Reversible Proximal Renal Tubular Dysfunction After One-Time Ifosfamide Exposure
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Inherited Renal Tubulopathies—Challenges and Controversies
G C A T T A C G G C A T genes Review Inherited Renal Tubulopathies—Challenges and Controversies Daniela Iancu 1,* and Emma Ashton 2 1 UCL-Centre for Nephrology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK 2 Rare & Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, Levels 4-6 Barclay House 37, Queen Square, London WC1N 3BH, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-2381204172; Fax: +44-020-74726476 Received: 11 February 2020; Accepted: 29 February 2020; Published: 5 March 2020 Abstract: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. Keywords: inherited tubulopathies; next generation sequencing; genetic heterogeneity; variant classification. 1. Introduction Mutations in genes that encode transporter proteins in the renal tubule alter kidney capacity to maintain homeostasis and cause diseases recognized under the generic name of inherited tubulopathies. -
Effects of Ramipril in Nondiabetic Nephropathy: Improved Parameters of Oxidatives Stress and Potential Modulation of Advanced Glycation End Products
Journal of Human Hypertension (2003) 17, 265–270 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARITICLE Effects of ramipril in nondiabetic nephropathy: improved parameters of oxidatives stress and potential modulation of advanced glycation end products KSˇ ebekova´1, K Gazdı´kova´1, D Syrova´2, P Blazˇı´cˇek2, R Schinzel3, A Heidland3, V Spustova´1 and R Dzu´ rik 1Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; 2Military Hospital, Bratislava, Slovakia; 3University Wuerzburg, Germany Enhanced oxidative stress is involved in the progres- patients on conventional therapy did not differ signifi- sion of renal disease. Since angiotensin converting cantly from the ramipril group, except for higher Hcy enzyme inhibitors (ACEI) have been shown to improve levels in the latter. Administration of ramipril resulted in the antioxidative defence, we investigated, in patients a drop in blood pressure and proteinuria, while creati- with nondiabetic nephropathy, the short-term effect of nine clearance remained the same. The fluorescent the ACEI ramipril on parameters of oxidative stress, AGEs exhibited a mild but significant decline, yet CML such as advanced glycation end products (AGEs), concentration was unchanged. The AOPP and malon- advanced oxidation protein products (AOPPs), homo- dialdehyde concentrations decreased, while a small rise cysteine (Hcy), and lipid peroxidation products. Ramipril in neopterin levels was evident after treatment. The (2.5–5.0 mg/day) was administered to 12 newly diag- mentioned parameters were not affected significantly in nosed patients for 2 months and data compared with a the conventionally treated patients. Evidence that rami- patient group under conventional therapy (diuretic/ pril administration results in a mild decline of fluores- b-blockers) and with age- and sex-matched healthy cent AGEs is herein presented for the first time. -
April 2020 Radar Diagnoses and Cohorts the Following Table Shows
RaDaR Diagnoses and Cohorts The following table shows which cohort to enter each patient into on RaDaR Diagnosis RaDaR Cohort Adenine Phosphoribosyltransferase Deficiency (APRT-D) APRT Deficiency AH amyloidosis MGRS AHL amyloidosis MGRS AL amyloidosis MGRS Alport Syndrome Carrier - Female heterozygote for X-linked Alport Alport Syndrome (COL4A5) Alport Syndrome Carrier - Heterozygote for autosomal Alport Alport Syndrome (COL4A3, COL4A4) Alport Syndrome Alport Anti-Glomerular Basement Membrane Disease (Goodpastures) Vasculitis Atypical Haemolytic Uraemic Syndrome (aHUS) aHUS Autoimmune distal renal tubular acidosis Tubulopathy Autosomal recessive distal renal tubular acidosis Tubulopathy Autosomal recessive proximal renal tubular acidosis Tubulopathy Autosomal Dominant Polycystic Kidney Disease (ARPKD) ADPKD Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) ADTKD Autosomal Recessive Polycystic Kidney Disease (ARPKD) ARPKD/NPHP Bartters Syndrome Tubulopathy BK Nephropathy BK Nephropathy C3 Glomerulopathy MPGN C3 glomerulonephritis with monoclonal gammopathy MGRS Calciphylaxis Calciphylaxis Crystalglobulinaemia MGRS Crystal-storing histiocytosis MGRS Cystinosis Cystinosis Cystinuria Cystinuria Dense Deposit Disease (DDD) MPGN Dent Disease Dent & Lowe Denys-Drash Syndrome INS Dominant hypophosphatemia with nephrolithiasis or osteoporosis Tubulopathy Drug induced Fanconi syndrome Tubulopathy Drug induced hypomagnesemia Tubulopathy Drug induced Nephrogenic Diabetes Insipidus Tubulopathy Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy -
Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease
Diabetes Volume 66, April 2017 791 Richard E. Gilbert Proximal Tubulopathy: Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease Diabetes 2017;66:791–800 | DOI: 10.2337/db16-0796 The current view of diabetic kidney disease, based on estimated glomerular filtration rate (eGFR) decline (2). In meticulously acquired ultrastructural morphometry and recognition of these findings, the term diabetic kidney the utility of measuring plasma creatinine and urinary al- disease rather than diabetic nephropathy is now commonly bumin, has been almost entirely focused on the glomer- used. On the background of recent advances in the role of ulus. While clearly of great importance, changes in the the proximal tubule as a prime mover in diabetic kidney PERSPECTIVES IN DIABETES glomerulus are not the major determinant of renal prog- pathology, this review highlights key recent developments. nosis in diabetes and may not be the primary event in the Published mostly in the general scientific and kidney- development of diabetic kidney disease either. Indeed, specific literature, these advances highlight the pivotal advances in biomarker discovery and a greater appreci- role this part of the nephron plays in the initiation, pro- ation of tubulointerstitial histopathology and the role of gression, staging, and therapeutic intervention in diabetic tubular hypoxia in the pathogenesis of chronic kidney kidney disease. From a pathogenetic perspective, as illus- disease have given us pause to reconsider the current trated in Fig. 1 and as elaborated on further in this review, “glomerulocentric” paradigm and focus attention on the proximal tubule that by virtue of the high energy require- tubular hypoxia as a consequence of increased energy de- ments and reliance on aerobic metabolism render it par- mands and reduced perfusion combine with nonhypoxia- ticularly susceptible to the derangements of the diabetic related forces to drive the development of tubular atrophy fi state. -
1 Fludrocortisone- a Treatment for Tubulopathy Post Paediatric Renal Transplantation: a National Paediatric Nephrology Unit Experience
Fludrocortisone- a treatment for tubulopathy post paediatric renal transplantation: A national paediatric nephrology unit experience Ali SR1, Shaheen I1, Young D2, Ramage I1, Maxwell H1, Hughes DA1, Athavale D1, Shaikh MG3 1. Department of Paediatric Nephrology, Royal Hospital for Children, 1345 Govan Road, Glasgow, UK, G51 4TF. 2. Department of Mathematics and Statistics, University of Strathclyde, 16 Richmond Street, Glasgow, UK, G1 1XQ. 3. Department of Paediatric Endocrinology and Diabetes, Royal Hospital for Children, 1345 Govan Road, Glasgow, UK, G51 4TF. Correspondence Dr MG Shaikh Department of Paediatric Endocrinology and Diabetes, Royal Hospital for Children, 1345 Govan Road, Glasgow, UK. G51 4TF Email: [email protected] Tel: 0141 451 6548 1 Fludrocortisone- a treatment for tubulopathy post paediatric renal transplantation: A national paediatric nephrology unit experience Ali SR, Shaheen I, Young D, Ramage I, Maxwell H, Hughes DA, Athavale D, Shaikh MG Pediatr Transplantation 2017 ABSTRACT Background Calcineurin inhibitors post renal transplantation are recognised to cause tubulopathies in the form of hyponatremia, hyperkalemia and acidosis. Sodium supplementation may be required, increasing medication burden and potentially resulting in poor compliance. Fludrocortisone has been beneficial in addressing tubulopathies in adult studies, with limited paediatric data available. Methods A retrospective review of data from an electronic renal database from December 2014 to January 2016. Results 47 post-transplant patients were reviewed with 23 (49%) patients on sodium chloride or bicarbonate. 9 patients, aged 8.3 years (range 4.9- 16.4) commenced fludrocortisone 22 months (range 1-80) after transplant and were followed up for 9 months (range 2-20). All patients stopped sodium bicarbonate; all had a reduction or no increase in total daily doses of sodium chloride. -
Advanced Oxidation Protein Products Contribute to Renal Tubulopathy Via Perturbation Of
Kidney360 Publish Ahead of Print, published on June 3, 2020 as doi:10.34067/KID.0000772019 Advanced oxidation protein products contribute to renal tubulopathy via perturbation of renal fatty acids Tadashi Imafuku1,2, Hiroshi Watanabe1,§, Takao Satoh3, Takashi Matsuzaka4,5, Tomoaki Inazumi6, Hiromasa Kato1, Shoma Tanaka1, Yuka Nakamura1, Takehiro Nakano1, Kai Tokumaru1, Hitoshi Maeda1, Ayumi Mukunoki7, Toru Takeo7, Naomi Nakagata7, Motoko Tanaka8, Kazutaka Matsushita8, Soken Tsuchiya6, Yukihiko Sugimoto6, Hitoshi Shimano4,9, Masafumi Fukagawa10, Toru Maruyama1,§ 1Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan 2Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto, Japan 3Kumamoto Industrial Research Institute, Kumamoto, Japan 4Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan 5Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan 6Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan 7Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto, Japan 8Department of Nephrology, Akebono Clinic, Kumamoto, Japan. 1 Copyright 2020 by American Society of Nephrology. 9AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo, Japan 10Division of Nephrology, -
Inherited Tubulopathies of the Kidney Insights from Genetics
CJASN ePress. Published on April 1, 2020 as doi: 10.2215/CJN.14481119 Inherited Tubulopathies of the Kidney Insights from Genetics Mallory L. Downie ,1,2 Sergio C. Lopez Garcia ,1,2 Robert Kleta,1,2 and Detlef Bockenhauer 1,2 Abstract The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of 1Department of Renal water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific Medicine, University transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific College London, London, United solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we will focus on Kingdom; and genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each 2Department of other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of Nephrology, Great genetically defined patients have shaped our understanding of kidney physiology. Ormond Street CJASN ccc–ccc Hospital for Children 16: , 2020. doi: https://doi.org/10.2215/CJN.14481119 NHS Foundation Trust, London, United Kingdom Introduction potentially underlying cause through clinical observa- Homeostasis refers to the maintenance of the “milieu tions. It is clinicians, who, together with genetic and Correspondence: Prof. interieur,” which, as expressed by the physiologist physiologic scientists, have often led the discovery of Detlef Bockenhauer, “ Department of Renal Claude Bernard, is a condition for a free and inde- these transport molecules and their encoding genes Medicine, University pendent existence” (1). -
Bartter Syndrome
Bartter syndrome Author: Dr Giacomo Colussi1 Creation date: August 2001 Update: September 2003, March 2005 Scientific Editor: Dr Adalberto Sessa 1A.O. Ospedale di Circolo e Fondazione Macchi, Viale Borri, 57, 21100 Varese, Italy. [email protected]: Abstract Keywords Disease name and synonyms Excluded diseases Definition Differential diagnosis Clinical description and mechanism Management including treatment Etiology Genetic counseling Antenatal diagnosis Unresolved questions References Abstract Bartter syndrome (BS) is a hereditary condition transmitted as an autosomal recessive (Bartter type 1 to 4) or dominant trait (Bartter type 5). The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. It is a consequence of abnormal function of the kidneys, which become unable to properly regulate the volume and composition of body fluids due to defective reabsorption of NaCl in a specific structure of the kidney called the " loop of Henle ". A first consequence of the tubular defect in BS is polyuria. Indeed, high urine volume is already present during fetal life, and is responsible for particular complications of pregnancy, i.e. polyhydramnios and premature delivery. Low potassium levels in the blood may result from overactivity of the renin-angiotensin II-aldosterone hormone system that is essential in controlling blood pressure. To date, at least five genes have been linked to BS, and characterize five types of BS. BS type 1 is linked to mutations of the gene SLC12A1 (Solute carrier family 12 sodium/potassium/chloride transporters, member 1) on chromosome 15 (15q15-q21.1). BS type 2 is linked to a gene called KCNJ1 (mapped to chromosome 11q21-25), BS type 3 is linked to the gene ClCNKb (mapped to chromosome 1p36) while BS type 4 is linked to gene BSND (mapped to chromosome 1p31). -
Inherited Tubulopathies of the Kidney Insights from Genetics
CJASN ePress. Published on April 6, 2020 as doi: 10.2215/CJN.14481119 Inherited Tubulopathies of the Kidney Insights from Genetics Mallory L. Downie ,1,2 Sergio C. Lopez Garcia ,1,2 Robert Kleta,1,2 and Detlef Bockenhauer 1,2 Abstract The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of 1Department of Renal water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific Medicine, University transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific College London, London, United solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we will focus on Kingdom; and genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each 2Department of other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of Nephrology, Great genetically defined patients have shaped our understanding of kidney physiology. Ormond Street CJASN ccc–ccc Hospital for Children 16: , 2020. doi: https://doi.org/10.2215/CJN.14481119 NHS Foundation Trust, London, United Kingdom Introduction potentially underlying cause through clinical observa- Homeostasis refers to the maintenance of the “milieu tions. It is clinicians, who, together with genetic and Correspondence: Prof. interieur,” which, as expressed by the physiologist physiologic scientists, have often led the discovery of Detlef Bockenhauer, “ Department of Renal Claude Bernard, is a condition for a free and inde- these transport molecules and their encoding genes Medicine, University pendent existence” (1). -
Factors Affecting the Environmentally Induced, Chronic Kidney Disease Of
environments Review Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings Sunil J. Wimalawansa 1,* and Chandra B. Dissanayake 2 1 Cardio Metabolic & Endocrine Institute, North Brunswick, NJ 08902, USA 2 Department of Geology, University of Peradeniya, National Institute of Fundamental Studies, Kandy 20000, Sri Lanka; [email protected] * Correspondence: [email protected] Received: 20 November 2019; Accepted: 11 December 2019; Published: 18 December 2019 Abstract: A new form of chronic tubulointerstitial kidney disease (CKD) not related to diabetes or hypertension appeared during the past four decades in several peri-equatorial and predominantly agricultural countries. Commonalities include underground stagnation of drinking water with prolonged contact with rocks, harsh climatic conditions with protracted dry seasons, and rampant poverty and malnutrition. In general, the cause is unknown, and the disease is therefore named CKD of unknown aetiology (CKDu). Since it is likely caused by a combination of factors, a better term would be CKD of multifactorial origin (CKDmfo). Middle-aged malnourished men with more than 10 years of exposure to environmental hazards are the most vulnerable. Over 30 factors have been proposed as causative, including agrochemicals and heavy metals, but none has been properly tested nor proven as causative, and unlikely to be the cause of CKDmfo/CKDu. Conditions such as, having favourable climatic patterns, adequate hydration, and less poverty and malnutrition seem to prevent the disease. With the right in vivo conditions, chemical species such as calcium, phosphate, oxalate, and fluoride form intra-renal nanomineral particles initiating the CKDmfo. This article examines the key potential chemical components causing CKDmfo together with the risk factors and vulnerabilities predisposing individuals to this disease. -
Renal Biopsy: Clinical Correlations November 9, 4:30-6:30 P.M
Renal Biopsy: Clinical Correlations November 9, 4:30-6:30 p.m. 20 19 Washington, DC Nov. 5–10 ASN Kidney Week 2019 – Renal Biopsy: Clinical Correlations (Full Syllabus) Case 1 from Kammi J. Henriksen, MD – University of Chicago A 50-year-old man with HIV infection (currently with an undetectable viral load), human herpesvirus 8 (HHV-8) infection, Kaposi sarcoma, and multicentric Castleman disease presented with 2 weeks of fatigue, vomiting, and anorexia. He had recently completed a course of trimethoprim and sulfamethoxazole for cellulitis. Notably, he was diagnosed with HIV infection 13 years prior to admission. He was started on highly active antiretroviral therapy (HAART) with a tenofovir-containing regimen 10 years after the diagnosis of HIV. Despite treatment, his CD4 levels remained low (100-200/µL). His HIV infection was complicated by multicentric Castleman disease, which was diagnosed 1 year prior to admission when the patient presented with fever and bilateral axillary adenopathy. Lymph node biopsy at that time showed follicular hyperplasia with HHV-8–positive cells. On admission, physical examination was significant for dry mucous membranes, sinus tachycardia, and a diffuse papular rash over his torso and extremities consistent with Kaposi sarcoma. Workup was significant for severe hyponatremia, AKI, and microscopic hematuria with dysmorphic red blood cells (RBCs). Laboratory findings were as follows: Serum Sodium 103 mEq/L Creatinine 3.7 mg/dL (previous baseline 0.9 mg/dL) HHV-8 33,700 copies/mL IL-6 83.2 pg/mL ANCA Negative Antinuclear antibodies Negative C3/C4 Negative Urine 24-Hour protein 2.1 g Urine sediment microscopy with renal tubular epithelial cells, granular casts, and RBCs. -
Combined Proximal Tubulopathy, Crystal-Storing Histiocytosis, And
Wu et al. BMC Nephrology (2017) 18:170 DOI 10.1186/s12882-017-0584-8 CASEREPORT Open Access Combined proximal tubulopathy, crystal- storing histiocytosis, and cast nephropathy in a patient with light chain multiple myeloma Chung-Kuan Wu1,2, An-Hang Yang3, Hung-Chih Lai4 and Bing-Shi Lin1,5* Abstract Background: The diagnosis of myeloma, a plasma dyscrasia, often results from the workup of unexplained renal disease. Persistent renal failure in myeloma is commonlycausedbytubularnephropathyduetocirculating immunoglobulins and free light chains. Myeloma cast nephropathy is characterized by crystalline precipitates of monoclonal light chains within distal tubules. Immunoglobulin crystallization rarely occurs intracellularly, within proximal tubular cells (light chain proximal tubulopathy) and interstitial histiocytes (crystal-storing histiocytosis). We present a case report of a rare simultaneous occurrence of light chain proximal tubulopathy, crystal-storing histiocytosis, and myeloma cast nephropathy in a patient with κ light chain multiple myeloma. Case presentation: A 48-years-old man presented with uremia and anemia. Laboratory examination revealed low levels of serum IgG, IgA, and IgM. Serum and urine immunofixation electrophoresis showed a free κ monoclonal band. Bone marrow aspiration and biopsy revealed hypercellularity with marked plasmacytosis. Light microscopy revealed eosinophilic cuboid- and rhomboid-shaped crystals in the cytoplasm of proximal tubular epithelial cells, diffuse large mononuclear and multinuclear cells in the interstitium, and obstructed distal tubules with cast and giant cell reaction. Immunohistochemical examination indicated intense staining for κ light chains within casts, histiocytes, and tubular epithelial cells. Electron microscopy revealed electro-dense cuboid-, rhomboid-, or needle-shaped crystalline inclusions in proximal tubular epithelial cells and interstitial histiocytes.