Publications by authors named "Helen Liapis"

100 Publications

Acute kidney injury pathology and pathophysiology: a retrospective review.

Clin Kidney J 2021 Feb 10;14(2):526-536. Epub 2020 Oct 10.

Department of Pathology and Immunology and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Acute kidney injury (AKI) is the clinical term used for decline or loss of renal function. It is associated with chronic kidney disease (CKD) and high morbidity and mortality. However, not all causes of AKI lead to severe consequences and some are reversible. The underlying pathology can be a guide for treatment and assessment of prognosis. The Kidney Disease: Improving Global Outcomes guidelines recommend that the cause of AKI should be identified if possible. Renal biopsy can distinguish specific AKI entities and assist in patient management. This review aims to show the pathology of AKI, including glomerular and tubular diseases.
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http://dx.doi.org/10.1093/ckj/sfaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886540PMC
February 2021

Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease.

J Am Soc Nephrol 2020 12 16;31(12):2773-2792. Epub 2020 Sep 16.

Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany

Background: The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that () asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; () UA crystal granulomas may form due to pre-existing CKD; and () proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.

Methods: MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.

Results: Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.

Conclusions: Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.
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http://dx.doi.org/10.1681/ASN.2020040523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790211PMC
December 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

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.

Sci Transl Med 2020 03;12(536)

Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
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http://dx.doi.org/10.1126/scitranslmed.aaw6003DOI Listing
March 2020

Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI.

J Am Soc Nephrol 2019 10 11;30(10):1857-1869. Epub 2019 Jul 11.

Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany;

Background: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function.

Methods: To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted studies in mouse and human kidney cells and studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl.

Results: Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of and or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI.

Conclusions: Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
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http://dx.doi.org/10.1681/ASN.2018121218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779355PMC
October 2019

Mitotic Catastrophe Causes Podocyte Loss in the Urine of Human Diabetics.

Am J Pathol 2019 02 23;189(2):248-257. Epub 2018 Nov 23.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; Renal Pathology, Arkana Laboratories, Little Rock, Arkansas. Electronic address:

Mitotic catastrophe (MC) is a major cause of podocyte loss in vitro and in vivo. We evaluated urine samples (n = 184 urine samples from diabetic patients; n = 41 patients) from diabetic patients and determined the presence of podocytes in the urine and studied their characteristics, specifically asking whether apoptosis versus MC is present. We also evaluated diabetic glomeruli in renal biopsy specimens by electron microscopy (n = 54). A battery of stains including the antibody to podocalyxin (PCX) were used. PCX and podocytes (PCX+podo) showed nuclear morphologies such as a i) mononucleated normal shape (8.7%), ii) large and abnormal shape (3.8%), iii) multinucleated with or without micronucleoli (31.2%), iv) mitotic spindles (8.2%), v) single nucleus and denucleation combined (10.3%), and vi) denucleation only (37.0%). Large size/abnormal shape, multinucleation, mitotic spindles, and a combination of single nucleus and denucleation were considered features of MC (53.5%). Dual staining of PCX+podo was positive for Glepp 1 (50%), whereas none of PCX+podo were positive for nephrin, podocin, leukocyte, or parietal epithelial cell markers (cytokeratin 8), annexin V, cleaved caspase-3, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Ten percent of PCX+podo were positive for phosphorylated vimentin. Electron microscopy identified cellular and nuclear podocyte changes characteristic of MC. The majority of urine podocytes in diabetic patients showed MC, not apoptosis. This noninvasive approach may be clinically useful in determining progressive diabetic nephropathy or response to therapeutic intervention.
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http://dx.doi.org/10.1016/j.ajpath.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943371PMC
February 2019

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study.

Kidney Int Rep 2018 Nov 3;3(6):1373-1384. Epub 2018 Aug 3.

Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients.

Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment.

Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years,  < 0.001), more frequently white (89.7% vs. 78.9%,  = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m,  < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl,  < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%,  < 0.001).

Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.
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http://dx.doi.org/10.1016/j.ekir.2018.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224619PMC
November 2018

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease.

JCI Insight 2017 12 7;2(23). Epub 2017 Dec 7.

Division of Nephrology, Department of Internal Medicine.

ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress-mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress-induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion-induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.
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http://dx.doi.org/10.1172/jci.insight.92896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752286PMC
December 2017

Collapsing glomerulopathy: a 30-year perspective and single, large center experience.

Clin Kidney J 2017 Aug 8;10(4):443-449. Epub 2017 May 8.

Renal Pathology Division, Arkana Laboratories, Little Rock, AR, USA.

Collapsing glomerulopathy (CGP) is a pattern of kidney injury seen on renal biopsy with multiple associations and etiologies. It is most commonly described in African-Americans and others with recent African ancestry. The disease is rapidly progressive and often presents with abrupt onset of renal failure and nephrotic-range proteinuria. Since its description 30 years ago, this entity has transformed from a morphologic diagnosis typically seen in the setting of HIV infection to a complicated diagnosis with numerous etiologies, many of which are associated with underlying apolipoprotein L1 ()-risk variants or other genetic disorders. We review the evolution of CGP, and its history and proposed pathomechanisms. We also present the disease spectrum from our experience with emphasis on recognizing the lesion, distinguishing from mimics and linking the histopathological pattern to a specific cause. Our understanding continues to evolve as clinicians and scientists work toward a more complete understanding of the molecular pathways of injury in this disease and how these might be disrupted for therapeutic purposes. Much still remains to be discovered in CGP as the molecular underpinnings leading to disease are still not completely understood and no effective treatment exists despite the high morbidity. Based on this rapid evolution, CGP is a modern template of how we diagnose and think about kidney disease. The story of CGP represents the current shift in nephrology and nephropathology from morphology-alone-based diagnosis to a comprehensive approach including molecular diagnostics. We believe this new, holistic approach will lead to pathogenesis-centered diagnoses that will help to individualize risk stratification and treatment protocols.
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http://dx.doi.org/10.1093/ckj/sfx029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570123PMC
August 2017

A rare case of renal thrombotic microangiopathy associated with Castleman's disease.

BMC Nephrol 2017 Feb 10;18(1):57. Epub 2017 Feb 10.

Division of Nephrology 8126, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.

Background: Castleman's disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment.

Case Presentation: An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function.

Conclusions: Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.
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http://dx.doi.org/10.1186/s12882-017-0472-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301347PMC
February 2017

Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI.

J Am Soc Nephrol 2017 Jun 10;28(6):1753-1768. Epub 2017 Jan 10.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany;

Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis , histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils. , ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.
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http://dx.doi.org/10.1681/ASN.2016080925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461800PMC
June 2017

MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury.

Cell Death Dis 2016 11 24;7(11):e2482. Epub 2016 Nov 24.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.

Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency. In vivo experiments in the zebrafish model demonstrated that the tubulus cells of the larvae undergo cell death after the knockdown of mdm2. Doxycycline-induced deletion of MDM2 in tubular cell-specific MDM2-knockout mice Pax8rtTa-cre; MDM2f/f caused acute kidney injury with increased plasma creatinine and blood urea nitrogen and sharp decline of glomerular filtration rate. Histological analysis showed massive swelling of renal tubular cells and later their loss and extensive tubular dilation, markedly in proximal tubules. Ultrastructural changes of tubular epithelial cells included swelling of the cytoplasm and mitochondria with the loss of cristae and their transformation in the vacuoles. The pathological phenotype of the tubular cell-specific MDM2-knockout mouse model was completely rescued by co-deletion of p53. Tubular epithelium compensates only partially for the cell loss caused by MDM2 depletion by proliferation of surviving tubular cells, with incomplete MDM2 deletion, but rather mesenchymal healing occurs. We conclude that MDM2 is a non-redundant survival factor for proximal tubular cells by protecting them from spontaneous p53 overexpression-related cell death.
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http://dx.doi.org/10.1038/cddis.2016.390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260907PMC
November 2016

Myoglobin casts in renal biopsies: immunohistochemistry and morphologic spectrum.

Hum Pathol 2016 08 30;54:25-30. Epub 2016 Mar 30.

Nephropath, Little Rock, AR, 72211.

Five hundred eighty renal biopsies from a pool of 27850 archived cases were identified in which a myoglobin stain was performed because of atypical casts. Two hundred and thirty-eight (41%) of these biopsies were found to be positive for myoglobin casts. The morphology of the myoglobin casts ranged from light, almost translucent and refractile, to pink, to dark red and slightly brown granular casts by hematoxylin and eosin, to beaded globular casts that stained brightly fuchsinophilic with Masson trichrome and partially argyrophilic with silver methenamine. All biopsies displayed acute tubular injury associated with intratubular debris and thinning and vacuolization of tubular epithelium. Approximately 20% of myoglobin-positive biopsies showed calcium oxalate or phosphate deposition. Positive myoglobin staining was present in casts, proximal tubular epithelial cells without casts, and also dehisced epithelial cells. Collecting ducts and occasionally the distal tubular epithelium also stained positive. One case showed concurrent myeloma cast nephropathy with "fractured" casts and translucent myoglobin-positive casts. Herein, we describe the morphologic spectrum of myoglobin-positive casts. We conclude that utilization of myoglobin immunohistochemistry is advantageous and, when not available, knowledge of the morphologic spectrum is important.
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http://dx.doi.org/10.1016/j.humpath.2016.02.026DOI Listing
August 2016

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis.

Nat Commun 2016 Jan 28;7:10274. Epub 2016 Jan 28.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität, München, Munich 80336, Germany.

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure.
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http://dx.doi.org/10.1038/ncomms10274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738349PMC
January 2016

Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology.

Lab Invest 2016 Apr 11;96(4):378-90. Epub 2016 Jan 11.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV der Ludwig-Maximilians Universität, Munich, Germany.

Acute kidney injury (AKI) involves nephron injury leading to irreversible nephron loss, ie, chronic kidney disease (CKD). Both AKI and CKD are associated with distinct histological patterns of tissue injury, but kidney atrophy in CKD involves tissue remodeling with interstitial inflammation and scarring. No doubt, nephron atrophy, inflammation, fibrosis, and renal dysfunction are associated with each other, but their hierarchical relationships remain speculative. To better understand the pathophysiology, we provide an overview of the fundamental danger response programs that assure host survival upon traumatic injury from as early as the first multicellular organisms, ie, bleeding control by coagulation, infection control by inflammation, epithelial barrier restoration by re-epithelialization, and tissue stabilization by mesenchymal repair. Although these processes assure survival in the majority of the populations, their dysregulation causes kidney disease in a minority. We discuss how, in genetically heterogeneous population, genetic variants shift balances and modulate danger responses toward kidney disease. We further discuss how classic kidney disease entities develop from an insufficient or overshooting activation of these danger response programs. Finally, we discuss molecular pathways linking, for example, inflammation and regeneration or inflammation and fibrosis. Understanding the causative and hierarchical relationships and the molecular links between the danger response programs should help to identify molecular targets to modulate kidney injury and to improve outcomes for kidney disease patients.
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http://dx.doi.org/10.1038/labinvest.2015.164DOI Listing
April 2016

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications.

J Am Soc Nephrol 2016 06 13;27(6):1635-49. Epub 2015 Nov 13.

Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.
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http://dx.doi.org/10.1681/ASN.2015020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884104PMC
June 2016

Focal segmental glomerulosclerosis: molecular genetics and targeted therapies.

BMC Nephrol 2015 Jul 9;16:101. Epub 2015 Jul 9.

, Nephropath, Little Rock, Arkansas.

Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS. A stratified and targeted approach based on the underlying molecular defects is evolving.
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http://dx.doi.org/10.1186/s12882-015-0090-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496884PMC
July 2015

C1q nephropathy in the setting of granulomatosis with polyangiitis treated with tacrolimus.

Clin Kidney J 2014 Oct 5;7(5):499-500. Epub 2014 Aug 5.

Department of Pediatrics , Washington University School of Medicine , St. Louis, MO 63110 , USA ; Department of Pediatrics , Children's National Medical Center , Washington, DC 20010 , USA.

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http://dx.doi.org/10.1093/ckj/sfu087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379345PMC
October 2014

A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring.

Front Med (Lausanne) 2015 20;2:13. Epub 2015 Mar 20.

Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA.

Background: Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies.

Methods: We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-β3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer.

Results: All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, β3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-β3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar(®) Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79 mg/dL with <1 g of proteinuria.

Conclusion: ACTH therapy was associated with improvement in renal function within 4 weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.
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http://dx.doi.org/10.3389/fmed.2015.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367432PMC
April 2015

Cell type specific changes in BMP-7 expression contribute to the progression of kidney disease in patients with obstructive uropathy.

J Urol 2015 May 24;193(5 Suppl):1860-1869. Epub 2015 Mar 24.

Department of Surgery, Division of Urology, St. Louis Children's Hospital and Department of Pathology and Immunology, Barnes-Jewish Hospital (HL), Washington University, St. Louis, Missouri.

Purpose: Congenital urinary tract obstruction is a leading cause of renal maldevelopment and pediatric kidney disease. Nonetheless, few groups have examined its molecular pathogenesis in humans. We evaluated the role of BMP-7, a protein required for renal injury repair and nephrogenesis, in disease progression in patients with obstructive uropathy.

Materials And Methods: Whole kidney and cell specific BMP-7 expression was examined in a murine model of unilateral ureteral obstruction and in patients with congenital ureteropelvic junction obstruction. Findings were correlated with molecular markers of renal injury and clinical parameters.

Results: Unilateral ureteral obstruction led to a dramatic decrease in BMP-7 expression in the proximal and distal tubules before the onset of significant loss of renal architecture and fibrosis, suggesting that this is a critical molecular event that drives early stage disease progression. Loss of BMP-7 expression then extended to the collecting ducts and glomeruli in end stage kidney disease. When translating these findings to patients with ureteropelvic junction obstruction, global loss of BMP-7 expression correlated with a decreased number of nephrons, loss of renal architecture, severe renal fibrosis and loss of kidney function.

Conclusions: Given that BMP-7 has a critical role in renal injury repair and nephrogenesis, these findings show that cell specific changes in BMP-7 expression contribute to the onset of irreversible renal injury and impaired kidney development secondary to congenital urinary tract obstruction. Accordingly therapies that target these cell populations to restore BMP-7 activity may limit disease progression in patients with obstructive uropathy.
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http://dx.doi.org/10.1016/j.juro.2014.10.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502418PMC
May 2015

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN.

J Am Soc Nephrol 2015 Oct 2;26(10):2399-413. Epub 2015 Feb 2.

Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti-glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.
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http://dx.doi.org/10.1681/ASN.2014070673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587690PMC
October 2015

Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes.

J Am Soc Nephrol 2015 07 27;26(7):1513-23. Epub 2014 Oct 27.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;

Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivation-related cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.
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http://dx.doi.org/10.1681/ASN.2014040345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483582PMC
July 2015

Cardiac and renal effects of atrasentan in combination with enalapril and paricalcitol in uremic rats.

Kidney Blood Press Res 2014 19;39(4):340-52. Epub 2014 Sep 19.

Renal Division, Washington University School of Medicine, St. Louis, MO, USA.

Background/aims: The search for new therapies providing cardiorenal protection in chronic kidney disease (CKD) has led to treatments that combine conventional renin-angiotensin-aldosterone-system inhibitors with other drugs that exhibit potential in disease management.

Methods: In rats made uremic by renal ablation, we examined the effects of addition of the endothelin-A receptor antagonist atrasentan to a previously examined combination of enalapril (angiotensin converting enzyme inhibitor) and paricalcitol (vitamin D receptor activator) on cardiac and renal parameters. The effects of the individual and combined drugs were examined after a 3-month treatment.

Results: A decrease in systolic blood pressure, serum creatinine and proteinuria, and improvement of renal histology in uremic rats were attributed to enalapril and/or paricalcitol treatment; atrasentan alone had no effect. In heart tissue, individual treatment with the drugs blunted the increase in cardiomyocyte size, and combined treatment additively decreased cardiomyocyte size to normal levels. Perivascular fibrosis was blunted in uremic control rats with atrasentan or enalapril treatment.

Conclusions: We found distinct cardiac and renal effects of atrasentan. Combination treatment with atrasentan, enalapril and paricalcitol provided positive effects on cardiac remodeling in uremic rats, whereas combination treatment did not offer further protective effects on blood pressure, proteinuria or renal histology.
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http://dx.doi.org/10.1159/000355811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225010PMC
June 2015

Significance of isolated vasculitis in the gynecological tract: what clinicians do with the pathologic diagnosis of vasculitis?

Ann Diagn Pathol 2014 Aug 13;18(4):199-202. Epub 2014 Apr 13.

Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

Vasculitides includes a heterogeneous group of disorders with the common histologic findings of vascular wall inflammation. Systemic or localized disease (eg, renal vasculitis) has serious consequences. The incidence of isolated gynecologic vasculitis diagnosed on pathology specimens and its significance is little known. We performed a 20 year retrospective review including 53 cases with vasculitis diagnosis affecting the female genital tract identified in pathology reports. None had prior symptoms or were diagnosed with generalized vasculitis, while one patient had prior diagnosis of fibromyalgia. Most patients presented with abnormal bleeding and were treated for conditions unrelated to vasculitis. The different types of vasculitis were: predominantly lymphocytic (nonspecific) 30 cases, necrotizing 17 cases and granulomatous 6 cases. Only 2 patients had additional serologic tests. None of the patients with isolated gynecologic vasculitis received corticosteroids or additional treatment related to the vasculitis. None of the patients developed systemic vasculitis at follow-up (2 months-19.5 years; mean, 5.5 years). Isolated gynecologic vasculitis diagnosed on pathology slides is rarely associated with systemic vasculitis. Potential isolated gynecologic vasculitis causes include: previous surgical interventions and vascular inflammation secondary to local neoplasm. In almost all cases, clinicians did not perform a thorough laboratory analysis to exclude systemic vasculitis and therapy was not required in any case, suggesting minimal clinical significance.
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http://dx.doi.org/10.1016/j.anndiagpath.2014.03.008DOI Listing
August 2014

American Society of Nephrology clinical pathological conference.

Clin J Am Soc Nephrol 2014 Apr 20;9(4):818-28. Epub 2014 Mar 20.

The Children Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania;, †Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, Missouri, ‡Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

A 13-year-old girl presented with proteinuria and acute kidney failure. She was born at full term via cesarean delivery (due to nuchal cord), but there were no other prenatal or perinatal complications. In early childhood the patient had two hospitalizations at ages 4.5 and 9 years, respectively, the latter for pneumonia. She had no history of symptoms of kidney disease. She came to the hospital at age 12 years for routine bilateral molar extractions. She was treated with oral antibiotics and discharged after the procedure without complications. At age 13 years, 10 months after the molar extraction, she was seen by a pediatrician because of puffiness and increased BP. She had had respiratory symptoms 2 weeks before presentation. The pediatrician prescribed furosemide and amlodipine. A few days later, the patient returned to the pediatrician's office because of hand, ankle, and facial swelling and malaise. The pediatrician recommended hospitalization and the patient was admitted at this time.
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http://dx.doi.org/10.2215/CJN.12481213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974370PMC
April 2014

Claudin 1 and nephrin label cellular crescents in diabetic glomerulosclerosis.

Hum Pathol 2014 Mar 12;45(3):628-35. Epub 2013 Nov 12.

Washington University School of Medicine, Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, St Louis, MO, USA. Electronic address:

Cellular crescents are typically inflammatory and associated with rapidly progressive glomerulonephritis. Their pathogenesis involves glomerular basement membrane rupture due to circulating or intrinsic factors. Crescents associated with diabetic glomerulosclerosis are rarely reported. Furthermore, the nature of cells forming crescents in diabetes is unknown. To investigate the nature of crescents in diabetes, we examined renal biopsies from diabetic patients with nodular glomerulosclerosis and crescents (n = 2), diabetes without crescents (n = 5), nondiabetic renal biopsies (n = 3), and crescentic glomerulonephritis with inflammatory crescents (n = 5). Electron microscopy and confocal immunofluorescence analysis with antibodies against nephrin (a podocyte marker) and claudin 1 (parietal epithelial cell marker) were performed. Diabetic glomeruli with crescents contained a mixture of crescentic cells expressing either claudin 1 (11 ± 1.4 cells/glomerulus) or nephrin (5.5 ± 3.0 cells/glomerulus). Rare crescentic cells coexpressed nephrin and claudin 1 (2.5 ± 1.6 cells/glomerulus). In contrast, inflammatory crescents were almost exclusively composed of claudin 1-positive cells (25 ± 5.3 cells/glomerulus). Cells coexpressing claudin 1 and nephrin were absent in inflammatory crescents and all cases without crescents. Electron microscopy showed podocyte bridge formation between the glomerular basement membrane and parietal basement membrane but no glomerular basement membrane rupture as in inflammatory crescents. Crescents in diabetes may occur in diabetes in the absence of a secondary etiology and are composed of a mixture of parietal epithelial cells and visceral podocytes. Cells coexpressing parietal epithelial and podocyte markers suggest that parietal epithelial cells may transdifferentiate into podocytes in response to severe glomerular injury.
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http://dx.doi.org/10.1016/j.humpath.2013.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156314PMC
March 2014

Clinicopathological course of acute kidney injury following brown recluse (Loxoscles reclusa) envenomation.

Clin Kidney J 2013 Dec 1;6(6):609-12. Epub 2013 Oct 1.

Department of Medicine , Washington University School of Medicine , St Louis , MO , USA.

We report a case of severe systemic loxoscelism in a previously healthy young man. This was associated with a Coombs-positive hemolytic anemia, striking leukomid reaction, renal failure, respiratory failure and cardiovascular collapse. This is the first documented case of a renal biopsy in a patient with renal failure after envenomation by the brown recluse spider. Associated systemic toxicity usually resolves but requires prompt recognition and supportive care in an intensive care setting. We also discuss the potential mechanism by which the venom of this small spider can lead to multiorgan failure and possibly death.
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http://dx.doi.org/10.1093/ckj/sft111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438362PMC
December 2013

Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria.

PLoS One 2013 10;8(10):e76360. Epub 2013 Oct 10.

Department of Internal Medicine (Renal division), Washington University School of Medicine, St. Louis, Missouri, United States of America.

We applied customized targeted next-generation exome sequencing (NGS) to determine if mutations in genes associated with renal malformations, Alport syndrome (AS) or nephrotic syndrome are a potential cause of renal abnormalities in patients with equivocal or atypical presentation. We first sequenced 4,041 exons representing 292 kidney disease genes in a Caucasian woman with a history of congenital vesicoureteral reflux (VUR), recurrent urinary tract infections and hydronephrosis who presented with nephrotic range proteinuria at the age of 45. Her biopsy was remarkable for focal segmental glomerulosclerosis (FSGS), a potential complication of longstanding VUR. She had no family history of renal disease. Her proteinuria improved initially, however, several years later she presented with worsening proteinuria and microhematuria. NGS analysis revealed two deleterious COL4A3 mutations, one novel and the other previously reported in AS, and a novel deleterious SALL2 mutation, a gene linked to renal malformations. Pedigree analysis confirmed that COL4A3 mutations were nonallelic and compound heterozygous. The genomic results in conjunction with subsequent abnormal electron microscopy, Collagen IV minor chain immunohistochemistry and progressive sensorineural hearing loss confirmed AS. We then modified our NGS approach to enable more efficient discovery of variants associated with AS or a subset of FSGS by multiplexing targeted exome sequencing of 19 genes associated with AS or FSGS in 14 patients. Using this approach, we found novel or known COL4A3 or COL4A5 mutations in a subset of patients with clinically diagnosed or suspected AS, APOL1 variants associated with FSGS in African Americans and novel mutations in genes associated with nephrotic syndrome. These studies demonstrate the successful application of targeted capture-based exome sequencing to simultaneously evaluate genetic variations in many genes in patients with complex renal phenotypes and provide insights into etiology of conditions with equivocal clinical and pathologic presentations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794937PMC
June 2014

Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification.

Kidney Int 2013 Dec 9;84(6):1145-53. Epub 2013 Oct 9.

Renal Division, Washington University School of Medicine, St Louis, Missouri, USA.

The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism, cardiovascular disease, and progression of renal failure is widely known. Here we studied effects of dietary phosphate restriction on mortality and vascular calcification in uremic rats. Control and uremic rats were fed a high-phosphate diet and at 3 months a portion of rats of each group were killed. Serum phosphate and the calcium phosphate product increased in uremic rats, as did aortic calcium. Of the rats, 56% had positive aortic staining for calcium (von Kossa), RUNX2, and osteopontin. The remaining uremic rats were continued on diets containing high phosphate without and with sevelamer, or low phosphate, and after 3 more months they were killed. Serum phosphate was highest in uremic rats on high phosphate. Serum PTH and FGF-23 were markedly lower in rats on low phosphate. Mortality on high phosphate was 71.4%, with sevelamer reducing this to 37.5% and phosphate restriction to 5.9%. Positive aortic staining for von Kossa, RUNX2, and osteopontin was increased, but phosphate restriction inhibited this. Kidneys from low-phosphate and sevelamer-treated uremic rats had less interstitial fibrosis, glomerulosclerosis, and inflammation than those of uremic rats on high phosphate. Importantly, kidneys from rats on low phosphate showed improvement over kidneys from high-phosphate rats at 3 months. Left ventricles from rats on low phosphate had less perivascular fibrosis and smaller cardiomyocyte size compared to rats on high phosphate. Thus, intensive phosphate restriction significantly reduces mortality in uremic rats with severe vascular calcification.
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http://dx.doi.org/10.1038/ki.2013.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589836PMC
December 2013