaa372DOI Listing
December 2020

Cutaneous leukocyte lineages in tolerant large animal and immunosuppressed clinical vascularized composite allograft recipients.

Am J Transplant 2021 02 29;21(2):582-592. Epub 2020 Aug 29.

Center for Transplantation Sciences, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.

Vascularized composite allografts (VCAs) can restore fully functional anatomic units in patients with limb amputations or severe facial tissue loss. However, acute rejection of the skin is frequently observed and underscores the importance of developing tolerance induction protocols. In this study, we have characterized the skin immune system in VCAs. We demonstrate infiltration of recipient leukocytes, regardless of rejection status, and in tolerant mixed hematopoietic chimeras, the co-existence of these cells with donor leukocytes in the absence of rejection. Here we characterize the dermal T cell and epidermal Langerhans cell components of the skin immune system in our porcine model of VCA tolerance, and the kinetics of cutaneous chimerism in both of these populations in VCAs transplanted to tolerant and nontolerant recipients, as well as in host skin. Furthermore, in biopsies from the first patient to receive a hand transplant in our program, we demonstrate the presence of recipient T cells in the skin of the transplanted limb in the absence of clinical or histological evidence of rejection.
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http://dx.doi.org/10.1111/ajt.16230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854956PMC
February 2021

AKI and Collapsing Glomerulopathy Associated with COVID-19 and High-Risk Genotype.

J Am Soc Nephrol 2020 Aug 19;31(8):1688-1695. Epub 2020 Jun 19.

Department of Nephrology, Ochsner Health System, New Orleans, Louisiana

Background: Kidney involvement is a feature of COVID-19 and it can be severe in Black patients. Previous research linked increased susceptibility to collapsing glomerulopathy, including in patients with HIV-associated nephropathy, to apo L1 () variants that are more common in those of African descent.

Methods: To investigate genetic, histopathologic, and molecular features in six Black patients with COVID-19 presenting with AKI and nephrotic-range proteinuria, we obtained biopsied kidney tissue, which was examined by hybridization for viral detection and by NanoString for COVID-19 and acute tubular injury-associated genes. We also collected peripheral blood for genotyping.

Results: This case series included six Black patients with COVID-19 (four men, two women), mean age 55 years. At biopsy day, mean serum creatinine was 6.5 mg/dl and mean urine protein-creatinine ratio was 11.5 g. Kidney biopsy specimens showed collapsing glomerulopathy, extensive foot process effacement, and focal/diffuse acute tubular injury. Three patients had endothelial reticular aggregates. We found no evidence of viral particles or SARS-CoV-2 RNA. NanoString showed elevated chemokine gene expression and changes in expression of genes associated with acute tubular injury compared with controls. All six patients had an high-risk genotype. Five patients needed dialysis (two of whom died); one partially recovered without dialysis.

Conclusions: Collapsing glomerulopathy in Black patients with COVID-19 was associated with high-risk variants. We found no direct viral infection in the kidneys, suggesting a possible alternative mechanism: a "two-hit" combination of genetic predisposition and cytokine-mediated host response to SARS-CoV-2 infection. Given this entity's resemblance with HIV-associated nephropathy, we propose the term COVID-19-associated nephropathy to describe it.
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http://dx.doi.org/10.1681/ASN.2020050558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460910PMC
August 2020

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

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

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

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

Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis.

Kidney Int 2020 09 23;98(3):758-768. Epub 2020 May 23.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.
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http://dx.doi.org/10.1016/j.kint.2020.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483801PMC
September 2020

Toward Development of the Delayed Tolerance Induction Protocol for Vascularized Composite Allografts in Nonhuman Primates.

Plast Reconstr Surg 2020 04;145(4):757e-768e

From the Division of Plastic and Reconstructive Surgery, the Vascularized Composite Allotransplantation Laboratory, Center for Transplantation Sciences, and the Massachusetts General Hospital Transplant Center, Massachusetts General Hospital, Harvard Medical School; the Shriners Hospital for Children; and the Service de Chirurgie Plastique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes.

Background: Transplantation of vascularized composite allografts is limited mainly by the need for life-long immunosuppression. The consequent side effects and looming specter of chronic rejection portend eventual allograft loss. Development of tolerogenic protocols is thus of utmost importance to the field of vascularized composite allograft transplantation.

Methods: With a modified delayed tolerance induction protocol, 10 cynomolgus macaques received hand (n = 2) or face vascularized composite allografts across both full and haploidentical major histocompatibility complex barriers before donor bone marrow transplantation at a later date. Protocol and for-cause allograft skin biopsies were performed for immunohistochemical analysis and analysis of donor-recipient leukocyte contribution; mixed chimerism in peripheral blood and in vitro immune responses were assessed serially.

Results: Before bone marrow transplantation, maintenance immunosuppression for 4 months led to lethal complications, including posttransplant lymphoproliferative disorder (in two of four recipients), which necessitated early study termination. Shortening the maintenance period to 2 months was clinically relevant and allowed all subsequent subjects (n = 6) to complete the delayed tolerance induction protocol. Acute rejection developed within the first 2 to 4 weeks after transplantation, with corresponding near-complete turnover of allograft leukocytes from donor to recipient origin, but donor-specific antibodies remained negative. After bone marrow transplantation, mixed chimerism failed to develop, although carboxyfluorescein succinimidyl ester mixed lymphocyte reaction demonstrated generalized unresponsiveness. However, the accrual of subsequent rejection episodes eventually culminated in graft vasculopathy and irreversible allograft loss.

Conclusions: Despite the various advantages of the delayed tolerance induction protocol, it failed to reliably induce mixed chimerism and thus immunologic tolerance to vascularized composite allografts, given currently available immunosuppression treatment options. Ongoing work shows promise in overcoming these limitations.
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http://dx.doi.org/10.1097/PRS.0000000000006676DOI Listing
April 2020

Long-term Kinetics of Intragraft Gene Signatures in Renal Allograft Tolerance Induced by Transient Mixed Chimerism.

Transplantation 2019 11;103(11):e334-e344

Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: Renal allograft tolerance (TOL) has been successfully induced in nonhuman primates (NHPs) and humans through the induction of transient mixed chimerism. To elucidate the mechanisms of TOL, we compared local immunologic responses in renal allografts with those in T-cell-mediated rejection (TCMR) and chronic antibody-mediated rejection (CAMR) in NHPs.

Methods: Using the NanoString nCounter platform, we retrospectively studied 52 mRNAs in 256 kidney allograft samples taken from NHP kidney recipients of donor BMT. No immunosuppression was given after 1-month post-donor BMT. Recipients who achieved TOL (n = 13) survived for >1840 ± 1724 days with normal kidney function, while recipients with CAMR (n = 13) survived for 899 ± 550 days with compromised graft function, and recipients with TCMR (n = 15) achieved only short-term survival (132 ± 69 days).

Results: The most prominent difference between the groups was FOXP3, which was significantly higher in TOL than in CAMR and TCMR, both early (<1 y, P < 0.01) and late (≥1 y, P < 0.05) after transplant. Other mRNAs related to regulatory T cells (Treg), such as IL10, TGFB, and GATA3, were also high in TOL. In contrast, transcripts of inflammatory cytokines were higher in TCMR, while activated endothelium-associated transcripts were higher in CAMR than in TOL. The receiver operating characteristic analyses revealed that intragraft FOXP3 and CAV1 can reliably distinguish TOL from CAMR.

Conclusions: High FOXP3 and other Treg-related mRNAs together with suppressed inflammatory responses and endothelial activation in renal allografts suggest that intragraft enrichment of Treg is a critical mechanism of renal allograft TOL induced by transient mixed chimerism.
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http://dx.doi.org/10.1097/TP.0000000000002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814550PMC
November 2019

The pathology of solid organ xenotransplantation.

Curr Opin Organ Transplant 2019 10;24(5):535-542

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Purpose Of Review: The use of genetically modified pigs has resulted in prolonged xenograft organ survival, overcoming the initial barriers that lead to hyperacute rejection and immediate loss of the graft. The purpose of the present review is to revisit the xenogeneic response and the pathologic changes in the xenograft organ in the context of recent publications of large animal studies that highlight existing challenges.

Recent Findings: Transgenic modifications that have included complement regulatory proteins and coagulation regulatory proteins have prolonged xenograft survival in pig to nonhuman primate kidneys, livers, and hearts. Modifications of immunosuppressive regimens such as the addition of mTOR inhibition and costimulatory blockade have also led to better outcomes. Antibody-mediated rejection and thrombotic microangiopathy persist as primary challenges to the field and require further systematic exploration.

Summary: The efforts to overcome the natural antibody response to xenoantigens are largely sufficient. There is great opportunity for designing immunosuppression protocols and for detecting early coagulopathies, complement activation, and donor-specific antibody response. With graft survival prolongation, there is also a greater need to understand mechanisms and to enhance diagnostic tools for pathologic evaluation.
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http://dx.doi.org/10.1097/MOT.0000000000000681DOI Listing
October 2019

Nonvascularized human skin chronic allograft rejection.

Am J Transplant 2019 11 13;19(11):3191-3196. Epub 2019 Aug 13.

Transplantation Center, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

A 65-year-old man had extensive burns of the lower legs in 1991, at the age of 40 years. He was treated by nonvascularized and de-epithelialized, allogeneic split-thickness skin allograft and cyclosporine monotherapy for 2 months. Ulcers developed between 10 and 25 years after transplantation and a surgical debridement on the lower extremities was required. Analyses of the removed tissue allografts showed chronic antibody-mediated and cellular rejection with extensive and dense fibrosis, and diffuse capillary C4d deposits. An anti-DRB1*08:01, donor-specific antibody was present. A unique clinical condition with late immunopathological features of human skin chronic allograft rejection is reported.
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http://dx.doi.org/10.1111/ajt.15542DOI Listing
November 2019

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

J Am Soc Nephrol 2019 08 5;30(8):1481-1494. Epub 2019 Jul 5.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;

Background: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies.

Methods: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort.

Results: Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.

Conclusions: Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.
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http://dx.doi.org/10.1681/ASN.2018111098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683710PMC
August 2019

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection.

JCI Insight 2019 06 6;4(11). Epub 2019 Jun 6.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8+ T cell gene signatures in pretransplant blood. We identified a 23-gene set that predicted EAR in the discovery (n = 81, and AUC = 0.80) and validation (n = 74, and AUC = 0.74) sets. Exclusion of recipients with 5 or 6 HLA donor mismatches increased the AUC to 0.89. The risk score derived from the gene set was also significantly associated with acute cellular rejection after 6 months, antibody-mediated rejection and/or de novo donor-specific antibodies, and graft loss in a cohort of 154 patients, combining the validation set and additional GoCAR patients with surveillance biopsies between 6 and 24 months (n = 80) posttransplant. This 23-gene set is a potentially important new tool for determination of the recipient's immunological risk before kidney transplantation, and facilitation of an individualized approach to immunosuppressive therapy.
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http://dx.doi.org/10.1172/jci.insight.127543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629121PMC
June 2019

Case 11-2019: A 49-Year-Old Man with HIV Infection and Chronic Kidney Disease.

N Engl J Med 2019 Apr;380(15):1464-1472

From the Departments of Medicine (D.W., R.T.G.) and Pathology (I.A.R.), Massachusetts General Hospital, and the Departments of Medicine (D.W., R.T.G.) and Pathology (I.A.R.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1900417DOI Listing
April 2019

Iatrogenic Hypercalcemia Postrenal Transplantation.

Kidney Int Rep 2019 Mar 19;4(3):487-490. Epub 2018 Nov 19.

Department of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.ekir.2018.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409389PMC
March 2019

Graft vasculopathy of vascularized composite allografts in humans: a literature review and retrospective study.

Transpl Int 2019 Aug 2;32(8):831-838. Epub 2019 Apr 2.

Vascularized Composite Allotransplantation Laboratory, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA.

Mechanisms of chronic rejection of vascularized composite allografts (VCA) remain poorly understood and likely present along a spectrum of highly varied clinicopathological findings. Across both animal and human VCA however, graft vasculopathy (GV) has been the most consistent pathological finding resulting clinically in irreversible allograft dysfunction and eventual loss. A literature review of all reported clinical VCA cases with documented GV up to December 2018 was thus performed to elucidate the possible mechanisms involved. Relevant data extracted include C4d deposition, donor-specific antibody (DSA) formation, extent of human leukocyte antigen (HLA) mismatch, pretransplant panel reactive antibody levels, induction and maintenance immunosuppression used, the number of preceding acute rejection episodes, and time to histological confirmation of GV. Approximately 6% (13 of 205) of all VCA patients reported to date developed GV at a mean of 6 years post-transplantation. 46% of these patients have either lost or had their VCAs removed. Neither C4d nor DSA alone was predictive of GV development; however, when both are present, VCA loss appears inevitable due to progressive GV. Of utmost concern, GV in VCA does not appear to be abrogated by currently available immunosuppressive treatment and is essentially irreversible by the time of diagnosis with allograft loss a likely eventuality.
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http://dx.doi.org/10.1111/tri.13421DOI Listing
August 2019

Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates.

Transplantation 2019 04;103(4):689-697

Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: Although induction of durable mixed chimerism is required for murine skin allograft tolerance (TOL), renal allograft TOL has been achieved after induction of only transient mixed chimerism in nonhuman primates (NHPs) and humans. To better define the level/duration of chimerism required for stable renal allograft TOL, we retrospectively analyzed these parameters and compared them with transplant outcomes in NHP combined kidney and bone marrow transplant recipients.

Methods: Peripheral blood levels and duration of myeloid or lymphoid chimerism were retrospectively analyzed in 34 NHP combined kidney and bone marrow transplantation recipients which were divided into 3 groups: TOL, n = 10; chronic antibody-mediated rejection (CAMR), n = 12; and T cell-mediated rejection (TCMR), n = 12.

Results: All 4 of the recipients that failed to develop any chimerism lost their allografts due to TCMR after discontinuation of immunosuppression (56 ± 3 d). Among 30 recipients who successfully developed multilineage chimerism, 10 achieved long-term immunosuppression-free survival without rejection (1258 ± 388 d), 12 eventually developed CAMR (932 ± 155 d), and 8 developed TCMR (82 ± 10 d). The maximum level but not duration of lymphoid chimerism was significantly higher in TOL recipients compared with both CAMR (P = 0.0159) and TCMR (P = 0.0074). On the other hand, the maximum myeloid chimerism was significantly higher in TOL than in TCMR (P = 0.0469), but not in CAMR. Receiver operating characteristic analyses revealed that lymphoid chimerism levels of 3.1% or greater could reliably predict long-term immunosuppression-free renal allograft survival (P < 0.0001).

Conclusions: This retrospective study confirmed that induction of chimerism is essential for long-term immunosuppression-free survival, which best correlates with lymphoid chimerism levels higher than 3.1%.
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http://dx.doi.org/10.1097/TP.0000000000002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433526PMC
April 2019

Complement 7 Is Up-Regulated in Human Early Diabetic Kidney Disease.

Am J Pathol 2018 10;188(10):2147-2154

Division of Nephrology, Massachusetts General Hospital and Partners Health Care, Harvard Medical School, Boston, Massachusetts.

There is a temporal window from the time diabetes is diagnosed to the appearance of overt kidney disease during which time the disease progresses quietly without detection. Currently, there is no way to detect early diabetic nephropathy (EDN). Herein, we performed an unbiased assessment of gene-expression analysis of postmortem human kidneys to identify candidate genes that may contribute to EDN. We then studied one of the most promising differentially expressed genes in both kidney tissue and blood samples. Differential transcriptome analysis of EDN kidneys and matched nondiabetic controls showed alterations in five canonical pathways, and among them the complement pathway was the most significantly altered. One specific complement pathway gene, complement 7 (C7), was significantly elevated in EDN kidney. Real-time PCR confirmed more than a twofold increase of C7 expression in EDN kidneys compared with controls. Changes in C7 gene product level were confirmed by immunohistochemistry. C7 protein levels were elevated in proximal tubules of EDN kidneys. Serum C7 protein levels were also measured in EDN and control donors. C7 levels were significantly higher in EDN serum than control serum. This latter finding was independently confirmed in a second set of blood samples from a previously collected data set. Together, our data suggest that C7 is associated with EDN, and can be used as a molecular target for detection and/or treatment of EDN.
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http://dx.doi.org/10.1016/j.ajpath.2018.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180251PMC
October 2018

Case 24-2018: A 71-Year-Old Man with Acute Renal Failure and Hematuria.

N Engl J Med 2018 Aug;379(6):568-578

From the Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (R.J.F.); and the Departments of Radiology (J.S.H.), Medicine (A.Z.F.), and Pathology (I.A.R.), Massachusetts General Hospital, and the Departments of Radiology (J.S.H.), Medicine (A.Z.F.), and Pathology (I.A.R.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1802829DOI Listing
August 2018

Both platelets and fibrin deposition are increased in the glomeruli of mice after treatment with Shiga toxin-2.

Kidney Int 2017 12;92(6):1556-1557

Department of Pediatrics, Cardiovascular Thrombosis Laboratory, MassGeneral Hospital for Children at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2017.09.009DOI Listing
December 2017

LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

J Am Soc Nephrol 2018 02 26;29(2):644-653. Epub 2017 Oct 26.

Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;

Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and circulating antibodies reactive with normal human kidney proximal tubular brush border. All but one of the patients also had segmental glomerular deposits on renal biopsy specimen. Patients with ABBA disease were elderly and presented with AKI and subnephrotic proteinuria. Serum from all patients but not controls recognized a high molecular weight protein in renal tubular protein extracts that we identified as LDL receptor-related protein 2 (LRP2), also known as megalin, by immunoprecipitation and mass spectrometry. Immunostaining revealed that LRP2 specifically colocalized with IgG in the tubular immune deposits on the ABBA biopsy specimen but not the control specimen analyzed. Finally, ABBA serum samples but not control samples showed reactivity against recombinantly expressed N-terminal LRP2 fragments on Western blots and immunoprecipitated the recombinantly expressed N-terminal region of LRP2. This case series details the clinicopathologic findings of patients with ABBA disease and shows that the antigenic target of these autoantibodies is LRP2. Future studies are needed to determine the disease prevalence, stimulus for ABBA, and optimal treatment.
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http://dx.doi.org/10.1681/ASN.2017060664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791069PMC
February 2018

Penis Transplantation: First US Experience.

Ann Surg 2018 05;267(5):983-988

Department of Surgery, Massachusetts General Hospital, Boston, MA.

Objective: We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer.

Background: Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide.

Methods: After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone.

Results: Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future.

Conclusions: We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000002241DOI Listing
May 2018

Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy.

Kidney Int Rep 2016 Sep;1(3):135-143

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.

Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.
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http://dx.doi.org/10.1016/j.ekir.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155703PMC
September 2016

Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study.

Lancet 2016 Sep 22;388(10048):983-93. Epub 2016 Jul 22.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Background: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis.

Methods: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702.

Findings: We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve [AUC] 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972).

Interpretation: Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(16)30826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014570PMC
September 2016

Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47.

Transplantation 2017 02;101(2):316-321

1 Transplantation Biology Research Center, MGH, Boston, MA. 2 Harvard Medical School, Boston, MA. 3 Columbia Center for Translational Immunology, Columbia University, New York, NY. 4 Pathology Service, Massachusetts General Hospital (MGH), Boston, MA.

Background: Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein α receptors. However, pig CD47 has previously been shown to be ineffective in transducing signals through primate signal regulatory protein α.

Methods: Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed after each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks after the last cell infusion and 7 weeks after the discontinuation of all immunosuppression to test immune response.

Results: The level and duration of transient chimerism were substantially greater in baboons receiving hematopoietic cells from a pig expressing high levels of human CD47. Skin graft survival on high CD47 recipients was prolonged as well, in 1 case showing no signs of rejection at least 53 days after placement.

Conclusions: Prolongation of transient porcine chimerism via transgenic expression of human CD47 in a primate model is associated with an immune modulating effect, leading to markedly prolonged survival of donor swine skin xenografts that may be applicable to clinical solid organ xenotransplantation.
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http://dx.doi.org/10.1097/TP.0000000000001267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124423PMC
February 2017

Hydroxyurea for Treatment of Nephrotic Syndrome Associated With Polycythemia Vera.

Am J Kidney Dis 2016 Sep 29;68(3):465-8. Epub 2016 Apr 29.

Division of Nephrology, Massachusetts General Hospital, Boston, MA.

Myeloproliferative disorders are a rare cause of focal segmental glomerulosclerosis (FSGS), although the mechanism is unclear. Hydroxyurea is commonly used in these disorders for its cytoreductive properties; however, the effect of this treatment on proteinuria or kidney function remains unclear in cases of myeloproliferative disorder-associated FSGS. We describe the clinical course of a patient with polycythemia vera and nephrotic-range proteinuria, demonstrated to have FSGS on biopsy. The patient had a distant history of granulomatosis with polyangiitis (Wegener's), for which he routinely had his kidney function and proteinuria measured, allowing for early detection of nephrotic syndrome soon after being diagnosed with polycythemia vera. Treatment with hydroxyurea resulted in rapid improvement in proteinuria that correlated with a decrease in hematocrit. This response was replicated 2 additional times when the patient was taken off and then restarted on hydroxyurea therapy. He now maintains a steady dose of hydroxyurea with favorable kidney measures (proteinuria with <1g/d of protein excretion and serum creatinine of 1.27mg/dL [corresponding to estimated glomerular filtration rate of 56mL/min/1.73 m(2)]). This case suggests that early screening and treatment for myeloproliferative disorder-associated FSGS may lead to improved long-standing kidney function.
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http://dx.doi.org/10.1053/j.ajkd.2016.02.056DOI Listing
September 2016

Glomerular disease with idiopathic linear immunoglobulin deposition: a rose by any other name would be atypical.

Kidney Int 2016 Apr;89(4):750-2

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:

Nasr et al. (2016) report 20 cases of "atypical anti-GBM disease," characterized by bright, linear glomerular basement membrane (GBM) immunoglobulin deposition in patients who lacked anti-GBM antibodies by conventional testing and who had a relatively benign course. Half had light chain restriction. The term "idiopathic linear immunoglobulin deposition" may be preferable until anti-GBM activity is demonstrable, since there are alternative mechanisms of linear deposition in the GBM, including physicochemical affinity for GBM components and alterations of the GBM itself.
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http://dx.doi.org/10.1016/j.kint.2016.01.018DOI Listing
April 2016

A Bridge to Somewhere: 25-day Survival After Pig-to-Baboon Liver Xenotransplantation.

Ann Surg 2016 06;263(6):1069-71

Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1097/SLA.0000000000001659DOI Listing
June 2016

Case Records of the Massachusetts General Hospital. Case 35-2015: A 72-Year-Old Woman with Proteinuria and a Kidney Mass.

N Engl J Med 2015 Nov;373(20):1958-67

A 72-year-old woman presented with flank pain, proteinuria, and a new kidney mass. Magnetic resonance imaging of the kidney revealed a complex, solid mass (3 cm x 2.9 cm x 2.9 cm) in the lower pole of the right kidney. Diagnostic tests were performed.
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http://dx.doi.org/10.1056/NEJMcpc1505527DOI Listing
November 2015

Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the Proximal Tubule Brush Border.

J Am Soc Nephrol 2016 Feb 2;27(2):380-4. Epub 2015 Sep 2.

Department of Pathology and.

Immune complex tubulointerstitial nephritis due to antibodies to brush border antigens of the proximal tubule has been demonstrated experimentally and rarely in humans. Our patient developed ESRD and early recurrence after transplantation. IgG and C3 deposits were conspicuous in the tubular basement membrane of proximal tubules, corresponding to deposits observed by electron microscopy. Rare subepithelial deposits were found in the glomeruli. The patient had no evidence of SLE and had normal complement levels. Serum samples from the patient reacted with the brush border of normal human kidney, in contrast with the negative results with 20 control serum samples. Preliminary characterization of the brush border target antigen excluded megalin, CD10, and maltase. We postulate that antibodies to brush border antigens cause direct epithelial injury, accumulate in the tubular basement membrane, and elicit an interstitial inflammatory response.
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http://dx.doi.org/10.1681/ASN.2015030334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731130PMC
February 2016