Publications by authors named "Hanni Menn-Josephy"

11 Publications

  • Page 1 of 1

Predictors and outcomes of acute kidney injury during autologous stem cell transplantation in AL amyloidosis.

Nephrol Dial Transplant 2021 May 27. Epub 2021 May 27.

Renal Section, Department of Medicine, Boston Medical Center, Boston, MA, USA.

Background: Acute kidney injury (AKI) is a common complication after high dose melphalan and autologous stem cell transplantation (HDM/SCT) in patients with AL amyloidosis. However, its incidence, predictors and outcomes are not well known.

Methods: This observational study included 223 patients with AL amyloidosis who underwent HDM/SCT. AKI was defined as an increase in serum creatinine to ≥ 1.5 times the baseline occurring within the first 30 days of HDM/SCT.

Results: The median age was 58 years (range: 30-77). Kidney and cardiac involvement were present in 86.1% and 56.8%, respectively. The median eGFR was 83.5 mL/min/1.73m2 (range: 9-213) and proteinuria was 2,899 mg/24 h (range: 0-19,966). AKI occurred in 29.1% of patients. Dialysis was initiated in 15 patients (6.7%) and of these 12 (80%) were able to discontinue dialysis. Most of the episodes of AKI occurred within the first 2 weeks. With a median follow-up of 4.5 years (range: 0.1-16.5), AKI was associated with increased overall mortality, HR 4.53 (95%CI [2-10.23]). The 10-year overall survival (OS) was 87.1% without AKI, versus 56.9% with AKI. AKI was also associated with an increased risk for end stage kidney disease (ESKD), HR 4.6 (95%CI [1.44-14.38]). The risk of developing ESKD at 10-year was 18.9% with AKI, versus 8.1% without AKI. Several risk factors were found and using multivariate logistic regression, a prediction model was developed which included 3 readily available variables: eGFR<60 mL/min/1.73m2, IVSd>12mm, and albumin<3 g/dL. This model was able to predict AKI development with an AUC of 0.8.

Conclusions: AKI is common in the post-HDM/SCT period and it leads to increased risk for ESKD and death. Our prediction model is an easily deployable tool in clinical settings as part of the discussion with patients who are being prepared for HDM/SCT.
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http://dx.doi.org/10.1093/ndt/gfab189DOI Listing
May 2021

IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation.

J Clin Invest 2021 Jun;131(12)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TECs from humans and mice with nephritis expressed increased levels of IL-23R and CaMK4 but reduced levels of ARG1. TEC-specific deletion of Il23r or Camk4 suppressed inflammation, whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer the first evidence to our knowledge of the immunosuppressive capacity of TECs through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine in the function of nonlymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TECs.
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http://dx.doi.org/10.1172/JCI142428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203450PMC
June 2021

The Role of Kidney Transplantation in Monoclonal Ig Deposition Disease.

Kidney Int Rep 2020 Apr 9;5(4):485-493. Epub 2020 Mar 9.

Renal Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA.

Introduction: Monoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney transplantation outcomes in MIDD are limited.

Methods: This was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation.

Results: The 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years,  = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment.

Conclusion: As treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation.
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http://dx.doi.org/10.1016/j.ekir.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136323PMC
April 2020

Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response.

J Immunol 2019 02 4;202(3):675-683. Epub 2019 Jan 4.

Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nucleic acids and nucleoproteins. Anti-dsDNA Abs are considered a hallmark of SLE, and previous studies have indicated that nucleic acid-containing immune complexes (ICs) induce B cell and dendritic cell activation in a TLR-dependent process. How ICs containing nucleic acids affect neutrophil function has not been well investigated. In this study, we report that nucleic acid-containing ICs derived from the sera of SLE patients induce human and mouse neutrophil activation through TLR-independent mechanisms. Soluble ICs containing Sm/RNP, an RNA Ag, activate human neutrophils to produce reactive oxygen species (ROS) and IL-8. In contrast, ICs containing DNA have to be immobilized to efficiently activate neutrophils. We found that deleting TLR7 or TLR9, the receptors for RNA and DNA, had no effect on mouse neutrophil activation induced by RNA-containing and immobilized DNA-containing ICs. Binding of ICs are mediated through FcγRIIA and FcγRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcγRIIA, as blocking FcγRIIA inhibited ROS release from neutrophils. RNA-containing ICs induce calcium flux, whereas TLR7/8 ligand R848 do not. Surprisingly, chloroquine inhibits calcium flux induced by RNA-containing ICs, suggesting that this lesser known function of chloroquine is involved in the neutrophil activation induced by ICs. These data indicate the SLE-derived ICs activate neutrophils to release ROS and chemokines in an FcγRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.
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http://dx.doi.org/10.4049/jimmunol.1800300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344272PMC
February 2019

Renal Interstitial Fibrosis: An Imperfect Predictor of Kidney Disease Progression in Some Patient Cohorts.

Am J Nephrol 2016 15;44(4):289-299. Epub 2016 Sep 15.

Department of Medicine, Boston University Medical Center, Boston, Mass., USA.

Background: The extent of interstitial fibrosis on kidney biopsy is regarded as a prognostic indicator and guide to treatment. Patients with extensive fibrosis are assigned to supportive treatments with the expectation that they have advanced beyond the point at which immunosuppressive or other disease-modifying therapies would be of benefit. Our study highlights some of the limitations of using interstitial fibrosis to predict who will develop end-stage renal disease (ESRD).

Methods: Analysis of 434 consecutive renal biopsies performed between 2001 and 2012 at a single center. We assessed the influence of various clinical factors along with fibrosis as predictors of ESRD and dialysis-free survival in various patient groups.

Results: Interstitial fibrosis performed well overall as a predictor of progression to dialysis. On average, patients with >50% fibrosis progressed more rapidly than those with either 25-49 or 0-24% fibrosis with a median time to dialysis of 1.2, 6.5 and >10 years, respectively. In contrast, interstitial fibrosis was of less value as a predictor of disease progression in a subset of cases that included patients over the age of 70 and those with diabetic nephropathy on biopsy. Surprisingly, 13.9% of patients with normal renal function had 25-49% fibrosis and 5% had more than 50% fibrosis on biopsy, and 5 years after undergoing biopsy 21% of patients with >50% fibrosis still remained dialysis free.

Conclusion: Renal fibrosis is an imperfect prognostic indicator for the development of ESRD and caution should be exercised in applying it too rigidly, especially in elderly or diabetic patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069171PMC
http://dx.doi.org/10.1159/000449511DOI Listing
January 2018

Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model.

Arthritis Rheumatol 2015 Dec;67(12):3146-57

Boston University School of Medicine, Boston, Massachusetts.

Objective: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development.

Methods: K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling.

Results: Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1β formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner.

Conclusion: Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.
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http://dx.doi.org/10.1002/art.39321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661118PMC
December 2015

IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis.

J Immunol 2015 Feb 16;194(4):1467-79. Epub 2015 Jan 16.

Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;

Premature atherosclerosis is a severe complication of lupus and other systemic autoimmune disorders. Gain-of-function polymorphisms in IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing lupus, and IRF5 deficiency in lupus mouse models ameliorates disease. However, whether IRF5 deficiency also protects against atherosclerosis development in lupus is not known. In this study, we addressed this question using the gld.apoE(-/-) mouse model. IRF5 deficiency markedly reduced lupus disease severity. Unexpectedly, despite the reduction in systemic immune activation, IRF5-deficient mice developed increased atherosclerosis and also exhibited metabolic dysregulation characterized by hyperlipidemia, increased adiposity, and insulin resistance. Levels of the atheroprotective cytokine IL-10 were reduced in aortae of IRF5-deficient mice, and in vitro studies demonstrated that IRF5 is required for IL-10 production downstream of TLR7 and TLR9 signaling in multiple immune cell types. Chimera studies showed that IRF5 deficiency in bone marrow-derived cells prevents lupus development and contributes in part to the increased atherosclerosis. Notably, IRF5 deficiency in non-bone marrow-derived cells also contributes to the increased atherosclerosis through the generation of hyperlipidemia and increased adiposity. Together, our results reveal a protective role for IRF5 in lupus-associated atherosclerosis that is mediated through the effects of IRF5 in both immune and nonimmune cells. These findings have implications for the proposed targeting of IRF5 in the treatment of autoimmune disease as global IRF5 inhibition may exacerbate cardiovascular disease in these patients.
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http://dx.doi.org/10.4049/jimmunol.1402807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323680PMC
February 2015

Recurrent glomerular disease in the kidney allograft.

Front Biosci (Elite Ed) 2015 Jan 1;7:135-48. Epub 2015 Jan 1.

Renal Section, Department of Medicine, Boston Medical Center, 650 Albany Street, Boston, MA.

Glomerulonephritis is responsible for nearly 15% of prevalent end-stage renal disease, and many of these patients will receive kidney transplants with the potential for a long duration of allograft survival. Recurrent glomerular disease, however, is not uncommon and can lead to both substantial morbidity and/or loss of the kidney allograft. The timing of recurrence after transplantation as well as the prevalence of recurrent disease vary by study, especially accounting for differences in protocol versus clinically-indicated biopsies, the use of immunofluorescence or electron microscopy in histopathological evaluation, and length of follow-up. Transplant immunosuppression alone may be sufficient to keep some recurrent disease in a subclinical form, whereas other recurrent glomerular diseases may be clinically evident and progress to threaten the allograft. This review highlights the epidemiology, diagnosis, and treatment of five common glomerular diseases that may recur in the transplant: focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A nephropathy (IgAN), and lupus nephritis (LN).
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http://dx.doi.org/10.2741/723DOI Listing
January 2015

A Case of Chronic Ethylene Glycol Intoxication Presenting without Classic Metabolic Derangements.

Case Rep Nephrol 2014 21;2014:128145. Epub 2014 Aug 21.

Renal Section, Boston University School of Medicine, 650 Albany Street, Rm 504, Boston, MA 02118, USA.

Acute ethylene glycol ingestion classically presents with high anion gap acidosis, elevated osmolar gap, altered mental status, and acute renal failure. However, chronic ingestion of ethylene glycol is a challenging diagnosis that can present as acute kidney injury with subtle physical findings and without the classic metabolic derangements. We present a case of chronic ethylene glycol ingestion in a patient who presented with acute kidney injury and repeated denials of an exposure history. Kidney biopsy was critical to the elucidation of the cause of his worsening renal function.
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http://dx.doi.org/10.1155/2014/128145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158266PMC
September 2014

Dose-related effects of hyperoxia on the lung inflammatory response in septic rats.

Shock 2012 Jan;37(1):95-102

Department of Neonatology, Carmel Medical Center and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

We evaluated the effects of hyperoxia on pulmonary inflammatory changes in sepsis induced by cecal ligation and puncture (CLP) in rats. Seven groups were studied: sham-operated rats breathing air for 20 or 48 h; CLP breathing air for 20 or 48 h; and CLP + 100% oxygen for 20 h, or 70% oxygen for 48 h, or 100% oxygen intermittently (6 h/d) for 48 h. Video microscopy was used to monitor lung macromolecular leak, microvascular flow velocity, and shear rates, and lung morphometry was used for leukocyte infiltration and solid tissue area. Cell counts, tumor necrosis factor α, and nitrites were determined in peripheral blood and lung lavage fluid. Expression of adhesion molecules in blood leukocytes was evaluated by flow cytometry. Cecal ligation and puncture induced inflammation manifested in leukopenia, left shift, thrombocytopenia, increased expression of L selectin and CD11, increased serum and lavage fluid tumor necrosis factor α and leukocytes, and increased lung tissue area, macromolecular leak, and sequestration of leukocytes. Inhalation of 100% oxygen for 20 h increased nitrites (P < 0.01) and decreased leukocyte count in lavage fluid (P < 0.05) and attenuated lung macromolecular leak and changes in solid tissue area (P < 0.01). Inhalation of 70% oxygen (48 h) attenuated expression of adhesion molecules (P < 0.001) but failed to attenuate markers of lung inflammation. In contrast, intermittent 100% oxygen exerted favorable effects on markers of inflammation, attenuated leukocyte expression of L selectin and CD11 (P < 0.01), decreased pulmonary sequestration of leukocytes (P < 0.001), and ameliorated changes in macromolecular leak (P < 0.01) and lung solid tissue area (P < 0.05). Our data support the beneficial effects of safe subtoxic regimens of normobaric hyperoxia on the systemic and pulmonary inflammatory response following CLP.
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http://dx.doi.org/10.1097/SHK.0b013e3182356fc3DOI Listing
January 2012

Modulation of lupus phenotype by adiponectin deficiency in autoimmune mouse models.

J Clin Immunol 2011 Apr 10;31(2):167-73. Epub 2010 Nov 10.

Molecular Cardiology, Whitaker Cardiovascular Institute, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA.

Adiponectin is an adipocyte-derived cytokine with anti-inflammatory properties. Paradoxically, circulating adiponectin levels are increased in a number of inflammatory diseases. Thus, we sought to define the role of adiponectin deficiency in mouse models of autoimmunity. Adiponectin-deficient mice on a C57BL/6 background do not develop an autoimmune phenotype. Autoimmunity was also not observed in adiponectin-deficient mice generated on the permissive MRL background. However, adiponectin deficiency exacerbated the autoimmune phenotype of MRL-lpr mice. Compared with MRL-lpr mice, MRL-lpr.apn(-/-) mice displayed greater lymphadenopathy and splenomegaly, as well as increased anti-nuclear antibody and anti-dsDNA production. In addition, evaluation of the kidney revealed larger glomerular tuft size, crescent formation, increased IgG and C3 deposits, and mesangial expansion in the MRL-lpr.apn(-/-) mice. The effects of adiponectin deficiency on the autoimmune phenotypes were more pronounced in female versus male mice. These data show that, while adiponectin deficiency is not sufficient to confer autoimmunity, adiponectin acts as a negative modulator of the autoimmune phenotype in a murine model of lupus.
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http://dx.doi.org/10.1007/s10875-010-9486-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505060PMC
April 2011