Tropical Nephrology [1st ed.] 9783030444990, 9783030445003

Citation preview

Tropical Nephrology Geraldo Bezerra da Silva Junior Elizabeth De Francesco Daher Elvino Barros Editors

123

Tropical Nephrology

Geraldo Bezerra da Silva Junior Elizabeth De Francesco Daher  •  Elvino Barros Editors

Tropical Nephrology

Editors Geraldo Bezerra da Silva Junior University of Fortaleza Fortaleza, Ceará Brazil

Elizabeth De Francesco Daher Federal University of Ceará Fortaleza, Ceará Brazil

Elvino Barros Federal University of Rio Grande do Sul Porto Alegre, Rio Grande do Sul Brazil

Original Portuguese edition published by Livraria Balieiro, São Paulo, Brazil, 2019 ISBN 978-3-030-44499-0    ISBN 978-3-030-44500-3 (eBook) https://doi.org/10.1007/978-3-030-44500-3 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to my wife, Ana, who taught me that the right to health is a fundamental right, that the neglected tropical diseases are not only a medical problem but a social problem, and that states and nations have a civil responsibility to control them. Also, I dedicate this book to all the patients affected by tropical diseases, who generously let us take care of them and voluntarily participate in our studies, contributing to the advance of this branch of science, which, as these diseases, is in some way neglected. Geraldo Bezerra da Silva Junior

Foreword

Since the publication of English naturalist Charles Darwin’s On the Origin of Species in 1859, it has been known that every living organism has a close relationship with its environment, through what Darwin termed “descent with modification” by the mechanism of natural selection, which was later to be called the theory of evolution. This is as true for multicellular organisms as it is for all others, at different adaptive velocities. This assumption suggests the need for studies that identify the actual association between kidney disease in individuals in the tropics and the diseases involved in these environmental conditions. That said, we believe this book does an excellent job of contextualizing kidney disease in the tropical latitudes and, particularly, in the Brazilian scenario. The book Tropical Nephrology fills a gap that is absolutely necessary to understand kidney disease and its many associations with diseases that are characteristic of tropical areas, which coincides not only with many of their endemic characteristics but especially with the precarious socioeconomic status of countries in this region of the world, thus severely affecting the health services available to their populations. Although the World Health Organization’s report  – Integrating Neglected Tropical Diseases in Global Health and Development – published in 2017 is quite optimistic about the advances made during the last 10 years in relation to what they call “neglected tropical diseases” (NTDs), the situation is still extremely alarming, even in a country such as Brazil, which, despite the universal health coverage provided by the Unified Health System like primary care services, vaccination campaigns, and drug distribution, still suffers from poor regional distribution of professionals and services. In addition, the country has to deal with basic sanitation issues, and also the outbreak of recent epidemics of previously controlled tropical diseases, or somewhat unexpected ones, such as the Zika and Chikungunya epidemics. The aforementioned report indicates that millions of individuals in Latin American countries are at risk from several diseases, some of which are manageable through simple measures, although accessible at different degrees in these countries. vii

viii

Foreword

The scope of this study establishes a very important parameter for the study of kidney disease. The different scenarios presented in the chapters show that research in Brazil, in spite of all known limitations, yields results that are relevant to knowledge. This is one of the merits of this work, which is to present the diversity of views having as the background kidney disease and its interactions with health problems, which, unfortunately, are still on the agenda in our health system. Considering the scarcity of resources and the growing number of individuals with some degree of kidney disease – the vast majority of which are undiagnosed or, due to exposures to tropical diseases, have underdiagnosed kidney conditions that become aggravated and chronic – this work provides a good starting point and opens up, for instance, the possibility for future studies that will consider the economic aspect and will perhaps apply the DALY (disability-adjusted life years) concept to our reality, which each tropical disease imposes on populations. Whether in preventive or curative programs, to adequately define this concept and combine it with kidney disease can be helpful at any given time and place, especially where resources can achieve their best results. I want to congratulate the willingness and the efforts of all who contributed to the creation of this work, its collaborating authors and organizers. The scientific quality of the material, added to the experience and ability of all those who dedicated themselves to making this material available, shows the indispensability of its careful reading. I would also like to congratulate the creators of this magnificent work, particularly the editors Geraldo Bezerra da Silva Junior, Elizabeth De Francesco Daher, and Elvino Barros of the Brazilian Society of Nephrology for their contribution to the world. Natalino Salgado Filho, MD, PhD Full Professor of Nephrology at the Federal University of Maranhão Full Member of the National Academy of Medicine Member of the Brazilian Academy of Medicine and Academy of Letters of Maranhão São Luís, Brazil

Acknowledgments

This book is based on the original Portuguese edition (Nefrologia Tropical) published by Livraria Balieiro, São Paulo, Brazil, 2019, and includes updates. We would like to acknowledge Sonia Strong for the translation of chapters in Portuguese to English and also the support from the Diretoria de Pesquisa, Desenvolvimento e Inovação (DPDI) of the Universidade de Fortaleza (UNIFOR), Fundação Edson Queiroz, Brazil.

ix

Contents

1 Tropical Diseases: A Public Health Problem with Impact on Nephrology��������������������������������������������������������������������    1 Nattachai Srisawat and Visith Sitprija 2 Renal Function Evaluation in Tropical Diseases����������������������������������   17 Geraldo Bezerra da Silva Junior, Elvino Barros, Elizabeth De Francesco Daher, and Francisco Veríssimo Veronese 3 Snakebites Accidents and Renal Complications������������������������������������   27 Jacqueline de Almeida Gonçalves Sachett, Sâmella Silva de Oliveira, Valquir Silva dos Santos, Vanderson de Souza Sampaio, Wuelton Marcelo Monteiro, and Marcus Vinícius Guimarães de Lacerda 4 Hemorrhagic Accidents Caused by Lonomia obliqua ��������������������������   41 Alaour Candida Duarte and Elvino Barros 5 Toxic Acute Kidney Injury����������������������������������������������������������������������   47 Polianna Lemos Moura Moreira Albuquerque and Fathima Shihana 6 Tropical Diseases in Kidney Transplantation����������������������������������������   67 Lúcio Roberto Requião Moura, Silvana Daher Costa, and Tainá Veras de Sandes-Freitas 7 Renal Involvement in Patients with Arbovirus Infections��������������������   91 Roberto da Justa Pires Neto and Geraldo Bezerra da Silva Junior 8 Renal Involvement in Chagas’ Disease (American Trypanosomiasis)������������������������������������������������������������������  105 Elizabeth De Francesco Daher, Geraldo Bezerra da Silva Junior, Elvino Barros, and Verônica Verleine Hörbe Antunes 9 Schistosomiasis Mansoni-Associated Kidney Disease��������������������������  113 Daniella Bezerra Duarte, Elizabeth De Francesco Daher, Maria Eliete Pinheiro, and Michelle Jacintha Cavalcante Oliveira

xi

xii

Contents

10 Acute Kidney Injury in Yellow Fever ����������������������������������������������������  131 Cassia Fernanda Estofolete, Rodrigo José Ramalho, Horácio José Ramalho, and Mauricio Lacerda Nogueira 11 Nephropathy in Lymphatic Filariasis����������������������������������������������������  137 Maria Eliete Pinheiro, Daniella Bezerra Duarte, Michelle Jacintha Cavalcante Oliveira, and Gilberto Fontes 12 Post-streptococcal and Epidemic Glomerulonephritis ������������������������  155 Ana Kleyce Correia Rocha, Artur Quintiliano Bezerra da Silva, and Gianna Mastroianni Kirsztajn 13 Leprosy Nephropathy������������������������������������������������������������������������������  167 Verônica Verleine Hörbe Antunes, Elvino Barros, Alice Maria Costa Martins, Gdayllon Cavalcante Meneses, Elizabeth De Francesco Daher, and Geraldo Bezerra da Silva Junior 14 Hantavirus Infection and the Renal Syndrome������������������������������������  175 Stefan Vilges de Oliveira and Álvaro Adolfo Faccini-Martínez 15 Viral Hepatitis and Kidney Disease��������������������������������������������������������  193 Roberto da Justa Pires Neto, Elodie Bomfim Hyppolito, and Geraldo Bezerra da Silva Junior 16 HIV-Associated Kidney Disease��������������������������������������������������������������  209 Geraldo Bezerra da Silva Junior, Juliana Gomes Ramalho de Oliveira, Elizabeth De Francesco Daher, and Saraladevi Naicker 17 Staphylococcal Infections and Kidney Disease��������������������������������������  223 Maria Almerinda Vieira Fernandes Ribeiro Alves 18 Renal Involvement in American Cutaneous Leishmaniasis ����������������  231 Rodrigo Alves de Oliveira, Guilherme Alves de Lima Henn, Paulo Sérgio Ramos de Araújo, and Claudio Gleidston Lima da Silva 19 Visceral Leishmaniasis (Kala-Azar) Nephropathy ������������������������������  249 Gdayllon Cavalcante Meneses, Guilherme Alves de Lima Henn, Alice Maria Costa Martins, Michelle Jacintha Cavalcante Oliveira, and Elizabeth De Francesco Daher 20 Leptospirosis and Weil’s Syndrome ������������������������������������������������������  263 Gabriela Studart Galdino, Geraldo Bezerra da Silva Junior, and Elizabeth De Francesco Daher 21 Malaria and Renal Complications����������������������������������������������������������  277 Valquir Silva dos Santos, Karla Cristina Silva Petruccelli, Alba Regina Jorge Brandão, Izabella Picinin Safe Lacerda, Fernando Fonseca de Almeida e Val, and Marcus Vinícius Guimarães de Lacerda

Contents

xiii

22 Acute Kidney Injury in Tetanus ������������������������������������������������������������  291 Juliana Gomes Ramalho de Oliveira, Geraldo Bezerra da Silva Junior, Guilherme Alves de Lima Henn, and Elizabeth De Francesco Daher 23 Renal Tuberculosis ����������������������������������������������������������������������������������  299 Rafael Siqueira Athayde Lima, Geraldo Bezerra da Silva Junior, Elvino Barros, and Elizabeth De Francesco Daher Index������������������������������������������������������������������������������������������������������������������  309

Editors and Contributors

Editors Elvino  Barros  School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Elizabeth  De  Francesco  Daher  Post-Graduation Program in Medical Sciences, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil Geraldo Bezerra da Silva Junior  Post-Graduation Programs in Public Health and Medical Sciences, School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil

Contributors Polianna  Lemos  Moura  Moreira  Albuquerque  Center for Toxicological Assistance and Information, Instituto Dr. José Frota, Fortaleza, Ceará, Brazil School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil Maria  Almerinda  Vieira  Fernandes  Ribeiro  Alves  Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil Verônica Verleine Hörbe Antunes  Division of Nephrology, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Paulo  Sérgio  Ramos  de Araújo  School of Medicine, Federal University of Pernambuco, Recife, Pernambuco, Brazil

xv

xvi

Editors and Contributors

Elvino  Barros  School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Alba  Regina  Jorge  Brandão  Critical Care Unit, Getulio Vargas University Hospital, Federal University of Amazonas, Manaus, Amazonas, Brazil Silvana  Daher  Costa  Division of Renal Transplantation, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Ceará, Brazil Division of Renal Transplantation, General Hospital of Fortaleza, Fortaleza, Ceará, Brazil Elizabeth  De  Francesco  Daher  Post-Graduation Program in Medical Sciences, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil Alaour Candida Duarte  School of Medicine, University of Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil Daniella  Bezerra  Duarte  School of Medicine, Federal University of Alagoas, Maceió, Alagoas, Brazil Cassia Fernanda Estofolete  Division of Infectious Diseases, Hospital de Base de São José do Rio Preto, School of Medicine of São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil Álvaro Adolfo Faccini-Martínez  Committee of Tropical Medicine, Zoonoses and Travel Medicine, Asociación Colombiana de Infectología, Bogotá, Colombia Tainá  Veras  de Sandes-Freitas  Division of Renal Transplantation, General Hospital of Fortaleza, Fortaleza, Ceará, Brazil Department of Internal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil Gilberto Fontes  Health Sciences Center, Federal University of São João del-Rei, São João del-Rei, Minas Gerais, Brazil Gabriela  Studart  Galdino  Division of Internal Medicine, Walter Cantidio University Hospital, Federal University of Ceará, School of Medicine, Unichristus University Center, Fortaleza, Ceará, Brazil Guilherme  Alves  de Lima  Henn  Department of Community Health, Federal University of Ceará, Fortaleza, Ceará, Brazil Elodie Bomfim Hyppolito  Walter Cantidio University Hospital, Federal University of Ceará, School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil Gianna Mastroianni Kirsztajn  Department of Medicine (Nephrology), Federal University of São Paulo, São Paulo, São Paulo, Brazil Izabella Picinin Safe Lacerda  Division of Infectious Diseases, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amanozas, Brazil

Editors and Contributors

xvii

Marcus  Vinícius  Guimarães  de Lacerda  Post-Graduation Program in Tropical Medicine, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, State University of Amazonas, Manaus, Amazonas, Brazil Rafael  Siqueira  Athayde  Lima  Division of Nephrology, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Ceará, Brazil Division of Nephrology, General Hospital of Fortaleza, Fortaleza, Ceará, Brazil Alice Maria Costa Martins  Department of Clinical and Toxicological Analyses, Post-Graduation Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, Ceará, Brazil Gdayllon Cavalcante Meneses  Department of Internal Medicine, Post-Graduation Program in Medical Sciences, Federal University of Ceará, Fortaleza, Ceará, Brazil Wuelton  Marcelo  Monteiro  Post-Graduation Program in Tropical Medicine, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, State University of Amazonas, Manaus, Amazonas, Brazil Lúcio Roberto Requião Moura  Department of Medicine (Nephrology), Federal University of São Paulo, São Paulo, SP, Brazil Renal Transplantation Division, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil Saraladevi Naicker  School of Clinical Medicine, University of the Witwatersrand, Johannesburg, Gauteng, South Africa Mauricio  Lacerda  Nogueira  Department of Parasitic and Infectious Diseases, School of Medicine of São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil Juliana Gomes Ramalho de Oliveira  Post-Graduation Program in Public Health, University of Fortaleza, Fortaleza, Ceará, Brazil Michelle Jacintha Cavalcante Oliveira  School of Medicine, Federal University of Alagoas, Maceió, Alagoas, Brazil Rodrigo Alves de Oliveira  School of Medicine, Federal University of Pernambuco, Caruaru, Pernambuco, Brazil Sâmella Silva de Oliveira  Post-Graduation Program in Tropical Diseases, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil Stefan Vilges de Oliveira  Department of Collective Health, School of Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil Karla  Cristina  Silva  Petruccelli  Department of Internal Medicine, Federal University of Amazonas, Manaus, Amazonas, Brazil Maria  Eliete  Pinheiro  School of Medicine, Federal University of Alagoas, Maceió, Alagoas, Brazil

xviii

Editors and Contributors

Roberto  da Justa  Pires  Neto  Department of Community Health, Federal University of Ceará, São José Hospital of Infectious Diseases, Fortaleza, Ceará, Brazil Horácio José Ramalho  Division of Nephrology, School of Medicine of São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil Rodrigo José Ramalho  Division of Infectious Diseases, Hospital de Base de São José do Rio Preto, School of Medicine of São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil Ana Kleyce Correia Rocha  School of Medicine, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil Natalino Salgado Filho  School of Medicine, Federal University of Maranhão, São Luís, Maranhão, Brazil Jacqueline de Almeida Gonçalves Sachett  Nursing School, State University of Amazonas, Manaus, Amazonas, Brazil Vanderson  de Souza  Sampaio  Post Graduation Programs in Tropical Medicine and Health Sciences, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil Department of Endemic Diseases, State Health Surveillance Foundation of Amazonas, Manaus, Amazonas, Brazil Valquir Silva dos Santos  Division of Nephrology, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil Fathima  Shihana  Translational Australian Clinical Toxicology Program, The University of Sydney, Sydney, NSW, Australia Artur Quintiliano Bezerra da Silva  School of Medicine, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil Claudio  Gleidston  Lima  da Silva  School of Medicine, Federal University of Cariri, Barbalha, Ceará, Brazil Geraldo Bezerra da Silva Junior  Post-Graduation Programs in Public Health and Medical Sciences, School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil Visith  Sitprija  Queen Saovabha Memorial Institute, Thai Red Cross, Bangkok, Thailand Nattachai  Srisawat  Division of Nephrology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand Critical Care Nephrology Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Academic of Science, Royal Society of Thailand, Bangkok, Thailand

Editors and Contributors

xix

Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand Excellence Center for Critical Care Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand Fernando Fonseca de Almeida e Val  Critical Care Unit, Post-Graduation Program in Tropical Medicine, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil Francisco  José  Veríssimo  Veronese  Department of Internal Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Chapter 1

Tropical Diseases: A Public Health Problem with Impact on Nephrology Nattachai Srisawat and Visith Sitprija

1.1  Geography of the Tropics The tropics are the region of the earth surrounding the equator. This area is located between the Tropic of Cancer in the northern hemisphere at 23°26′13.8″ N and the Tropic of Capricorn in the southern hemisphere at 23°26′13.8″ S. These latitudes correspond to the axial tilt of the earth. The tropics include all the areas on the earth where the sun reaches a subsolar point, a point directly overhead at least once during the solar year. This zone comprises the Northern part of Australia, most of Southeast Asia and South Asia, almost all of Africa, and Central and Southern parts of the American continent. The tropics currently contain nearly 150 countries and account for 40% of the world’s population, and it is predicted that by 2050 approximately 55% of the world’s population will live in this region. Indeed, most of the countries in this region have been grouped by the World Bank into low- to low-middle income countries that have limited access to many services, including health care.

N. Srisawat (*) Division of Nephrology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand Critical Care Nephrology Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Academic of Science, Royal Society of Thailand, Bangkok, Thailand Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand Excellence Center for Critical Care Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand V. Sitprija Queen Saovabha Memorial Institute, Thai Red Cross, Bangkok, Thailand © Springer Nature Switzerland AG 2020 G. Bezerra da Silva Junior et al. (eds.), Tropical Nephrology, https://doi.org/10.1007/978-3-030-44500-3_1

1

2

N. Srisawat and V. Sitprija

The World Health Organization (WHO) uses the terminology “Neglected Tropical Diseases” or NTDs to describe a diverse group of communicable and noncommunicable diseases. NTDs mainly affect populations living in poverty, without adequate sanitation and in close contact with infectious vectors, domestic animals, and livestock. Neglected Zoonotic Diseases (NZDs) are a critically important subset of NTDs.

1.2  Overview of Tropical Renal Diseases Tropical renal diseases are the common causes of acute kidney injury (AKI), being recognized as any disease in the tropics that affects the kidneys, although one may consider infectious and non-infectious etiologies such as snakebite ­toxins, plant toxins, and chemical toxins to contribute toward AKI in tropical areas, and the WHO has included snakebite envenoming in the list of NTDs [1, 2]. There are only a few reports that have studied the impact of tropical diseases causing AKI on a multinational level. A recent major report from the 0by25 Global Snapshot team revealed that of a total of 4105 AKI cases, 50% occurred in tropical areas (13% in Africa, 14% in Latin American/Caribbean countries, 4% in Oceania/ Southeast Asia, and 19% in South Asia). As previously mentioned, most of the tropical countries in this study were defined as low-income countries and lower middle-­ income countries (LLMIC). While dehydration was the leading cause of AKI (nearly 50%), sepsis, pregnancy-related AKI, and envenomation were more common in LLMIC than other income areas [3]. The causes of tropical renal diseases causing AKI can be broadly divided into infectious and non-infectious causes (Table 1.1). The leading infectious causes are leptospirosis, malaria, dengue virus, and hantavirus. The distribution of these infections can also vary by geographical area. Leptospirosis-associated AKI is highly prevalent in the Caribbean, South America, South Asia, and Southeast Asia. Malaria-associated AKI is highly prevalent in Sub-­ Saharan Africa, Southeast Asia, the Caribbean, and South America. Dengue-­ associated AKI is highly prevalent in the Caribbean, South America, and Southeast Asia. Hantavirus-associated AKI is highly prevalent in East Asia.

1.3  P  ublic Health Risk Dimensions That Have an Impact on Tropical Renal Diseases 1.3.1  Environmental Factors As summarized in Fig. 1.1, there are many factors predisposing to renal disease in the tropics. Due to the great heterogeneity of the area, the etiology and pattern of tropical renal diseases also differ among regions in the tropics. Large parts of the tropics are prone to earthquakes, landslides, floods, typhoons, and tsunamis. Many of the

1  Tropical Diseases: A Public Health Problem with Impact on Nephrology Table 1.1  Specific causes of tropical renal diseases

3

Infectious causes Viral infections  Dengue infectiona  Hantaan virus infection Bacterial infections  Leptospirosisa  Melioidosis  Scrub typhus  Salmonellosis  Shigellosis Parasitic infections  Malariaa  Leishmaniasis (kala-azar) Noninfectious causes Plant and fungal toxins  Herbal medicines  Djenkol beans  Snake envenomation  Wasp, hornet, and bee stings  Spider bites  Scorpion stings  Jellyfish stings  Raw carp bile Chemical nephrotoxins  Ethylene glycol  N, N′-dimethyl-4,4′-bipyridinium dichloride  Ethylene dibromide  Copper sulfate  Chromic acid Environmental factors  Heatstroke  Natural disasters Miscellaneous  Obstetric complications a

Common cause

tropical renal diseases have been linked to poverty, lack of potable water, poor sanitation, and poor housing conditions [4]. The tropical climate also predisposes to the proliferation of tropical infectious diseases such as leptospirosis, dengue, malaria, parasites, and others. High temperature, humid weather, and high salinity favor the persistence of infections in animal reservoirs, intermediate hosts, and vectors of parasitic diseases, as well as promote the survival of pathogenic microorganisms outside the human host, thereby increasing the population of vectors and the transmission of waterborne diseases [5–8]. Heavy rains or floods have been linked to a higher number of cases of leptospirosis. Soil with a pH greater than 7.0 is suspected to promote the survival of the Leptospira bacteria. Leptospirosis is also considered an occupational disease, affecting rice laborers, sewer workers, animal handlers, and gold miners [9, 10]. Flooding is also related to the increased incidence of snakebites. During the flooding, the snakes change their habitat from the burrows to the surface. This fact puts a

4

N. Srisawat and V. Sitprija

Environment

Socioeconomic

- Tropical climates

- Limited health care access

- Variation in race

Inherent

- Poor sanitations

- Limited health care budget

- Multiple comorbidities: diabetes, hypertension,

- Poor water quality

- Health beliefs

dyslipidemia

- Natural disasters: flooding, earthquakes - Variation of geology: high altitudes, island - lnadequate control of vectors (mosquitoes)

Tropical Renal Diseases

Process of care

Exposure - Tropical infections: Malaria/dengue/leptospirosis

- Shortage health care providers (physicians, nurses)

- Toxin: snake bites Russel vipers), bee stings, etc.

- Lack of standardization of test, ie. serum creatinine

- Dehydration: diarrhea

- Limited health care technology: ultrasound, imaging, point of care testing

- Matemal/fetal complications

- Lack of standard check lists/protocol, clinical practice guideline

- Herbal use - NSAIDs

Fig. 1.1  Public health impact of tropical renal diseases

large number of farmers or workers working in the fields planting crops at risk for snakebites [11, 12]. Not only the flooding but earthquakes also constitute a common type of natural disaster in the tropics. AKI is among the top three complications after earthquakes [13]. However, it is difficult to estimate the incidence of AKI after natural disasters because a large number of patients with AKI will probably go undiagnosed and underreported. Earthquake victims often have crush syndrome, which develops as a result of rhabdomyolysis after being trapped under rubble. The systemic manifestations include hypovolemic shock, acute oliguric AKI, hyperkalemia, metabolic acidosis, and psychological trauma. The mortality rate in dialyzed patients with crush-syndrome-related AKI was reported as being within the range of 15–40% [14–16]. The main prevention treatment for crush syndrome is early adequate fluid resuscitation [17]. Due to the risk of hyperkalemia, the resuscitation fluid should be a potassium-sparing fluid [18]. Besides crush syndrome, several other factors also contribute to the development of earthquakes disaster-related AKI. Traumatic bleeding can lead to hypovolemic shock, which results in pre-renal AKI and, subsequently, in acute tubular necrosis. Nephrotoxic drugs can contribute to at least one-third of trauma-related AKI, and penetrating trauma to the urinary tract system can cause post-renal AKI. The soil in the tropics is fragile due to high temperatures and heavy precipitation leaching minerals and organic compounds, which enter flowing water, leading to waterlogging and contamination of grain fields. Contaminated water with heavy metals is considered the cause of chronic kidney disease of unknown etiology (CKDu). CKDu is a new terminology to describe CKD that is not attributable to any traditional risk factor, such as diabetes, hypertension, or HIV.  CKDu is being reported with increasing frequency in many parts of the tropics, such as Central America, East Asia, and South Asia [19–22].

1  Tropical Diseases: A Public Health Problem with Impact on Nephrology

5

1.3.2  Socioeconomic Factors Populations in the tropics are characterized by greater heterogeneity than in temperate climates in terms of socioeconomic status, lifestyle, level of education, access to goods, services, and medical care. Patterns of tropical renal diseases in those resource-sufficient settings were considered to be similar to those in high-income western countries. Their patients tend to be older, comorbid with chronic diseases, complicated with postsurgical conditions, and often develop hospital-acquired AKI [23, 24]. Interestingly, national GDP (gross domestic product) per capita is consistently lower in countries in tropical latitudes than in those in higher latitudes, in both the northern and southern hemispheres. Tropical countries with low GDP consistently show higher prevalence rates of community-acquired AKI. In contrast, tropical renal diseases in resource-limited settings, such as in South Asia and Southeast Asia, are likely to be community-acquired ones, affecting mainly the young and healthy population. In many parts of the tropics, people living in rural areas face environmental health risks, malnutrition, besides being unable to access standard health care and, therefore, are at risk for AKI. Maternal malnutrition results in low birth weight children with low nephron counts, which predisposes to impaired immunity, high blood pressure, cardiovascular disease, and kidney disease in the elderly [4]. Furthermore, almost all cities in tropical countries contain large slum areas, where basic amenities are as limited as those in rural areas, making their disease patterns almost indistinguishable. Poverty and lack of appropriate regulations also increase the risk of getting in contact with industrial toxins that can cause AKI [25].

1.3.3  Process of Care Factors 1.3.3.1  Shortage of Nephrologist in the Tropics Despite the size and population of the tropics, there are substantial differences regarding economic prosperity and the gross national product in each country. Shortage of doctors, especially internists and nephrologists, is a severe hindrance in almost every area [26]. The registries of nephrologists in each country are mostly unpublished and out-of-date. From the available data, the ratio of nephrologists per million population (pmp) ranged from 0.2 to 79 pmp [27–30]. There is also an uneven distribution of nephrologists in each region of the country, with the majority of nephrologists working in the capitals or regional hospitals. For example, the number of nephrologists is approximately 25 pmp in Bangkok, but an average of only 12 pmp in regional areas of Thailand. The scarcity of nephrologists in provincial hospitals and massive workloads for internists and general practitioners are barriers to tropical renal diseases recognition and proper initial management, which leads to a delayed referral to nephrologists (Fig. 1.2).

6

N. Srisawat and V. Sitprija

Myanmar

0,2

Indonesia

0,2

Laos

0,7

India

0,7

Vietnam

0,8

Phillippines

2

Pakistan

2

China

6

Thailand

12

Brunei

25

Japan

79 0

10

20

30

40

50

60

70

80

pmp 90

Fig. 1.2  Distribution of Nephrologists in Asian countries

1.3.4  Exposure Factors Tropical infections are one of the most common exposure/causes of tropical renal diseases and are recognized as community-acquired renal emergencies [1, 2]. The source of tropical infections causing AKI can be broadly divided into those caused by viruses, bacteria, and parasites. The leading causes are leptospirosis, malaria, dengue virus, and hantavirus. Leptospirosis is an important zoonosis, especially in tropical areas. However, with the impact of world globalization, there have also been reports of this disease as sporadic cases in developed countries. A recent report has shown that the endemic area of leptospirosis include the Caribbean and Central and South America, as well as Southeast Asia and Oceania [31]. Kidney injury with hyperbilirubinemia represents a severe form of renal disease called Weil’s syndrome. AKI is one of the most severe complications of leptospirosis. The incidence of AKI in leptospirosis, when using the standard AKI criteria, is up to 84% [32]. This is approximately two times higher than AKI incidence in the intensive care unit (ICU) [33]. This specific situation injures the kidney through a direct effect, as well as indirect effects, such as dehydration, rhabdomyolysis, and bleeding [34, 35]. Tropical and subtropical regions are endemic areas of malaria transmission. Malaria is caused by five species of the genus Plasmodium, namely Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. There has been a trend of reductions in the number of malaria cases, as well as deaths over the past 15 years. It was estimated that the number of

1  Tropical Diseases: A Public Health Problem with Impact on Nephrology

7

malaria cases has decreased from 262 million in 2000 to 214 million in 2015 (about 20% reduction), while the number of deaths has decreased from 839,000 to 438,000 (about 50% in death cases). Most cases in 2015 were estimated to occur in the WHO African region (88%), followed by the WHO Southeast Asia region (10%) and the WHO Eastern Mediterranean region (2%). Similarly, it was estimated that in 2015 most deaths (90%) occurred in the WHO African region, followed by the WHO Southeast Asia region (7%) and the WHO Eastern Mediterranean region (2%). The incidence of malaria-associated AKI widely ranges from 0.5% to 30% in different series, because this depends on the cohort of patients and the criteria used for AKI definition [36–41]. Dengue infection is endemic mainly in the tropics and subtropics, with approximately one third of the world’s population being at risk for dengue infection. The worldwide infection rate is close to 50–100 million each year [42]. The clinical spectrum of dengue infection and kidney disease includes pre-renal, acute tubular necrosis due to direct and indirect effects, thrombotic microangiopathy, glomerulopathy such as IgG, C3, IgM deposition, and proliferative glomerulonephritis [43]. The prevalence of dengue-associated AKI in previous studies varied widely due to the heterogeneous AKI definitions, population age groups, and the severity of dengue virus infection. Current available data were mainly derived from case reports and retrospective studies. Two studies use the elevation of serum creatinine to more than 2 mg/dL for AKI definition and may underestimate the prevalence of AKI [44, 45]. However, later studies have applied the Acute Kidney Injury Network (AKIN) criteria and the risk, injury, failure, loss of kidney function, and end-stage acute kidney disease (RIFLE) criteria, which allowed an increase in the diagnosis of AKI [46, 47]. In summary, the prevalence of acute kidney injury ranges from 0.2 to 35.7%. Fluid and electrolyte disorders are common in patients with tropical diseases. Changes in serum electrolyte and mineral levels associated with tropical diseases include hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, hyperphosphatemia, and hypomagnesemia [48]. Kositseth et al. reported that 75% of patients with leptospirosis had hypermagnesuria, whereas 50% of patients had a decreased threshold of tubular reabsorption of phosphate. These abnormal findings were significantly improved within 2 weeks after admission [49]. In addition to infectious etiologies, noninfectious etiologies such as snakebite, plant, and chemical toxins are also common causes of AKI in the tropics [50]. A recent major report from the 0by25 Global Snapshot team revealed that of a total of 4105 AKI cases, 51% occurred in Asia (28% in North and East Asia, 4% in Oceania/ Southeast Asia, and 19% in South Asia). Dehydration was the leading cause of AKI (nearly 50%), followed by sepsis, pregnancy-related AKI, and envenomation [3]. Snakebite-induced AKI contributes to 70% of community-acquired AKI in Myanmar, 2–3% in India, and 1–2% in Thailand [25]. The mechanisms have been attributed to direct and indirect effects, such as dehydration, hemolysis, rhabdomyolysis, and disseminated intravascular coagulation. Data from retrospective series reported an AKI incidence of 1.4–38%, with a mortality rate ranging from 1 to 20%

8

N. Srisawat and V. Sitprija

[50, 51] depending on the snake species. Kidney injury usually occurs within hours but can also occur as late as several days after the bite. More than 90% of the patients develop oliguria and require dialysis [50]. The most common AKI pattern is acute tubular necrosis, followed by acute interstitial nephritis and acute renal cortical necrosis. Occasionally, necrotizing and crescentic glomerulonephritis can be seen. Early administration of specific monovalent antivenom, before AKI onset, is critical. Dialysis should be performed early and frequently, when indicated. Raw carp bile (fish gall bladder), which is used for treating acne, improving visual efficiency and relieving arthritis, is another common animal toxin in Asia. This ichthyotoxicity (toxicity produced by fish) is caused by a toxin, sodium cyprinol sulfate, a C27 (fish) bile acid. Sodium cyprinol sulfate is heat stable, and thus, even after cooked, the fish can still be toxic [52]. Many toxins from tropical plants can cause AKI, such as Djenkol beans in southern Thailand [53], impila (Callilepis laureola) [54, 55], star fruit (Averrhoa carambola) [56], poisonous mushrooms (Amanita phalloides) [57], cotton seed oil (gossypol) in southern China, which causes hypokalemia and distal renal tubular acidosis [58], and Chinese herbs (Aristolochic acid) inducing tubular atrophy and interstitial fibrosis [59]. The use of these herbal medicines, which may be effective in folk medicine, is also the part of basic beliefs in each culture. Therefore, kidney disease in the tropics is an expression of the relationship between culture, beliefs, and the environment. Wasp and bee stings are other common causes of AKI in the tropics, especially in South Asia, and in South America, where Africanized bees cause many cases of AKI since the 1950s [60]. Recently, the large report from China showed that the severity of wasp sting depend on the number of stings. The critical number of stings for severe systemic symptoms such as kidney and liver injury is around ten stings [61]. Obstetric complications deserve special consideration as a cause of AKI in Asia. Reports from India showed AKI in 0.06–2% of delivery cases, with placental abruption, pre-eclampsia, and puerperal sepsis being the leading causes of pregnancy-­ related AKI [62, 63]. This type of complication is also another example of the consequence of poor access to healthcare facilities.

1.4  Inherent Factors The inherent factors associated with AKI include age, gender, genetic susceptibility, and other comorbidities, such as diabetes mellitus, hypertension, malignancy, and preexisting chronic kidney disease [26]. In the past, this factor might have had a lesser impact on AKI than the other factors, compared to developed countries. However, with the effect of urbanization/globalization, we believe the inherent factors should have a higher impact on the incidence of AKI in the tropics, not far or less.

1  Tropical Diseases: A Public Health Problem with Impact on Nephrology

9

Moreover, there are also genetic disorders that are common in the tropics, such as the occurrence of glucose 6 phosphate dehydrogenase deficiency, which increases the incidence of intravascular hemolysis [64], and the human AE2 anion exchanger (AE2 mutation), which causes distal renal tubular acidosis and renal stones in Thailand [65]. Takayasu arteritis, a disease that causes inflammation of the aorta and its main branch, is seen in South Asia and Southeast Asia [66–68].

1.5  Tropical Renal Diseases and the “One Health” Approach The predominant cause of tropical renal diseases in developing countries is community-­acquired AKI, of which one of the main causes is tropical infectious diseases. This is in contrast to AKI in developed countries, where hospital-acquired AKI is a predominant cause of the disease [69]. Therefore, prevention through the “One Health” approach is the key to success in controlling infection-related AKI in the tropics. The “One Health” approach comprises the aspects of human, animal (reservoir), and environmental factors [9]. The “One Health” working definition states that it is feasible to integrate human, animal, and environmental health efforts to predict and control certain diseases at the human–animal–ecosystem interface; integrated approaches that consider human, animal, and environmental health components can improve prediction and control of certain diseases. Leptospirosis and malaria, two of the most common tropical infections causing AKI, are an excellent example for the “One Health” approach, where the association between humans, animals, and ecosystems is studied to improve knowledge about a disease and to enhance collaborative inter-sectoral and multidisciplinary control strategies. Socioeconomic drivers include living in dense urban or peri-urban areas with inadequate waste collection and sanitation. Many of the tropical infections causing AKI have been linked to poverty, lack of access to drinkable water and sanitation services, and poor housing conditions [4]. Heavy rains or floods have been associated with a higher number of leptospirosis cases. Alkaline and neutral soils are suspected of promoting longer survival for these bacteria [9, 10]. Leptospirosis is also considered an occupational disease, affecting rice laborers, sewer workers, animal handlers, and gold miners. A better understanding of the drivers for leptospirosis would provide crucial information for decision-makers to be able to target risk areas for priority interventions. In malaria, the main transmission route is the mosquito bite. Data from systematic reviews showed that climate change, lack of preventive tools such as bed nets, repellants, poor infrastructure, less qualified healthcare professionals, noncompliance, and lack of efficacy of drugs play an important role in malarial transmission [4, 70].

10

N. Srisawat and V. Sitprija

Indeed, to compete with these types of zoonosis diseases, the current gaps in scientific and technological knowledge that might delay case detection and limit surveillance programs must be addressed. Finally, vaccines have been identified as the perfect key instrument to overcome all tropical infections causing AKI, but they are not available at this time.

1.6  Strategies to Improve AKI Recognition in the Tropics 1.6.1  Risk Assessment and Use of Clinical Risk Scores In general settings, the risk factors for AKI are age, presence of heart failure, liver failure, chronic kidney disease, anemia, and exposure to nephrotoxic agents. Infections, sepsis, shock, need for mechanical ventilation, and surgery are high-risk settings for the development of AKI [71, 72]. Community-acquired AKI also have different risk factors from hospital-acquired AKI. In a Southeast Asia (SEA)-AKI study, female gender, obesity, diabetes, and APACHE II were risk factors for community-acquired AKI, while obesity, APACHE II, and observation periods were risk factors for hospital-acquired AKI (Srisawat N, unpublished data). Sukmark et al. proposed the THAI LEPTO score to help physicians in the rural area to attain an early diagnosis of leptospirosis. The score is based on clinical parameters and simple laboratory tests. The simplified score with 7 variables consists in the summation of the odds ratio values as follows: hypotension = 3, jaundice = 2, muscle pain = 2, AKI = 1.5, low hemoglobin = 3, hypokalemia with hyponatremia = 3, and neutrophilia = 1. The score showed the highest discriminatory power with an area under the curve (AUC) = 0.82 (95%CI: 0.67 ± 0.97) on fever days 3 and 4 [73]. Srisawat et al. recently reported the role of urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) in the early diagnosis of leptospirosisassociated AKI.  The AUC-ROC values of urinary NGAL (uNGAL) and plasma NGAL (pNGAL) for AKI diagnosis were 0.91 and 0.92, respectively [74]. In malaria, the risk factors for AKI were age, absence of fever, higher heart rate, lower diastolic blood pressure, icterus, hepatomegaly, and direct bilirubin [75]. Whereas in dengue patients, presence of dengue hemorrhagic fever, rhabdomyolysis, multiple-organ dysfunction, diabetes mellitus, delayed hospitalization, and use of nephrotoxic drugs were associated with AKI [76]. Aye KP et al. studied patients with snake envenomation in Myanmar and found that snakebites from the Viperidae family, WBC greater than 10 × 103 cells/ɥL, overt disseminated intravascular coagulation, serum creatinine kinase >500 IU/L, serum sodium 6 hours) [39].

3.7  Kidney Injury in Snakebite Accidents The kidneys are highly vascularized organs with excretory function with marked vulnerability to direct toxin action, since they are mainly eliminated through the kidneys [33]. The degree of renal toxicity will depend on several factors, such as snake genus, accident classification, and time of exposure to the venom [49]. AKI is a common systemic complication in Viperidae snake poisoning in Africa, Echis carinatus, sea kraits, and Russell’s viper in Asia, and Bothrops and Crotalus genera in the Americas. The complications are associated with the high lethality among the victims [50–52]. The pathogenesis of AKI has yet to be fully elucidated. Some studies have proposed a multifactorial origin [53] while the triggering factors may act in combination [15, 45, 54, 55]. The mechanisms involved are hemodynamic disorders, immunological reactions, and the nephrotoxic action of the venom itself [56]. Hemodynamic disorders may be triggered by changes in hemostasis [52]. These alterations are related to (1) activation of factor X and prothrombin; (2) conversion of fibrinogen into fibrin by thrombin-like substances; (3) thrombocytopenia; (4) metalloproteinase action, which compromise the integrity of the endothelial wall both locally and systemically [21, 52]. Hemolysis and hematuria are involved in the kidney injury process through the deposition and accumulation of hemoglobin and myoglobin cylinders, causing obstruction and induction of vasoconstriction, culminating in ischemia and AKI [53]. Disseminated intravascular coagulation (DIC) can occur in patients that are victims of bothropic accidents, and it plays an important role in the development of AKI, with deposition of fibrin thrombi in the renal parenchyma and microvasculature [57]. Approximately 25% of victims who developed AKI concomitantly had DIC [49].

34

J. de Almeida Gonçalves Sachett et al.

Of less relevance, the presence of C3 and IgM in the glomeruli suggests the formation of immunocomplexes and, consequently, they may be associated with the development of glomerulonephritis [51]. Although there is some controversy regarding the direct venom action on the renal parenchyma, experimental models have been developed, and this phenomenon has been shown to occur in the presence of high venom concentrations [56]. Hypoperfusion and nephrotoxicity are believed to act synergistically by increasing the frequency of acute tubular necrosis (ATN) [58]. The rapid onset of the clinical picture, ranging from 24 to 48 hours, suggests, however, a direct action of the venom in the renal tissue [49]. Some studies have pointed out that PLA2 present in the venom promote renal alterations [51, 59]. In crotalic accidents, in addition to the aforementioned mechanisms, rhabdomyolysis due to myotoxic action can cause myoglobinuria, hyperkalemia, and AKI. Crotoxin constitutes 50% of the venom and explains the high occurrence of muscle injury and consequent AKI [52]. Although bothropic and crotalic accidents are more frequent causes of AKI, the mechanism of kidney injury is different. In bothropic envenomation, this complication is due to changes in hemostasis, while in crotalic accidents, AKI occurs due to the myotoxic action of the venom [55]. ATN and acute interstitial nephritis (AIN) are the most common anatomopathological injuries seen in snakebite accidents and may be reversed. In some cases, bilateral cortical necrosis (BCN) is an irreversible condition that progresses to chronic kidney disease (CKD) [45, 55]. However, it has been observed that the mechanism of kidney injury occurs through ATN in snakebite accidents [60]. AKI diagnosis is usually established within the first 24–48 hours [45, 52, 60]. The most common alterations found in the laboratory tests of patients with AKI are alterations in urinary sediment, glycosuria, proteinuria, leukocyturia, epithelial cells, cylinders, hematuria, hemoglobinuria, decreased hematocrit, and increased serum urea and creatinine levels [15, 61]. Figure 3.3 illustrates the processes involved in the pathophysiology of kidney injury due to snake envenomation. In India, approximately 13.5% of snakebite accidents develop AKI, and almost 50% of them require dialysis therapy [57]. Among the genera that cause snakebite accidents in Brazil, bothropic accidents show a prevalence between 1.4 and 38% of AKI, and in crotalic accidents, the prevalence ranges from 10 to 29% [45, 52]. Mortality among the victims varies between 13 and 19% [45]. In Amazonas, a study based on officially reported data disclosed that of the 9191 reported cases, most were caused by the Bothrops genus, and approximately 12.6% of the victims developed AKI [39]. In a referral unit located in the city of Manaus, capital of the Amazonas state, Brazil, of 212 patients with confirmed B. atrox envenomation, 10.9% developed AKI [62]. Several variables are involved in the development of post-envenomation AKI: snake species, victim’s age, children due to their smaller body surface area, time until the AV is administered, and the presence of comorbidities such as diabetes, hypertension, previous nephropathy, and coronary heart disease [45, 49, 55].

3  Snakebites Accidents and Renal Complications

35

TOXINS Immunological reactions

Vasoactive mediators and cytokines

Vasoactive mediators and cytokines Inflammation Modulation of adhesion molecule expression Complement activation Free radical generation Release of inflammatory mediators Increased blood Viscosity Hypovolemia

Anaphylaxis

Immunocomplexes

Direct venom effects

Ion channel modulators

Pore formation

Coagulopathy

Membrane lysis

Hemolysis Rhabdomyolysis

Cytoskeleton destruction

Hemodynamic alteration

Kidney injury

Fig. 3.3  Flowchart of the pathophysiology of toxin-induced kidney injury. (Adapted from Albuquerque et al. [45], with permission. © 2013 Instituto de Medicina Tropical de São Paulo)

3.8  Management of Kidney Injury in Snakebite Accidents The initial approach to the patient with kidney dysfunction that has been a victim of a snakebite accident involves general supportive measures, usual measures for patients with kidney injury, and specific ones, especially when the condition progresses with the need for renal replacement therapy. As overall measures, it is important to evaluate factors that may aggravate the already established kidney injury, such as the use of nephrotoxic drugs, especially non-hormonal anti-inflammatory drugs; the presence of associated bacterial infections in patients with cellulitis or abscesses, with treatment being preferentially based on culture results; daily assessment of edema, if present, as well as of arterial pulses and tissue perfusion. The onset of compartment syndrome requires prompt surgical intervention. Clinical suspicion occurs in the presence of tense edema, sensitivity alterations, functional limitation, and changes in perfusion. Rhabdomyolysis is another possible complication, and when present, it worsens kidney injury. In such cases, with the use of the same approach as in traumatic injuries, urine output should be maintained between 200 and 300 mL/h. Among the usual measures in patients with kidney injury, volume replacement is an essential one. An infusion of 0.9% saline solution or lactated Ringer’s solution is used for blood volume replacement. Strict diuresis control should be maintained every hour, especially in accidents classified as moderate or severe. Typically, adolescents and adults have a urinary output >0.5 mL/kg/h (30–40 mL/h) and children have >1.0–2.0 mL/kg/h. It is important to note that such replacement aims mainly at

36

J. de Almeida Gonçalves Sachett et al.

achieving normovolemia, since bleeding and nausea with vomiting add to large fluid sequestrations in the interstitium of affected areas. Other basic measures for the treatment of AKI are the correction of electrolyte disorders using diuretics and vasoactive drugs. Specific treatment with AV use according to the accident classification is crucial. Several studies have reported that late administration of the AV is a risk factor for the development of AKI, and its early administration may reverse kidney injuries [60]. Maintaining a high urinary flow protects the renal parenchyma and keeps a normal blood flow. Nevertheless, it is imperative to remember that there is invariably an already established kidney injury, and that renal replacement therapy will be necessary in the absence of diuresis (80% for disease diagnosis [118]. A significant percentage of patients develop chronic polyarthritis, which can last from months to years [119]. In immunosuppressed patients, the intensity of joint symptoms may be milder or absent, and discontinuation of joint complaints is common after a short period of the acute phase [116, 120]. Laboratory diagnosis depends on the stage of the disease. In the first week, when the viremia occurs, the examination of choice is by PCR, but in transplant patients, it is estimated that the viremia is shorter, and thus, it is recommended that the diagnostic examination be performed within the first days of symptom onset [121]. By the fifth day, IgM becomes positive and may persist for several months. IgG positivity can last for years. Viral isolation is the gold standard method, but it is difficult to achieve. Treatment is usually restricted to symptom management. In animal models, the effect of immunotherapy and in vitro antiviral activity have been demonstrated using favipiravir, as well as interferon-associated ribavirin, but these strategies still need proof of efficacy and safety through clinical studies [122–124].

82

L. R. Requião Moura et al.

6.6.5.3  Zika In Brazil, the first confirmed case of zika occurred in 2015 [125]. In addition to mosquito bites, transmission can occur through sexual contact, perinatal transmission, and transfusion of blood products [13]. There are no reports of transmission through transplanted organs. The viremia lasts about 7–10  days. Recent studies have shown that viruria is more intense and lasts longer than viremia [126]. The Brazilian Health Regulatory Agency (ANVISA) advises waiting at least 30  days after the resolution of the condition or after sexual contact with a partner with suspected infection to donate cells, organs, and tissues [127, 128]. In living donor transplants, however, when the donor has a recognized infection, it is suggested to wait at least 120 days after the resolution of the condition to perform the donation. There are few reports of the disease in transplant patients, which can be underdiagnosed, considering the potential for asymptomatic evolution. It is widely known that zika infection may be associated with neonatal microcephaly, neurological complications, and Guillain–Barré syndrome [129]. Due to few case reports in transplant patients, the precise clinical picture, disease evolution, and duration of viremia in this population are not known; however, there have been reports of associations with renal graft dysfunction, but with complete function recovery after resolution of the infection [128]. Diagnosis can be made by serology, but there have been reports of cross-reaction with dengue virus, which may cause false-positive results for dengue. Treatment is restricted to supportive measures.

6.7  Strongyloidiasis Strongyloides stercoralis infection is endemic to Brazil, with an estimated incidence of over 20% of the overall population, and therefore, it is one of the most relevant helminth diseases in the country [36, 130, 131]. In kidney transplant recipients, as in any solid-organ transplantation, strongyloidiasis can have a catastrophic evolution, which justifies the discussion of prophylactic strategies and a better understanding of this infection in this specific population. The disease can occur through the reactivation of a pre-existing chronic intestinal infection, which is the most common form in transplant recipients, followed by de novo acquisition in endemic areas and, eventually, transmission through the graft [36, 61, 132, 133]. Four different forms of the infection can be clinically identified [130, 134–137]: acute, chronic intestinal, hyperinfection syndrome, and disseminated strongyloidiasis. The acute form is characterized by nonspecific abdominal pain, usually associated with nausea, vomiting and, more often, with diarrhea, in addition to skin lesions, which may occur sporadically together with signs of pulmonary involvement, such as dry cough and wheezing, which characterizes Loeffler’s syndrome. The chronic intestinal form, which is the most frequent one, is characterized by unspecific and intermittent signs and symptoms such as anorexia, diarrhea, constipation, abdominal pain, and epigastric pain. In more severe but rare cases, it may progress to malabsorption syndrome, paralytic ileus, intestinal obstruction,

6  Tropical Diseases in Kidney Transplantation

83

duodenal obstruction, and gastrointestinal bleeding. Intensification of the intestinal condition, associated with more severe pulmonary manifestations, such as dyspnea and hemoptysis, occur in the hyperinfection syndrome, when there is an amplification in the normal life cycle of Strongyloides stercoralis, accompanied by a large number of larvae in the duodenum, which migrate to the lungs through the venous system. In these three forms, the helminth larvae are found only at the sites of their usual life cycle. Finally, in disseminated strongyloidiasis, the clinical picture of hyperinfection syndrome is associated with other systemic complications, such as meningitis, cholecystitis, liver abscess, pancreatitis, or septic shock, so the larvae are found in different sites other than those of their natural life cycle. The severe forms are associated with mortality rate of >50% and are more frequently observed in individuals receiving immunosuppressants, especially those with intensified immunosuppression, such as the one that occurs at the beginning of transplantation or after treatment for acute rejection episodes [60, 134]. The clinical picture in transplant individuals is quite nonspecific, but in general, there are symptoms of gastrointestinal tract involvement, which can be mistaken for other common infections in the first months after transplantation, such as cytomegalovirus, but more often, abdominal distension and signs of acute abdomen are observed, progressing to severe sepsis and septic shock. The degree of suspicion should be high and empirical treatment cannot be delayed. The diagnosis can be based on parasitological, serological, or histological methods; however, in this population, the diagnosis is most often attained by identification of the larva in body fluids, such as tracheal aspirate, bronchoalveolar lavage, pleural fluid, urine, cerebrospinal fluid, and peritoneal fluid [138]. The treatment of acute or chronic intestinal infection is preferably carried out with ivermectin administration for 2  days or alternatively with albendazole for 3 days, and the regimen should be repeated within 1 week [139, 140]. In hyperinfection or disseminated disease, the choice is ivermectin and the treatment time depends on the clinical evolution, which, on average, should be carried out for 10–14 days. In severe cases without the possibility of oral intake, the rectal route may be used, or even the parenteral formulation for veterinary use through subcutaneous route may be considered [137, 141]. As previously described, prophylaxis should be instituted for all kidney transplant recipients, preferably with ivermectin for 2  days, 2 weeks before transplantation, in the case of living donor recipients, or shortly after surgery in any case, as well as after the treatment for acute rejection episodes or the need for intensified immunosuppression for any other reason.

References 1. Cusumano AM, Di Gioia C, Hermida O, Lavorato C. Latin American registry of dialysis and renal transplantation. The Latin American dialysis and renal transplantation registry annual report 2002. Kidney Int Suppl. 2005;97:S46–52. 2. de Castro Rodrigues Ferreira F, Cristelli MP, Paula MI, Proença H, Felipe CR, Tedesco-Silva H, et al. Infectious complications as the leading cause of death after kidney transplantation: analysis of more than 10,000 transplants from a single center. J Nephrol. 2017;30(4):601–6.

84

L. R. Requião Moura et al.

3. El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM, et al. Identifying specific causes of kidney allograft loss. Am J Transplant. 2009;9(3):527–35. 4. Anzdata Australia and New Zealand dialysis and transplant registry [Internet] [cited 1 May 2018]. Available from: http://www.anzdata.org.au/v1/report_2016.html. 5. CTS Newsletter 2:2012: death with a functioning graft [Internet] [cited 1 May 2018]. Available from: http://www.ctstransplant.org/public/newsletters/2012/png/2012-2. html?ts=9334835325429464. 6. Medina-Pestana JO, Duro-Garcia V.  Strategies for establishing organ transplant programs in developing countries: the Latin America and Caribbean experience. Artif Organs. 2006;30(7):498–500. 7. Machado CM, Martins TC, Colturato I, Leite MS, Simione AJ, de Souza MP, et  al. Epidemiology of neglected tropical diseases in transplant recipients. Review of the literature and experience of a Brazilian HSCT center. Rev Inst Med Trop Sao Paulo. 2009;51(6):309–24. 8. Franco-Paredes C, Jacob JT, Hidron A, Rodriguez-Morales AJ, Kuhar D, Caliendo AM. Transplantation and tropical infectious diseases. Int J Infect Dis. 2010;14(3):e189–96. 9. Kotton CN. Zoonoses in solid-organ and hematopoietic stem cell transplant recipients. Clin Infect Dis. 2007;44(6):857–66. 10. Barsoum RS.  Parasitic infections in transplant recipients. Nat Clin Pract Nephrol. 2006;2(9):490–503. 11. Valar C, Keitel E, Dal Prá RL, Gnatta D, Santos AF, Bianco PD, et al. Parasitic infection in renal transplant recipients. Transplant Proc. 2007;39(2):460–2. 12. Machado CM, Levi JE. Transplant-associated and blood transfusion-associated tropical and parasitic infections. Infect Dis Clin N Am. 2012;26(2):225–41. 13. Motta IJF, Spencer BR, Cordeiro da Silva SG, Arruda MB, Dobbin JA, YBM G, et al. Evidence for transmission of zika virus by platelet transfusion. N Engl J Med. 2016;375(11):1101–3. 14. Fishman JA. Infection in organ transplantation. Am J Transplant. 2017;17(4):856–79. 15. Martín-Dávila P, Fortún J, López-Vélez R, Norman F, Montes de Oca M, Zamarrón P, et al. Transmission of tropical and geographically restricted infections during solid-organ transplantation. Clin Microbiol Rev. 2008;21(1):60–96. 16. Sawyer RG, Crabtree TD, Gleason TG, Antevil JL, Pruett TL. Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections. Clin Transpl. 1999;13(3):260–5. 17. Mahmoud KM, Sobh MA, El-Agroudy AE, Mostafa FE, Baz ME, Shokeir AA, et al. Impact of schistosomiasis on patient and graft outcome after renal transplantation: 10 years’ follow­up. Nephrol Dial Transplant. 2001;16(11):2214–21. 18. Boulware DR, Stauffer WM, Hendel-Paterson BR, Rocha JLL, Seet RC-S, Summer AP, et al. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med. 2007;120(6):545.e1–8. 19. Duvignaud A, Receveur M-C, Ezzedine K, Pistone T, Malvy D. Visceral leishmaniasis due to Leishmania infantum in a kidney transplant recipient living in France. Travel Med Infect Dis. 2015;13(1):115–6. 20. Nüesch R, Cynke E, Jost MC, Zimmerli W. Thrombocytopenia after kidney transplantation. Am J Kidney Dis. 2000;35(3):537–8. 21. Carrillo E, Carrasco-Antón N, López-Medrano F, Salto E, Fernández L, San Martín JV, et  al. Cytokine release assays as tests for exposure to Leishmania, and for confirming cure from Leishmaniasis, in solid organ transplant recipients. PLoS Negl Trop Dis. 2015;9(10):e0004179. 22. Redelman-Sidi G, Sepkowitz KA.  IFN-γ release assays in the diagnosis of latent tuberculosis infection among immunocompromised adults. Am J Respir Crit Care Med. 2013;188(4):422–31. 23. Costa SD, de Sandes-Freitas TV, Jacinto CN, Martiniano LVM, Amaral YS, Paes FJVN, et al. Tuberculosis after kidney transplantation is associated with significantly impaired allograft function. Transpl Infect Dis. 2017;19(5). https://doi.org/10.1111/tid.12750. Epub 2017 Sep 4.

6  Tropical Diseases in Kidney Transplantation

85

24. Viana LA.  Tuberculose diagnosticada após o transplante renal. Tese de Mestrado. Unifesp. 2017. 25. San-Juan R, De Dios B, Navarro D, García-Reyne A, Lumbreras C, Bravo D, et al. Epstein-­ Barr virus DNAemia is an early surrogate marker of the net state of immunosuppresion in solid organ transplant recipients. Transplantation. 2013;95(5):688–93. 26. Clemente W, Vidal E, Girão E, Ramos ASD, Govedic F, Merino E, et al. Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case-control study. Clin Microbiol Infect. 2015;21(1):89–95. 27. Ross AGP, Bartley PB, Sleigh AC, Olds GR, Li Y, Williams GM, et al. Schistosomiasis. N Engl J Med. 2002;346(16):1212–20. 28. da Silva GB, Pinto JR, Barros EJG, Farias GMN, Daher EDF. Kidney involvement in malaria: an update. Rev Inst Med Trop Sao Paulo. 2017;59:e53. 29. Daher EDF, de Abreu KLS, da Silva Junior GB. Leptospirosis-associated acute kidney injury. J Bras Nefrol. 2010;32(4):400–7. 30. Daher EDF, da Junior Silva GB, Vieira APF, de Souza JB, Falcão FDS, da Costa CR, et al. Acute kidney injury in a tropical country: a cohort study of 253 patients in an infectious diseases intensive care unit. Rev Soc Bras Med Trop. 2014;47(1):86–9. 31. Jasenosky LD, Scriba TJ, Hanekom WA, Goldfeld AE.  T cells and adaptive immunity to Mycobacterium tuberculosis in humans. Immunol Rev. 2015;264(1):74–87. 32. Chen C-Y, Liu C-J, Feng J-Y, Loong C-C, Liu C, Hsia C-Y, et al. Incidence and risk factors for tuberculosis after liver transplantation in an endemic area: a nationwide population-based matched cohort study. Am J Transplant. 2015;15(8):2180–7. 33. Guirao-Arrabal E, Santos F, Redel-Montero J, Vaquero JM, Cantisán S, Vidal E, et  al. Risk of tuberculosis after lung transplantation: the value of pretransplant chest computed tomography and the impact of mTOR inhibitors and azathioprine use. Transpl Infect Dis. 2016;18(4):512–9. 34. Vale S. Reactivation versus clearance of Mycobacterium tuberculosis using mammalian target of rapamycin inhibitors in patients with cancer can be context dependent. J Clin Oncol. 2013;31(20):2634. 35. Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10(3):547–57. 36. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev. 2004;17(1):208–17. 37. Matsuzawa K, Nakamura F, Abe M, Okamoto K.  Immunosuppressive and antiparasitic effects of cyclosporin A on Hymenolepis nana infection in mice. Int J Parasitol. 1998;28(4): 579–88. 38. Munro GH, Brannan LR, Chappell LH, Thomson AW, McLaren DJ. The larvicidal activity of cyclosporin A against Schistosoma mansoni in mice. Parasitology. 1991;102(Pt 1):57–63. 39. Schad GA.  Cyclosporine may eliminate the threat of overwhelming strongyloidiasis in immunosuppressed patients. J Infect Dis. 1986;153(1):178. 40. Qing M, Yang F, Zhang B, Zou G, Robida JM, Yuan Z, et al. Cyclosporine inhibits flavivirus replication through blocking the interaction between host cyclophilins and viral NS5 protein. Antimicrob Agents Chemother. 2009;53(8):3226–35. 41. Muñoz L, Santin M.  Prevention and management of tuberculosis in transplant recipients: from guidelines to clinical practice. Transplantation. 2016;100(9):1840–52. 42. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2S Suppl 2):S60–5. 43. Jha V, Chugh KS.  Posttransplant infections in the tropical countries. Artif Organs. 2002;26(9):770–7. 44. van Griensven J, Carrillo E, López-Vélez R, Lynen L, Moreno J. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect. 2014;20(4):286–99.

86

L. R. Requião Moura et al.

45. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção, Especializada e Temática, Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção. Diretrizes Clínicas para o Cuidado ao paciente com Doença Renal Crônica – DRC no Sistema Único de Saúde/Ministério da Saúde. 2014. 46. Home [Internet]. [cited 1 May 2018 ]. Available from: http://www.abto.org.br/abtov03/ default.aspx?mn=476&c=0&s=157&pop=true. 47. Adult immunization schedules for adults in easy-to-read formats CDC [Internet]. 2018 [cited 30 Apr 2018]. Available from: https://www.cdc.gov/vaccines/schedules/easy-to-read/ adult.html. 48. Facincani T, Guimarães MNC, De Sousa Dos Santos S. Yellow fever vaccination status and safety in hemodialysis patients. Int J Infect Dis. 2016;48:91–5. 49. Ministério da Saúde [Internet]. [cited 1 May 2018]. Available from: http://bvsms.saude.gov. br/bvs/saudelegis/gm/2009/prt2600_21_10_2009.html. 50. Fischer SA, Avery RK, AST Infectious Disease Community of Practice. Screening of donor and recipient prior to solid organ transplantation. Am J Transplant. 2009;9(Suppl 4):S7–18. 51. Sousa AA, Lobo MCSG, Barbosa RA, Bello V. Chagas seropositive donors in kidney transplantation. Transplant Proc. 2004;36(4):868–9. 52. Mello MAG, da Conceição AF, Sousa SMB, Alcântara LC, Marin LJ, Regina da Silva Raiol M, et al. HTLV-1 in pregnant women from the Southern Bahia, Brazil: a neglected condition despite the high prevalence. Virol J. 2014;11:28. 53. de Morais MPE, Gato CM, Maciel LA, Lalwani P, Costa CA, Lalwani JDB. Prevalence of human T-lymphotropic virus type 1 and 2 among blood donors in Manaus, Amazonas State, Brazil. Rev Inst Med Trop Sao Paulo. 2017;59:e80. 54. Tedla F, Brar A, John D, Sumrani N. Risk of transmission of human T-lymphotropic virus through transplant. Am J Transplant. 2015;15(4):1123–4. 55. Dosik H, Goldstein MF, Poiesz BJ, Williams L, Fahnrich B, Ehrlich GD, et al. Seroprevalence of human T-lymphotropic virus in blacks from a selected central Brooklyn population. Cancer Investig. 1994;12(3):289–95. 56. Moreno-Ajona D, Yuste JR, Martín P, Gállego P-LJ. HTLV-1 myelopathy after renal transplant and antiviral prophylaxis: the need for screening. J Neurovirol. 2018;24:523. 57. Pierrotti LC, Kotton CN. Transplantation in the tropics: lessons on prevention and management of tropical infectious diseases. Curr Infect Dis Rep. 2015;17(7):492. 58. Clemente WT, Pierrotti LC, Abdala E, Morris MI, Azevedo LS, López-Vélez R, et  al. Recommendations for management of endemic diseases and travel medicine in solid-organ transplant recipients and donors: Latin America. Transplantation. 2018;102(2):193–208. 59. Subramanian A, Dorman S. AST infectious diseases community of practice. Mycobacterium tuberculosis in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S57–62. 60. Kotton CN, Lattes R, AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S234–51. 61. Camargo LFA, Kamar N, Gotuzzo E, Wright AJ. Schistosomiasis and Strongyloidiasis recommendations for solid-organ transplant recipients and donors. Transplantation. 2018;102(2S Suppl 2):S27–34. 62. Clemente WT, Mourão PHO, Lopez-Medrano F, Schwartz BS, García-Donoso C, Torre-­ Cisneros J. Visceral and cutaneous leishmaniasis recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2S Suppl 2):S8–15. 63. Copeland NK, Aronson NE. Leishmaniasis: treatment updates and clinical practice guidelines review. Curr Opin Infect Dis. 2015;28(5):426–37. 64. Pierrotti LC, Levi ME, Di Santi SM, Segurado AC, Petersen E. Malaria disease recommendations for solid organ transplant recipients and donors. Transplantation. 2018;102(2S Suppl 2):S16–26. 65. Meinerz G, da Silva CK, Goldani JC, Garcia VD, Keitel E. Epidemiology of tuberculosis after kidney transplantation in a developing country. Transpl Infect Dis. 2016;18(2):176–82. 66. Marques IDB, Azevedo LS, Pierrotti LC, Caires RA, Sato VAH, Carmo LPF, et al. Clinical features and outcomes of tuberculosis in kidney transplant recipients in Brazil: a report of the last decade. Clin Transpl. 2013;27(2):E169–76.

6  Tropical Diseases in Kidney Transplantation

87

67. Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis. 2008;8(3):191–9. 68. Oliveira CMC, Oliveira MLMB, Andrade SCA, Girão ES, Ponte CN, Mota MU, et  al. Visceral leishmaniasis in renal transplant recipients: clinical aspects, diagnostic problems, and response to treatment. Transplant Proc. 2008;40(3):755–60. 69. Alves da Silva A, Pacheco-Silva A, de Castro Cintra Sesso R, Esmeraldo RM, Costa de Oliveira CM, Fernandes PFCBC, et al. The risk factors for and effects of visceral leishmaniasis in graft and renal transplant recipients. Transplantation. 2013;95(5):721–7. 70. de Silva AA, Pacheco e Silva Filho Á, de Sesso R C, de Esmeraldo R M, de Oliveira CM, Fernandes PF, et al. Epidemiologic, clinical, diagnostic and therapeutic aspects of visceral leishmaniasis in renal transplant recipients: experience from thirty cases. BMC Infect Dis. 2015;15:96. 71. Bern C. Chagas’ disease. N Engl J Med. 2015;373(19):1882. 72. Souza-Lima R d C d, Barbosa M d GV, Coura JR, ARL A, Nascimento A d S, JMBB F, et al. Outbreak of acute Chagas disease associated with oral transmission in the Rio Negro region, Brazilian Amazon. Rev Soc Bras Med Trop. 2013;46(4):510–4. 73. Prata A.  Clinical and epidemiological aspects of Chagas disease. Lancet Infect Dis. 2001;1(2):92–100. 74. Huprikar S, Bosserman E, Patel G, Moore A, Pinney S, Anyanwu A, et al. Donor-derived Trypanosoma cruzi infection in solid organ recipients in the United States, 2001-2011. Am J Transplant. 2013;13(9):2418–25. 75. Riarte A, Luna C, Sabatiello R, Sinagra A, Schiavelli R, De Rissio A, et  al. Chagas’ disease in patients with kidney transplants: 7 years of experience 1989-1996. Clin Infect Dis. 1999;29(3):561–7. 76. Schmunis GA, Yadon ZE.  Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 2010;115(1–2):14–21. 77. Cicora F, Escurra V, Silguero S, González IM, Roberti JE. Use of kidneys from trypanosoma cruzi-infected donors in naive transplant recipients without prophylactic therapy: the experience in a high-risk area. Transplantation. 2014;97(1):e3–4. 78. Wendel S.  Transfusion transmitted Chagas disease: is it really under control? Acta Trop. 2010;115(1–2):28–34. 79. Lattes R, Lasala MB.  Chagas disease in the immunosuppressed patient. Clin Microbiol Infect. 2014;20(4):300–9. 80. Kransdorf EP, Zakowski PC, Kobashigawa JA. Chagas disease in solid organ and heart transplantation. Curr Opin Infect Dis. 2014;27(5):418–24. 81. Campos SV, Strabelli TMV, Amato Neto V, Silva CP, Bacal F, Bocchi EA, et al. Risk factors for Chagas’ disease reactivation after heart transplantation. J Heart Lung Transplant. 2008;27(6):597–602. 82. Ortiz AM, Troncoso P, Sainz M, Vilches S. Prophylaxis and treatment of Chagas disease in renal transplant donor and recipient: case report. Transplant Proc. 2010;42(1):393–4. 83. Pinazo M-J, Miranda B, Rodríguez-Villar C, Altclas J, Brunet Serra M, García-Otero EC, et al. Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas. Transplant Rev (Orlando). 2011;25(3):91–101. 84. Bacal F, Silva CP, Bocchi EA, Pires PV, Moreira LFP, Issa VS, et al. Mychophenolate mofetil increased Chagas disease reactivation in heart transplanted patients: comparison between two different protocols. Am J Transplant. 2005;5(8):2017–21. 85. Bestetti RB, Souza TR, Lima MF, Theodoropoulos TAD, Cordeiro JA, Burdmann EA. Effects of a mycophenolate mofetil-based immunosuppressive regimen in Chagas’ heart transplant recipients. Transplantation. 2007;84(3):441–2. 86. Barquilla A, Crespo JL, Navarro M. Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation. Proc Natl Acad Sci U S A. 2008;105(38):14579–84. 87. Anesi JA, Baddley JW. Approach to the solid organ transplant patient with suspected fungal infection. Infect Dis Clin N Am. 2016;30(1):277–96. 88. Shoham S. Emerging fungal infections in solid organ transplant recipients. Infect Dis Clin N Am. 2013;27(2):305–16.

88

L. R. Requião Moura et al.

89. Guimarães LFA, Halpern M, de Lemos AS, de Gouvêa EF, Gonçalves RT, da Rosa SMA, et al. Invasive fungal disease in renal transplant recipients at a Brazilian center: local epidemiology matters. Transplant Proc. 2016;48(7):2306–9. 90. Grim SA, Proia L, Miller R, Alhyraba M, Costas-Chavarri A, Oberholzer J, et al. A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation. Transpl Infect Dis. 2012;14(1):17–23. 91. Proia L, Miller R, AST Infectious Diseases Community of Practice. Endemic fungal infections in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S199–207. 92. Khan A, El-Charabaty E, El-Sayegh S. Fungal infections in renal transplant patients. J Clin Med Res. 2015;7(6):371–8. 93. Sahin SZ, Akalin H, Ersoy A, Yildiz A, Ocakoglu G, Cetinoglu ED, et al. Invasive fungal infections in renal transplant recipients: epidemiology and risk factors. Mycopathologia. 2015;180(1–2):43–50. 94. Trabelsi H, Néji S, Sellami H, Yaich S, Cheikhrouhou F, Guidara R, et  al. Invasive fungal infections in renal transplant recipients: about 11 cases. J Mycol Med. 2013;23(4): 255–60. 95. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11. 96. Pappas PG, Silveira FP, AST Infectious Diseases Community of Practice. Candida in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S173–9. 97. Andes DR, Safdar N, Baddley JW, Alexander B, Brumble L, Freifeld A, et al. The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the transplant-associated infection surveillance network (TRANSNET). Transpl Infect Dis. 2016;18(6):921–31. 98. Gassiep I, McDougall D, Douglas J, Francis R, Playford EG. Cryptococcal infections in solid organ transplant recipients over a 15-year period at a state transplant center. Transpl Infect Dis. 2017;19(1). https://doi.org/10.1111/tid.12639. Epub 2017 Jan 17. 99. Singh N, Forrest G, AST Infectious Diseases Community of Practice. Cryptococcosis in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S192–8. 100. Singh N, Husain S, AST Infectious Diseases Community of Practice. Invasive aspergillosis in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S180–91. 101. Moretti ML, Resende MR, Lazéra MDS, Colombo AL, Shikanai-Yasuda MA. Guidelines in cryptococcosis--2008. Rev Soc Bras Med Trop. 2008;41(5):524–44. 102. Sun H-Y, Alexander BD, Lortholary O, Dromer F, Forrest GN, Lyon GM, et al. Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis. Clin Infect Dis. 2009;49(11):1721–8. 103. Kubak BM, Huprikar SS, AST Infectious Diseases Community of Practice. Emerging & rare fungal infections in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S208–26. 104. Singh N, Limaye AP, Forrest G, Safdar N, Muñoz P, Pursell K, et  al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006;81(3):320–6. 105. Gavaldà J, Meije Y, Fortún J, Roilides E, Saliba F, Lortholary O, et al. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect. 2014;20(Suppl 7):27–48. 106. World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and ­control – New edition: WHO; 2009. 107. Nasim A, Anis S, Baqi S, Akhtar SF, Baig-Ansari N. Clinical presentation and outcome of dengue viral infection in live-related renal transplant recipients in Karachi, Pakistan. Transpl Infect Dis. 2013;15(5):516–25. 108. Costa SD, da Silva GB, Jacinto CN, Martiniano LVM, Amaral YS, Paes FJVN, et al. Dengue fever among renal transplant recipients: a series of 10 cases in a tropical country. Am J Trop Med Hyg. 2015;93(2):394–6.

6  Tropical Diseases in Kidney Transplantation

89

109. Fernandes PFCBC, Siqueira RA, Girão ES, Siqueira RA, Mota MU, Marques LCBF, et al. Dengue in renal transplant recipients: clinical course and impact on renal function. World J Transplant. 2017;7(1):57–63. 110. Maia SHF, Brasil IRC, Esmeraldo RDM, Ponte CND, Costa RCS, Lira RA. Severe dengue in the early postoperative period after kidney transplantation: two case reports from Hospital Geral de Fortaleza. Rev Soc Bras Med Trop. 2015;48(6):783–5. 111. Tang KF, Ooi EE.  Diagnosis of dengue: an update. Expert Rev Anti-Infect Ther. 2012;10(8):895–907. 112. Robinson MC. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53. I. Clinical features. Trans R Soc Trop Med Hyg. 1955;49(1):28–32. 113. Rodrigues Faria N, Lourenço J, Marques de Cerqueira E, Maia de Lima M, Pybus O, Carlos Junior Alcantara L. Epidemiology of Chikungunya Virus in Bahia, Brazil, 2014-2015. PLoS Curr. 2016;8. pii: ecurrents.outbreaks.c97507e3e48efb946401755d468c28b2. https://doi. org/10.1371/currents.outbreaks.c97507e3e48efb946401755d468c28b2. 114. Collucci C. Brazil sees sharp rise in chikungunya cases. BMJ. 2016;354:i4560. 115. Darrigo LG, de Sant’Anna Carvalho AM, Machado CM. Chikungunya, dengue, and Zika in immunocompromised hosts. Curr Infect Dis Rep. 2018;20(4):5. 116. Pierrotti LC, Lopes MIBF, APD N, Caiaffa-Filho H, FBC L, Reusing JO, et al. Chikungunya in kidney transplant recipients: a series of cases. Int J Infect Dis. 2017;64:96–9. 117. Girão ES, Rodrigues Dos Santos BG, do Amaral ES, PEG C, Pereira KB, de Araujo Filho AH, et  al. Chikungunya infection in solid organ transplant recipients. Transplant Proc. 2017;49(9):2076–81. 118. Staikowsky F, Talarmin F, Grivard P, Souab A, Schuffenecker I, Le Roux K, et al. Prospective study of chikungunya virus acute infection in the island of La Réunion during the 2005-2006 outbreak. PLoS One. 2009;4(10):e7603. 119. McCarthy MK, Morrison TE. Chronic chikungunya virus musculoskeletal disease: what are the underlying mechanisms? Future Microbiol. 2016;11(3):331–4. 120. Kee ACL, Yang S, Tambyah P.  Atypical chikungunya virus infections in immunocompromised patients. Emerg Infect Dis. 2010;16(6):1038–40. 121. Machado CM, Pereira BB d S, Felix AC, Oliveira MC, Darrigo LG, de Souza MP, et al. Zika and chikungunya virus infections in hematopoietic stem cell transplant recipients and oncohematological patients. Blood Adv. 2017;1(10):624–7. 122. da Cunha RV, Trinta KS. Chikungunya virus: clinical aspects and treatment - a review. Mem Inst Oswaldo Cruz. 2017;112(8):523–31. 123. Delang L, Segura Guerrero N, Tas A, Quérat G, Pastorino B, Froeyen M, et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-­ spectrum antiviral. J Antimicrob Chemother. 2014;69(10):2770–84. 124. Briolant S, Garin D, Scaramozzino N, Jouan A, Crance JM. In vitro inhibition of chikungunya and Semliki forest viruses replication by antiviral compounds: synergistic effect of interferon-alpha and ribavirin combination. Antivir Res. 2004;61(2):111–7. 125. Zika virus outbreaks in the Americas. Wkly Epidemiol Rec. 2015;90(45):609–10. 126. Gourinat A-C, O’Connor O, Calvez E, Goarant C, Dupont-Rouzeyrol M. Detection of Zika virus in urine. Emerg Infect Dis. 2015;21(1):84–6. 127. Jimenez A, Shaz BH, Kessler D, Bloch EM. How do we manage blood donors and recipients after a positive Zika screening result? Transfusion (Paris). 2017;57(9):2077–83. 128. Nogueira ML, Estofolete CF, Terzian ACB, do Vale EPB M, da Silva RCMA, da Silva RF, et al. Zika virus infection and solid organ transplantation: a new challenge. Am J Transplant. 2017;17(3):791–5. 129. Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951–8. 130. Abdalhamid BA, Al Abadi ANM, Al Saghier MI, Joudeh AA, Shorman MA, Amr SS. Strongyloides stercoralis infection in kidney transplant recipients. Saudi J Kidney Dis Transpl. 2015;26(1):98–102.

90

L. R. Requião Moura et al.

131. Marcos LA, Terashima A, Canales M, Gotuzzo E. Update on strongyloidiasis in the immunocompromised host. Curr Infect Dis Rep. 2011;13(1):35–46. 132. Abanyie FA, Gray EB, Delli Carpini KW, Yanofsky A, McAuliffe I, Rana M, et al. Donor-­ derived Strongyloides stercoralis infection in solid organ transplant recipients in the United States, 2009-2013. Am J Transplant. 2015;15(5):1369–75. 133. Rego Silva J, Macau RA, Mateus A, Cruz P, Aleixo MJ, Brito M, et  al. Successful treatment of Strongyloides stercoralis hyperinfection in a kidney transplant recipient: case report. Transplant Proc. 2018;50(3):861–6. 134. Ferreira CJA, da Silva DA, Almeida PH, da Silva LSV, Carvalho VP, Coutinho AF, et  al. Fatal disseminated strongyloidiasis after kidney transplantation. Rev Soc Bras Med Trop. 2012;45(5):652–4. 135. Buonfrate D, Requena-Mendez A, Angheben A, Muñoz J, Gobbi F, Van Den Ende J, et al. Severe strongyloidiasis: a systematic review of case reports. BMC Infect Dis. 2013;13:78. 136. Khuroo MS. Hyperinfection strongyloidiasis in renal transplant recipients. BMJ Case Rep. 2014;2014. pii: bcr2014205068. https://doi.org/10.1136/bcr-2014-205068. 137. Donadello K, Cristallini S, Taccone FS, Lorent S, Vincent J-L, de Backer D, et  al. Strongyloides disseminated infection successfully treated with parenteral ivermectin: case report with drug concentration measurements and review of the literature. Int J Antimicrob Agents. 2013;42(6):580–3. 138. Siddiqui AA, Berk SL.  Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001;33(7):1040–7. 139. Suputtamongkol Y, Premasathian N, Bhumimuang K, Waywa D, Nilganuwong S, Karuphong E, et al. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis. PLoS Negl Trop Dis. 2011;5(5):e1044. 140. Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, et al. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg. 1996;55(5):477–81. 141. Suputtamongkol Y, Kungpanichkul N, Silpasakorn S, Beeching NJ. Efficacy and safety of a single-dose veterinary preparation of ivermectin versus 7-day high-dose albendazole for chronic strongyloidiasis. Int J Antimicrob Agents. 2008;31(1):46–9.

Chapter 7

Renal Involvement in Patients with Arbovirus Infections Roberto da Justa Pires Neto and Geraldo Bezerra da Silva Junior

7.1  Introduction Arbovirus infections are caused by a group of viruses called arboviruses (arthropod-­ borne viruses), which belong to different families, but share a common characteristic, i.e., they are transmitted to humans and other animals through the bite of hematophagous arthropods. The clinical spectrum of this group of diseases varies, and there may be asymptomatic forms and severe forms, characterized by bleeding events (hemorrhagic fever) or neurological manifestations, or mild forms with febrile events, sometimes accompanied by exanthema (acute exanthematous febrile illness). Complications involving specific systems and organs, including the kidneys, have been increasingly observed and seem to have important consequences in arbovirus-­related morbidity and mortality. Arboviruses are mainly found in tropical and subtropical regions; however, they are considered hyperendemic in regions of Asia and Latin America, especially in Brazil [1, 2]. Currently, the four arbovirus-related infections of main public health importance are yellow fever (YF), dengue fever (DEN), chikungunya (CHIK), and Zika (ZIKA), all capable of being transmitted by the same vectors, mainly Aedes aegypti and Aedes albopictus. In Brazil, several epidemics have been reported, mainly caused by DEN, for several years, and more recently by CHIK and ZIKA, and they are associated with the presence of these vectors in different regions of the country, especially in urban centers, showing their great potential for adaptation and R. da Justa Pires Neto Department of Community Health, Federal University of Ceará, Sao Jose Hospital of Infectious Diseases, Fortaleza, Ceara, Brazil G. Bezerra da Silva Junior (*) Post-Graduation Programs in Public Health and Medical Sciences, School of Medicine, University of Fortaleza, Fortaleza, Ceara, Brazil e-mail: [email protected] © Springer Nature Switzerland AG 2020 G. Bezerra da Silva Junior et al. (eds.), Tropical Nephrology, https://doi.org/10.1007/978-3-030-44500-3_7

91

92

R. da Justa Pires Neto and G. Bezerra da Silva Junior

dispersion. This is mainly due to the climatic conditions that favor the proliferation of these vectors and the poor infrastructure of basic sanitation services available in Brazil [3–7]. This chapter aims to describe the most common arbovirus-related diseases in Brazil, their clinical and epidemiological aspects, while emphasizing the features related to renal involvement in these diseases. This chapter will initially address the biological, epidemiological, and clinical aspects of each arbovirus. Subsequently, the main scientific evidence will be shown on renal involvement in arbovirus-related diseases, especially in YF and DEN, the oldest, most disseminated arboviruses worldwide and, thus, the most studied ones.

7.2  Epidemiology YF is an acute, febrile, non-communicable infectious disease caused by a virus of the genus Flavivirus of the family Flaviviridae, transmitted through the bite of hematophagous insects of the genera Aedes and Haemagogus. It was the first hemorrhagic viral fever described in the world. The disease has two transmission cycles: a wild one (when the transmission occurs in rural or wooded areas) and urban. The disease has epidemiological importance due to its clinical severity and potential for dissemination in urban areas infested with the Aedes aegypti mosquito. YF is endemic to tropical areas of Africa and South America, periodically causing isolated outbreaks or epidemics, especially when there is human contact with the wild transmission cycle. In Brazil, there have been no records of cases of urban YF since 1942. Since then, YF has irregularly occurred only in its wild cycle, with periods of endemic (isolated cases restricted to the Amazon region) and epidemic (when cases occur in non-vaccinated individuals in the midwest, southeast, and south regions) patterns. In the last years, since 2017, the country has shown an epidemic of wild YF cases, mainly in the states of the southeast region. From July 1, 2017, to April 3, 2018, 1127 cases of yellow fever and 328 deaths have been confirmed. Prevention is carried out through vector control and vaccination [8–10]. DEN is the most prevalent arbovirus-related disease in the world, and it is present in five of the six regions of the World Health Organization (WHO), with 2.5 billion individuals living in regions at risk of exposure. The disease is caused by a virus of the family Flaviviridae of the genus Flavivirus. There are 4 distinct viral serotypes, called DENV-1, DENV-2, DENV-3, and DENV-4. Its main form of transmission occurs through the bite of the female Aedes aegypti mosquito infected by the virus. Other less frequent forms of transmission of DEN are vertical transmission, reported in small case series, and the nosocomial form of the disease, mainly related to transfusion of blood products. It has an estimated annual global incidence of 390 million cases. In Brazil, in 2017, 251,711 probable cases of DEN were recorded, with an incidence of 122.3 cases/100,000 inhabitants. The northeast region had the highest number of probable cases (86,386 cases; 34.3%) in relation to the total number of cases in the country, followed by the midwest (78,729 cases;

7  Renal Involvement in Patients with Arbovirus Infections

93

31.2%) and southeast (59,601 cases; 23.6%) regions. Also, regarding official data from Brazil, in 2017, 271 cases of severe DEN and 2590 cases of DEN with warning signs were confirmed. During this same period, 141 deaths were confirmed. Several studies suggest an increased incidence of complicated DEN affecting different organs and systems such as the gastrointestinal, hepatic, respiratory, cardiac, neurological, and renal systems [1, 11–16]. CHIK is an arbovirus-related disease caused by a virus of the Togaviridae family and of the Alphavirus genus. The main form of transmission occurs through the bite of the female Aedes aegypti and Aedes albopictus mosquitos infected by the virus. Vertical transmission may also occur, especially during the intrapartum period in viremic pregnant women and also through blood transfusions. It has a mean incubation period of 2–4 days, which may vary from 1 to 14 days. The Ministry of Health defines a suspected case of CHIK as any individual with a sudden-onset fever of >38.5 °C and arthralgia or severe acute-onset arthritis, not explained by other conditions. In Brazil, in 2017, 185,854 probable cases of CHIK were recorded, with an incidence of 90.1 cases/100,000 inhabitants. A total of 173 deaths caused by CHIK were confirmed by laboratory tests [1, 2, 7, 9, 16]. ZIKA is an acute viral disease caused by an arbovirus of the genus Flavivirus of the Flaviviridae family. Its main form of transmission is through the bite of mosquitoes, such as Aedes aegypti, the same one that transmits DEN and CHIK. According to a publication by the Ministry of Health, a suspected case of ZIKA infection is defined as any patient presenting with pruriginous maculopapular exanthema accompanied by two or more of the following signs and symptoms: fever, conjunctival hyperemia without secretion and pruritus, polyarthralgia, and periarticular edema. In Brazil, in 2017, 17,594 probable cases of Zika virus fever were recorded in the country, with an incidence rate of 8.5 cases/100,000 inhabitants and two laboratory-­confirmed deaths from ZIKA. Regarding pregnant women, 2160 probable ZIKA cases were recorded in 2017, of which 949 were confirmed by clinical-­ epidemiological or laboratory criteria [1, 2, 6].

7.3  Clinical Manifestations and Diagnosis The clinical spectrum of YF ranges from an asymptomatic condition characterized by nonspecific febrile illness to fulminant disease, characterized by multiple-organ dysfunction. Most individuals infected with the YF virus develop mild symptoms or have no manifestations of the disease. The incubation period usually ranges from 3 to 6 days. The initial YF symptoms include sudden-onset fever, chills, severe headache, backache, general body aches, nausea and vomiting, fatigue, and weakness. Most people improve after these initial symptoms. After 3 or 4  days, most patients (80–90%) recover completely and are permanently immunized against the disease. Between 10% and 20% of patients develop severe YF, with high lethality. In general, 1 or 2 days after a period of apparent improvement (which may not occur),

94

R. da Justa Pires Neto and G. Bezerra da Silva Junior

symptoms such as fever, chills, severe headache, low back pain, generalized myalgia, anorexia, nausea, vomiting, abdominal pain, and diarrhea are exacerbated. Jaundice and hemorrhagic manifestations also appear, such as melena, epistaxis, metrorrhagia, petechiae, ecchymosis, and diffuse mucosal bleeding, which may evolve with hepatic encephalopathy and acute kidney injury (AKI), characterized by oliguria or anuria. Death can occur in up to 50% of the severe forms, even under the best medical care conditions. Surviving patients fully recover. In the severe form, laboratory data show markedly elevated liver enzymes (>2000 IU /L) and bilirubin (>10 mg/dL), especially with an increase in the direct fraction. Coagulation disorder occurs due to poor synthesis of vitamin K-dependent coagulation factors. Thrombocytopenia, leukopenia, and elevated levels of urea and creatinine can also be observed. The diagnosis of YF is achieved by serological tests (MAC-ELISA), PCR, or virus isolation in cultures. YF does not have a specific treatment. People with suspected disease should be hospitalized for diagnostic investigation and supportive treatment, which is basically carried out through hydration and antipyretic use. Severe forms of the disease require intensive treatment and additional therapeutic measures, such as dialysis and, possibly, blood transfusions [9, 17]. The clinical manifestations of DEN range from asymptomatic disease to undifferentiated febrile illness to severe forms or unusual manifestations, including multiple-­organ failure. According to the 1997 WHO classification, clinical manifestations of dengue were classified as classical dengue (CD), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). In 2009, the clinical manifestations of dengue started to be classified as dengue with and without warning signs and severe dengue. In DEN, fever typically lasts from 2 to 7 days. Exanthema occurs in approximately 50% of cases and is mainly characterized by the presence of macules and papules, which may or may not be pruriginous. Exanthema usually appears on the face, trunk, and appendicular skeleton, not sparing the palm-plantar region and most commonly appearing after the fever disappears. Neurological involvement occurs in the severe forms of the disease and may manifest during the febrile period or later at the convalescence phase. Clinical presentations are varied and include the presence of lymphomonocyte meningitis, encephalitis, Reye’s syndrome, polyradiculoneuritis, Guillain-Barré syndrome, and encephalitis. Laboratory confirmation of DEN can be performed through several methods and depends on the stage of the disease. In the acute phase, until the fifth day of the disease, diagnosis can be achieved by detecting viral antigens such as NS1, viral isolation in cell cultures, real-time PCR (RT-PCR), and immunohistochemistry. The diagnosis of DEN after the fifth day of the disease should be made by serology (Enzyme-Linked Immunosorbent Assay – ELISA) with the detection of IgM antibodies. Previous infection can also be investigated by ELISA with IgG antibody detection. The treatment of DEN is carried out through symptomatic medication and clinical support measures, with no specific antiviral therapy [18–21]. In CHIK, the fever usually lasts between 3 and 5 days. The presence of arthralgia usually occurs 2–4 days after fever onset and often presents with the involvement of

7  Renal Involvement in Patients with Arbovirus Infections

95

several joints. Exanthema appears in half of the affected individuals. It usually consists of a macular or maculopapular rash, which appears between the second and fifth days after fever onset. It mainly affects the trunk and limbs, including the palms and soles, and may also appear on the face. Pruritus occurs in 50% of CHIK cases. Other less common cutaneous manifestations are vesiculobullous rash, exfoliative dermatitis, hyperpigmentation, photosensitivity, oral ulcers, and lesions similar to erythema nodosum. In addition to these findings in the acute phase, exanthema may also be present during the subacute phase (up to 3 months of symptom onset) and chronic phase. Central nervous system involvement in CHIK is considered an atypical manifestation. The clinical spectrum includes the presence of meningoencephalitis, encephalopathy, seizures, Guillain-Barré syndrome, cerebellar syndrome, paresis, paralysis, and neuropathy. The laboratory findings in CHIK are nonspecific and include the presence of lymphopenia and thrombocytopenia. Diagnostic confirmation is performed by viral isolation, PCR, and detection of IgM antibodies (collected during the acute or convalescent phase). Another possibility includes a four-fold increase in antibody titers between the acute and chronic phase specimens, preferably collected 15–45 days after symptom onset, or 10–14 days after acute phase specimen collection [2, 21, 22]. In ZIKA, the symptomatic form usually occurs in 20% of affected individuals. Symptom onset appears 2–12 days after the vector’s bite and is characterized by the presence of pruritic maculopapular rash, intermittent fever, non-purulent conjunctival hyperemia without pruritus, arthralgia, myalgia, and headache. The exanthematic picture in ZIKA is usually more pronounced when compared to the cutaneous picture of DEN and CHIK. The disease has a benign course and symptoms usually resolve spontaneously after 3–7 days. At the laboratory, ZIKA infection leads to less evident changes in white blood cell and platelet counts, when compared with DEN and CHIK. Neurological manifestations in ZIKA include encephalitis, meningoencephalitis, myelitis, and Guillain-Barré syndrome, among others. Some countries have noted an unusual increase in cases of Guillain-Barré concomitantly with the ZIKA epidemic. In Brazil, the occurrence of neurological syndrome was confirmed in July 2015 after investigations made by the Federal University of Pernambuco, based on the identification of the virus in a sample of 6 patients with a history of exanthematic infection. Acute disseminated encephalomyelitis (ADEM) occurred in 2 of these patients and Guillain-Barré syndrome in 4. The specific laboratory diagnosis of ZIKA is based mainly on the detection of viral RNA from clinical specimens. The viremic period has not been established yet, but it is believed to be short, which would allow direct detection of the virus up to 4–7 days after symptom onset. In the urine, the virus has been detected within 3 weeks of symptom onset. There is currently no commercially available serology test for the detection of ZIKA antibodies in Brazil. Currently, only viral isolation and RT-PCR tests are available and are restricted to reference laboratories [1, 2, 21].

96

R. da Justa Pires Neto and G. Bezerra da Silva Junior

7.4  Renal Involvement in Yellow Fever Renal involvement is common in severe YF. Renal dysfunction usually appears between the fifth and seventh day of the disease and manifests as reduced urinary volume and the presence of albuminuria. Urinary volume of 30 mg/day), which is a known early marker of glomerular injury, was found in 20% of our hepatosplenic patients [53]. A recent study evaluated the presence of microalbuminuria in schistosomiasis, comparing microalbuminuria levels between treated and untreated S. mansoni-­ infected patients with a healthy control group and found no difference between the three groups [55]. The prevalence of chronic kidney disease (CKD) in patients with schistosomiasis is unclear. A small proportion of patients may present with advanced renal failure,

9  Schistosomiasis Mansoni-Associated Kidney Disease

123

and approximately 30–40% of patients have arterial hypertension at the time of the diagnosis of kidney disease [50]. The disease is progressive, and it is not influenced by antiparasitic or immunosuppressive therapy [56].

9.7  Other Types of Renal Involvement in Schistosomiasis 9.7.1  Renal Tubular Abnormalities Contrary to schistosomal glomerulopathy, tubular involvement in schistosomiasis has not been described in the literature. In our service, studying patients with compensated hepatosplenic schistosomiasis (HSS) with preserved glomerular filtration and, similar to other infectious diseases, such as American cutaneous leishmaniasis, kala-azar, and leprosy [57–59], we found a high incidence of tubular alterations, with the incapacity to concentrate urine in 85% of cases and a urinary acidification deficit in 45%. Urinary osmolarity and values of the urine and plasma osmolarity ratio also seem to be lower in patients with HSS. Urinary pH, in turn, was significantly higher in patients with HSS, compared with controls, suggesting that these patients may have distal renal tubular acidosis [53]. The mechanism through which patients with HSS show urinary concentration and acidification deficit remains unclear, but it may also be related to immune components activated by the parasitic infection.

9.7.2  Acute Kidney Injury There are no reports describing acute kidney injury (AKI) in patients with schistosomiasis and, therefore, its pathophysiology is not fully understood. We carried out a retrospective study in our service with 60 patients with hepatosplenic schistosomiasis hospitalized after clinical decompensation of the disease. AKI was defined according to the RIFLE criteria, and it was present in 43.3% of cases during hospitalization. Older mean age, longer hospital length of stay, presence of ascites, and diuretic use were conditions associated with AKI. Death occurred in five cases, with four in the AKI group. The classifications of Child-Pugh and MELD [60, 61], used to assess the severity and prognosis of chronic liver disease, showed higher scores among AKI patients. Acute kidney injury seems to be an important characteristic of decompensated schistosomiasis and is associated with significant morbidity and mortality [62]. However, the mechanisms through which schistosomiasis can lead to AKI remain unclear, whether by mechanisms resulting from transient hepatic failure observed in these patients or by any additional mechanism related to the chronic infection.

124

D. B. Duarte et al.

9.7.3  New Kidney Injury Biomarkers The search for new renal biomarkers is very important, as it can provide an early diagnosis of renal alterations, allowing the adoption of measures that can prevent the progression to end-stage renal disease. Monocyte chemotactic protein-1 (MCP-1), a chemokine that acts as a potent monocyte/macrophage activator [63], has been suggested as one of these new biomarkers and seems to play an important role in the pathogenesis of progressive renal failure and in several types of kidney disease, based on the observations from several animal and human models [64]. A recent study evaluated, for the first time, urinary MCP-1 levels in schistosomiasis, finding a significant increase in this biomarker in the urine of patients with active and treated schistosomiasis mansoni, compared with the control group, in addition to correlating urinary MCP-1 with microalbuminuria levels. Even though no difference was observed between the groups regarding urinary albumin excretion rate, an increase in urinary MCP-1 levels was observed in patients with active or treated infection by S. mansoni, suggesting that the infection can induce a state of chronic renal inflammation, which is not interrupted by specific treatment of the parasite [55]. In our service, we compared urinary MCP-1 levels in patients with compensated hepatosplenic schistosomiasis with a control group of healthy subjects, finding higher urinary MCP-1 levels in patients with schistosomiasis. Moreover, there was a positive correlation between MCP-1 levels and 24-hour microalbuminuria and proteinuria levels in patients with schistosomiasis (Figs. 9.6 and 9.7). The finding of the difference in MCP-1 levels, but not in microalbuminuria 400

Microalbuminuria (mg/day)

350 300 250 200

r = 0.86 p < 0.001

150 100 50 0 -50

0

100

200

300

400

500

600

700

Urinary MCP-1(pg/mg of creatinine)

Fig. 9.6  Correlation between urinary MCP-1 and microalbuminuria in patients with hepatosplenic schistosomiasis (HSS). (Reproduced from Hanemann et  al. [55], with permission. © 2013 Hanemann et al. under the terms of the Creative Commons Attribution License)

9  Schistosomiasis Mansoni-Associated Kidney Disease

125

700

Proteinuria (mg/day)

600 500 400

r = 0.77 p < 0.001

300 200 100 0 0

100

200

300

400

500

600

700

Urinary MCP-1(pg/mg of creatinine)

Fig. 9.7 Correlation between urinary MCP-1 and 24-hour proteinuria in patients with HSS. (Reproduced from Hanemann et al. [55], with permission. © 2013 Hanemann et al. under the terms of the Creative Commons Attribution License)

and proteinuria levels when comparing the schistosomiasis group and the control group, may suggest a role of MCP-1  in the early detection of schistosomiasis-­ associated kidney injury [53].

9.7.4  Treatment and Outcomes Treatment with antiparasitic drugs, such as oxamniquine or praziquantel, is indicated in all cases where there is evidence of active disease, except for contraindications. It has benefits such as symptom improvement, feeling of well-being, reduced liver and spleen size, and decrease in liver fibrosis [4, 51, 65]. Praziquantel is presented as 600-mg tablets and given as a single oral dose of 50 mg/kg to adults and 60 mg/kg to children. For oxamniquine, the recommended doses are 20 mg/kg for children and 15  mg/kg for adults. Both medications should be taken as a single dose, approximately 1 hour after a meal [30]. The treatment of severe acute schistosomiasis should be started with prednisone (1  mg/kg bodyweight/day), followed by the antiparasitic drug (oxamniquine or praziquantel) 24–48 hours later [30]. Regarding the portal hypertension, surgical treatment is used in patients with hepatosplenic schistosomiasis with upper gastrointestinal hemorrhage, with splenectomy associated with left gastric vein ligation or splenectomy with azygoportal disconnection being the most often used techniques [17, 30].

126

D. B. Duarte et al.

As for renal involvement, some studies have suggested that the kidney injuries are irreversible, because many cases have a delayed diagnosis. The specific antiparasitic treatment, however, may alter the development of kidney disease or its progression, when implemented at the early stages of the disease. Patients with the proliferative forms do not respond to antiparasitic treatment or immunosuppression, suggesting this type of glomerular involvement has a progressive pattern [50]. Once the clinical condition is in progress, the glomerulopathy is already advanced and irreversible, in a stage in which the non-immunological mechanisms of kidney disease progression are already activated, and does not depend on the presence or absence of the parasite. It is possible that antiparasitic treatment in the early stages of the disease, in patients with no clinical manifestations of kidney disease, may alter the development or progression of nephropathy [50, 51]. The evolution of patients with focal segmental glomerulosclerosis secondary to schistosomiasis is similar to the idiopathic form, with evolution to renal failure in approximately 60% of the cases [66]. It is probable that tubular alterations also contribute to the progression of nephropathy and evolution to end-stage renal disease. However, data related to this topic are scarce and need to be better clarified. In Egypt, about 10% of chronic hemodialysis patients have schistosomiasis as the cause of renal failure [44].

9.8  Conclusion In addition to important well-documented glomerular alterations, schistosomiasis mansoni is also associated with tubular alterations, such as concentration deficit and urinary acidification. Most of the time, these alterations are asymptomatic from the point of view of urinary abnormalities. Moreover, the disease predominates in younger individuals who are at risk of loss of renal function and who benefit from measures to slow the progression of kidney disease. These aspects reinforce the importance of testing for renal function in all cases of schistosomiasis mansoni and may include more specific tests, such as urinary concentration and acidification, as well as microalbuminuria and urinary MCP-1, which seem to be useful biomarkers for the early detection of schistosomal nephropathy. Screening for subclinical alterations through serum and urinary tests may be useful for the early diagnosis of renal involvement in schistosomiasis and for the consequent prevention of renal disease progression. Renal function alterations are asymptomatic in most cases, and the patient may only develop symptoms when significant loss of renal function occurs. Acknowledgments  To Fabio Rocha, for his help in developing the figures used in the chapter.

9  Schistosomiasis Mansoni-Associated Kidney Disease

127

References 1. AAF M. Esquistossomose. In: Bennett JC, Plum F, editors. Cecil: Tratado de Medicina Interna. 20th ed. Rio de Janeiro: Guanabara-Koogan; 1997. p. 2127–32. 2. Ross AGP, Bartley PB, Sleigh AC, et al. Schistosomiasis. N Engl J Med. 2002;346:1212–20. 3. Chitsulo L, Loverde P, Engels D. Disease watch: schistosomiasis. TDR Nat Rev Microbiol. 2004;2:12–3. 4. Maguire JH. Trematodes (Schistosomes and Other Flukes). In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett’s: principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone Elsevier; 2010. p. 3595–605. 5. Molyneu DH, Hotez PJ, Fenwick A. “Rapid-impact interventions”: how a policy of integrated control for Africa’s neglected tropical diseases could benefit the poor. PLoS Med. 2005;2:1064–70. 6. Vanderwerf MJ, De Valasl SJ, Brooker S, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop. 2003;86:125–39. 7. Steinmann P, Keiser J, Bos R, et al. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis. 2006;6:411–25. 8. Passos ADC, Amaral RS. Esquistossomose mansônica: aspectos epidemiológicos e de controle. Rev Soc Bras Med Trop. 1998;31:61–74. 9. Katz N, Peixoto SV. Análise crítica da estimativa do número de portadores de esquistossomose mansoni no Brasil. Rev Soc Bras Med Trop. 2000;33:303–8. 10. Resendes APC, Souza SR, Barbosa CS. Hospitalization and mortality from mansoni schistosomiasis in the State of Pernambuco, Brazil,1992/2000. Cad Saúde Pública. 2005;21:1392–401. 11. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de vigilância epidemiológica. 7th ed. Brasília, DF; 2010. 12. BRASIL.  Ministério da Saúde. Sistema de informação de agravos de notificação/ Sistema de informação da esquistossomose. Casos confirmados de Esquistossomose: Brasil, Grandes Regiões e Unidades Federadas. 1995a 2011. Brasília; 2012. Available at:http://portal.saude. gov.br/portal/arquivos/pdf/serie_historica_esquistossomose_07_08_2012.pdf. Accessed 03 abr 2013. 13. Ministério da Saúde. DATASUS. http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sinan/pce/ cnv/ pcebr.def. Accessed 25 Mar 2018. 14. Blanchard TJ. Schistosomiasis. Travel Med Infect Dis. 2004;2:5–11. 15. BRASIL.  Ministério da Saúde. Secretaria de Vigilância em Saúde. Doenças infecciosas e parasitárias: guia de bolso. 5. ed. ampl. Brasília; 2005a. Available at: www.saude.gov.br/svs. Accessed 8 Mar 2012. 16. Martinelli R, Silveira MA, Rocha H. Glomerulonefrites associadas às doenças parasitárias. In: Barros RT, editor. Glomerulopatias: patogenia, clínica e tratamento. São Paulo: Sarvier; 2006. p. 352–71. 17. Domingues ALC, Novais S. Esquistossomose mansônica. In: Filgueira NA, editor. Condutas em clínica médica. Rio de Janeiro: Medsi; 2004. p. 659–69. 18. Coutinho HM, Acosta LP, Wu HW, et al. Th2 cytokines are associated with persistent hepatic fibrosis in human Schistosoma japonicum infection. J Infect Dis. 2007;195:288–95. 19. Cheever AW, Hoffmann KF, Wynn TA. Immunopathology of schistosomiasis mansoni in mice and men. Immunol Today. 2000;21:465–6. 20. Corachan M. Schistosomiasis and international travel. Clin Infect Dis. 2002;35:446–50. 21. Mountford AP. Immunological aspects of schistosomiasis. Parasite Immunol. 2005;27:243–6. 22. Bina JC. Influência da terapêutica específica na evolução da esquistossomose mansoni. Rev Patol Trop. 1981;10:221–67. 23. Stephenson L.  The impact of schistosomiasis on human nutrition. Parasitology. 1993;107:107–23. 24. Lamyman MJ, Noble DJ, Narang S, Dehalvi N. Small bowel obstruction secondary to intestinal schistosomiasis. Trans R Soc Trop Med Hyg. 2006;100:885–7.

128

D. B. Duarte et al.

25. Domingues ALC, Domingues LAW. Forma intestinal, hepatointestinal e hepatoesplênica. In: Malta J, editor. Esquistossomose mansônica, vol. 5. Recife: Ed UFPE; 1994. p. 91–105. 26. Lambertucci JR, Serufo JC, Gerspacher-Lara R, et al. Schistosoma mansoni: assessment of morbidity before and after control. Acta Trop. 2000;77:101–9. 27. Andrade ZA, Van Marck EAE.  Schistosomal glomerular disease. Mem Inst Oswaldo Cruz. 1984;79:499–506. 28. Prata A.  Esquistossomose mansoni. In: Veronesi R, Foccacia R, editors. Tratado de Infectologia. São Paulo: Atheneu; 1997. p. 1354–72. 29. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Programa de Controle da Esquistossomose. Brasília; 2006. 30. BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Vigilância da Esquistossomose Mansoni: diretrizes técnicas/Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância das Doenças Transmissíveis. 4th ed. Brasília: Ministério da Saúde; 2014. 144p: il. 31. Barsoum RS. Schistosomal glomerulopathies. Kidney Int. 1993;44:1–12. 32. Van Velthuysen MLF.  Glomerulopathy associated with parasitic infections. ParasitToday. 1996;12:102–7. 33. Rodrigues VL, Otoni A, Voieta I, et al. Glomerulonephritis in schistosomiasis mansoni: a time to reappraise. Rev Soc Bras Med Trop. 2010;43:638–42. 34. Queiroz FP, Brito E, Martinelli R. Influence of regional factors in the distribution of the histologic patterns of glomerulopathies in the nephrotic syndrome. Nephron. 1975;14:466–70. 35. Dos Santos WLC, Sweet GMM, Azevêdo LG, et al. Current distribution pattern of biopsy-­ proven glomerular disease in Salvador, Brazil, 40 years after an initial assessment. Braz J Nephrol. 2017;39(4):376–83. 36. Melo ME, Silveira MA, Martinelli R. Alterações renais nas doenças parasitárias: esquistossomose, leptospirose e malária. In: Barros E, editor. Nefrologia: rotinas, diagnóstico e tratamento. Porto Alegre: Artmed; 2006. p. 309–16. 37. Deelder AM, Kornelis D, Marck V, et al. Schistosoma mansoni: characterization of two circulating polysaccharide antigens and the immunological response to these antigens in the mouse, hamster, and human infection. Exp. Parasitology. 1980;50:16–32. 38. Van Marck EA, Deelder AM, Gigase PL. Effect of partial portal vein ligation on immune glomerular deposits in Schistosoma mansoni infected mice. Br J Exp Pathol. 1977;58:412–7. 39. De Water R, Van Marck EA, Fransen JA, et al. Schistosoma mansoni: ultrastructural localization of the circulating anodic antigen and the circulating cathodic antigen in the mouse kidney glomerulus. Am J Trop Med Hyg. 1988;38:118–24. 40. Barsoum RS.  Schistosomal glomerulopathy: selection factors. Nephrol Dial Transplant. 1987;2:488–97. 41. De Brito T, Carneiro CR, Nakhle MC, et al. Localization by immunoelectron microscopy of Schistosoma mansoni antigens in the glomerulus of the hamster (Mesocricetusauratus). Kidney Exp Nephrol. 1998;6:368–76. 42. Digeon M, Droz D, Noel LH, et al. The role of circulating immune complexes in the glomerular disease of experimental hepatosplenic schistosomiasis. Clin Exp Immunol. 1979;35:329–37. 43. Sobh M, Moustafa F, Ramzy R, et al. Schistosoma mansoni nephropathy in Syrian golden hamsters: effect of dose and duration of infection. Nephron. 1991;59:121–30. 44. Barsoum R. The changing face of schistosomal glomerulopathy. Kidney Int. 2004;66:2472–84. 45. Brito T. Schistosoma mansoni associated glomerulopathy. Rev Inst Med Trop. 1999;41:269–72. 46. Nussenzveig I, De Brito T, Carneiro CR, et al. Human Schistosoma mansoni-associated glomerulopathy in Brazil. Nephrol Dial Transplant. 2002;17:4–7. 47. Abensur H, Nussenzveig I, Saldanha LB, et al. Nephrotic syndrome associated with hepatointestinal schistosomiasis. Rev Inst Med Trop Sao Paulo. 1992;34:273–6. 48. Dos Santos WLC, Sweet GMM, Bahiense-Oliveira M, et  al. Schistosomal glomerulopathy and changes in the distribution of histological patterns of glomerular diseases in Bahia, Brazil. Mem Inst Oswaldo Cruz. 2011;106:901–4.

9  Schistosomiasis Mansoni-Associated Kidney Disease

129

4 9. Andrade ZA, Rocha H. Schistosomal glomerulopathy. Kidney Int. 1979;16:23–9. 50. Martinelli R, Rocha H. Revisão/Atualização em Nefrologia Clínica: Envolvimento glomerular na esquistossomose mansônica. J Bras Nefrol. 1996;18:279–82. 51. Silva Júnior GB, Duarte DB, Barros EJG, et al. Schistosomiasis-associated kidney disease: a review. Asian Pac J Trop Dis. 2013;3:79–84. 52. Martinelli R, Brito E, Rocha H.  Value of beta 1C/1A globulin serum levels as an early index of glomerular involvement in Schistosoma mansoni infection. Am J Trop Med Hyg. 1980;29:882–995. 53. Duarte DB, Vanderlei LA, Bispo RKV, et al. Renal function in Hepatosplenic schistosomiasis – an assessment of renal tubular disorders. PLoS One. 2014;9:1–15. 54. Sobh M, Moustafa F, El-Arbagy, et al. Nephropathy in asymptomatic patients with active Schistosoma mansoni infection. Inter Urol Nephr. 1990;22:37–43. 55. Hanemann ALP, Libório AB, Daher EF, et al. Monocyte chemotactic Protein-1 (MCP-1) in patients with chronic schistosomiasis mansoni: evidences of subclinical renal inflammation. PLoS One. 2013;8:1–5. 56. Martinelli R, Noblat ACB, Brito E, et al. Schistosoma mansoni-induced mesangiocapillary glomerulonephrites: influence of therapy. Kidney Int. 1989;35:1227–33. 57. Lima Verde EM, Lima Verde FAA, Silva Júnior GB, et  al. Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil. J Nephrol. 2007;20:432–8. 58. Oliveira RA, Silva Júnior GB, Souza CJ, et al. Evaluation of renal function in leprosy: a study of 59 consecutive patients. Nephrol Dial Transplant. 2008;23:256–62. 59. Oliveira RA, Lima CG, Mota RMS, et al. Renal function evaluation in patients with American Cutaneous Leishmaniasis after specific treatment with pentavalent antimonial. BMC Nephrol. 2012;13:44–9. 60. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal hypertension. Philadelphia: Saunders; 1964. p. 50–64. 61. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-­ stage liver disease. Hepatology. 2001;33:464–70. 62. Duarte DB, Vanderlei LA, Bispo RKV, et al. Acute kidney injury in schistosomiasis: a retrospective cohort of 60 patients in Brazil. J Parasitol. 2015;101:244–7. 63. Jiang Y, Beller DI, Frendl G, et  al. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol. 1992;148:2423–8. 64. Segerer S, Nelson PJ, Schlöndorff D.  Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol. 2000;11:152–76. 65. Gryseels B, Polman K, Clerinx J, et al. Human schistosomiasis. Lancet. 2006;368:1106–18. 66. Martinelli R, Pereira JLC, Brito E, et al. Clinical course of focal segmental glomerulosclerosis associated with hepatosplenic Schistosomiasis mansoni. Nephron. 1995;69:131–4.

Chapter 10

Acute Kidney Injury in Yellow Fever Cassia Fernanda Estofolete, Rodrigo José Ramalho, Horácio José Ramalho, and Mauricio Lacerda Nogueira

10.1  Introduction Yellow fever is an acute disease caused by an RNA virus of the genus Flavivirus of the Flaviviridae family (from Latin flavus = yellow). The yellow fever virus belongs to the same genus as other main arthropod-borne viruses (arbovirus) that cause human disease, including the Dengue virus, West Nile virus, and Saint Louis encephalitis virus [1]. The yellow fever virus was isolated in 1927, and its complete genome was sequenced in 1985 [2]. The virus is transmitted to humans through the bite of infected female mosquitos and remains in the environment in two epidemiological cycles: the wild cycle, which occurs in nonhuman primates (monkeys) and mosquitoes of the genus Haemagogus and Sabethes, and the urban cycle, which involves humans and Aedes aegypti mosquitoes [3, 4]. Although the cycles are different, from the clinical–pathophysiological point of view, the infection is the same. After a meal of infected blood, the virus migrates to the mosquito’s salivary glands and multiplies after an incubation period (extrinsic incubation period = 8–12 weeks). From then on, the female mosquito is able to transmit the virus throughout her life (6–8 weeks) [5].

C. F. Estofolete · R. J. Ramalho Division of Infectious Diseases, Hospital de Base de Sao Jose do Rio Preto, School of Medicine of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Sao Paulo, Brazil H. J. Ramalho Division of Nephrology, School of Medicine of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Sao Paulo, Brazil M. L. Nogueira (*) Department of Parasitic and Infectious Diseases, School of Medicine of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Sao Paulo, Brazil e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 G. Bezerra da Silva Junior et al. (eds.), Tropical Nephrology, https://doi.org/10.1007/978-3-030-44500-3_10

131

132

C. F. Estofolete et al.

10.2  Epidemiology Yellow fever has been responsible for urban outbreaks in the African and South American continents throughout the ages. Recent outbreaks have been described in Brazil, Paraguay and Argentina (2007–2009), Uganda (2010), and Sudan and Ethiopia (2012–2013). Approximately 1 billion people live in endemic areas and are at risk of the disease in both continents [6]. Since 1942, there have been no records of urban yellow fever in Brazil [7]. In the last two decades, transmissions of the virus were recorded beyond the limits of the area considered to be endemic in Brazil (the Amazon region), in the east-south areas of the country, considered unaffected until then, regions that are densely populated, with unvaccinated populations and infested by vectors [8]. During the period 2016–2017, there was a significant moment of reemergence of the virus in Brazil, with dissemination into the Atlantic Forest, accounting for 777 confirmed human cases and 261 deaths. Most cases recorded during the outbreaks occur in males, from rural areas, of economically productive age and who are at risk mainly due to their work activities [9]. Wild yellow fever is characterized by cyclic intervals of 3–7  years, resulting from epizootics in nonhuman primates, coinciding with the appearance of new vulnerable populations [9].

10.3  Clinical Manifestations Virus susceptibility is universal, and a natural resistance factor to the virus is not known [10]. Human viremia lasts a maximum of 7 days, starting 24–48 hours before symptom onset [5]. After an incubation period of 3–6 days, the infection may show a wide spectrum of clinical manifestations, ranging from mild disease, with unspecific symptoms and difficult clinical diagnosis, to severe and fulminant disease, with a lethality of up to 20–50% [11–13]. The variability in the response to the virus is associated with the pathogenic potential of the viral strains and the host’s genetic and acquired resistance factors [2]. The yellow fever virus is viscerotropic, with the liver, kidney, spleen, lymph nodes, and heart being the most affected organs [14]. The disease usually occurs in two stages. The first phase includes fever, myalgia, headache, nausea, and vomiting, which may disappear after 3–4 days. Approximately, 15% of patients progress to a second, toxemic phase within 24  hours of the initial remission, characterized by high fever, chills, jaundice, bleeding episodes, albuminuria, and multiple organ dysfunction, especially hepatorenal failure [6]. At this stage, the Faget sign can be observed, characterized by the occurrence of bradycardia in the presence of high fever.

10  Acute Kidney Injury in Yellow Fever

133

10.4  Diagnosis The diagnosis of yellow fever is difficult, especially at symptom onset, as they are nonspecific and may be mistaken for signs of symptoms of other febrile illnesses, such as dengue, Zika, leptospirosis, and viral hepatitis. Specific diagnosis of the infection can be attained by virological methods (virus identification in cell culture, antigens (immunohistochemistry) or viral RNA (RT–PCR, reverse transcription polymerase chain reaction), in blood or tissue and/or serological samples, associated with clinical and epidemiological data. As for serological methods, the detection of yellow fever IgM antibodies (MAC-ELISA) can be made on the fifth day after disease onset; however, it may be susceptible to cross-reactions with other flavivirus antibodies [15]. It is important to recall that yellow fever vaccination also induces IgM formation. Rising antibody titers between a specimen collected in the acute phase and another collected during the convalescent phase, with a fourfold or greater increase, raise the possibility of a recent yellow fever virus infection (hemagglutination inhibition tests in paired samples) [5, 13]. During the infection course, nonspecific biochemical tests may evidence thrombocytopenia, accompanied or not by hemorrhagic episodes, leukopenia, hyperbilirubinemia, especially with increased direct fraction and very high aminotransferase levels, with AST (aspartate aminotransferase) levels exceeding that of ALT (alanine aminotransferase), due to a possible cytopathic effect of the yellow fever virus on the myocardium and skeletal muscles [2, 11]. Urinary sediment may show the presence of bilirubins, red blood cells, and especially proteinuria [16].

10.5  Pathophysiology of Renal Involvement Acute kidney injury is a complication observed in the severe forms of yellow fever, of which etiology is yet to be completely elucidated. The involvement is a multifactorial one, with an initial pre-renal phase and subsequent tubular injury occurrence. The possible mechanisms start from the systemic inflammatory response determined by the viremia, with activation of some circulating inflammatory factors, such as interleukins 12 and 6 [17]. Thus, the main etiology seems to be renal ischemia, associated with disseminated intravascular coagulation and often accompanied by shock. In an African case series, renal impairment predisposed to increased mortality, mainly in individuals without jaundice or liver disease, prevailing the oliguric aspect associated with uremic complaints [18].

10.6  Renal Biopsy Findings Most data on renal biopsy for yellow fever come from animal studies. Using Rhesus monkeys, the main findings are acute tubular lesions, including older references identifying the virus in renal tissue [12]. In an experimental mouse model,

134

C. F. Estofolete et al.

after the virus inoculation, it was possible to detect them soon in the interstitium [19]; also, in monkeys, 48 hours after contact, viral antigens were detected in the glomeruli [12]. Also associated with acute tubular injury, there have been reports of biopsies in humans with eosinophilic degeneration in the tubules, perhaps indicating associated interstitial nephritis. More recently, and contrary to previous findings, an experimental study with monkeys found liver, kidney, and lymph node lesions, but virus antigens were only expressed in liver tissue. These findings corroborate the hypothesis that tissue damage is caused by an indirect effect of viral replication [20].

10.7  Treatment There is no specific antiviral treatment for yellow fever. Mild cases may have spontaneous resolution, managed with clinical support and symptomatic control. Prevention through immunization is an important factor to reduce the morbidity and mortality of yellow fever. A single dose of 17-D vaccine is indicated for individuals aged 9 months or older, travelers, or residents of areas at risk of acquiring the infection and can provide lifelong immunity in over 90% of the vaccinated population, after at least 10 days of vaccination. However, because it is an attenuated virus vaccine, there are contraindications: pregnant women, children younger than 6 months, and severe immunodeficiency [21, 22]. Regarding renal support, amidst the excess of severe cases of yellow fever, the following recommendations were suggested for the management of acute renal failure in these patients [23]: • The nephrologist should be called as soon as possible, and it should be done when creatinine is ≥1.2 mg/dL; or bicarbonate 100 μmol/L, and bicarbonate 50%), and leukocytosis are common, sometimes with leukemoid reaction. Bleeding is common in the oliguric phase and can be observed in the conjunctiva, skin and mucosa, digestive tract, and central nervous system; microscopic hematuria is also frequent at this stage. Renal function deteriorates (increased creatinine and blood urea nitrogen), usually 24 hours after hypotension, with the onset of oliguria or even anuria, which requires the use of dialysis methods. Recovery from this moment onward can be rapid, with the onset of intense diuresis (above 3 L per day), hydroelectrolytic disorder (hypokalemia, hyponatremia, hyperphosphatemia), and episodes of arterial hypertension. Deaths are due to kidney failure in the oliguric phase and/or shock in the hypotensive, oliguric, or diuretic phase. This disease should be clinically differentiated from leptospirosis and other viral hemorrhagic fevers that occur in the same areas of occurrence of hantavirus infections [26, 52–56]. Although uncommon, some patients can have renal sequelae in the first months or years after the convalescence phase, such as increased glomerular filtration rate

14  Hantavirus Infection and the Renal Syndrome

181

and proteinuria. However, such sequelae tend to disappear over time, without evidence of chronic kidney disease or end-stage renal failure [57]. Recent studies in Europe have indicated that smoking, in addition to being a common condition in patients infected with Puumala virus, is a risk factor for developing acute renal failure and severe disease [58].

14.5  Clinical Manifestations of HCPS 14.5.1  Prodromal Phase

Signs and symptoms

In the prodromal phase, the most frequent manifestations are fever, myalgia, back pain, abdominal pain, asthenia, severe headache, and gastrointestinal symptoms, such as nausea, vomiting, and diarrhea (Fig. 14.3). This unspecific condition may last from 1 to 6 days or for up to 15 days, and then regress. Approximately 70% of the cases in Brazil develop into the cardiopulmonary clinical phase. Dry cough may already be present at the end of this stage [18]. Fever Dyspnea Headache Myalgia Cough Nausea/vomiting Respiratory failure Asthenia Chest pain Abdominal pain Hypotension Dizziness Backache Diarrhea Shock Kidney failure Heart failure Petechiae Neurological symptoms Hemorrhagic manifestations 0.0

20.0 40.0 60.0 80.0 100.0 Frequency of occurrence (%)

Fig. 14.3  Main signs and symptoms found in confirmed HCPS cases notified to the Brazilian Ministry of Health at the Notifiable Diseases Information System from 2007 to 2017

182

S. V. de Oliveira and Á. A. Faccini-Martínez

14.5.2  Cardiopulmonary Phase It is characterized by the onset of coughing, which is usually dry, although in some cases it may be productive, accompanied by tachycardia, tachydyspnea, and hypoxemia. Such manifestations may be followed by a rapid evolution to noncardiogenic pulmonary edema, hypotension, and circulatory collapse. The chest X-ray shows, in 60% of cases, bilateral diffuse interstitial infiltrate that rapidly evolves with alveolar filling, especially in the hila and pulmonary bases. Pleural effusion, mainly bilateral, of small magnitude, is a common finding. The cardiac area is normal. The cardiac index is low, and the peripheral vascular resistance is high, the opposite of what is observed in septic shock. Renal impairment may appear, but it is usually mild to moderate, although acute renal failure may occur, especially in infections by the Bayou, Black Creek Canal, and Andes virus. The case fatality rate is high at this stage, usually around 45% [17, 18].

14.6  Diagnosis Laboratory diagnosis of cases of hantavirus human infection is commonly performed by the enzyme-linked immunosorbent assay (ELISA), which aims to detect mainly the IgM antibodies associated with recent infection. Such diagnosis is possible even in the acute phase of the disease, because antibodies in HCPS appear with the onset of signs and symptoms [13, 17, 18]. The reverse transcription polymerase chain reaction (RT-PCR) methodology, which detects hantavirus RNA in clinical samples, is extremely useful and practical for the diagnosis of HCPS [17, 18].

14.7  Laboratory Diagnosis The laboratory tests, performed by reference laboratories for the Brazilian Ministry of Health, are as follows: IgM-ELISA: Approximately 95% of HCPS patients have detectable IgM in a serum sample collected at symptom onset; thus, it is an effective method for the diagnosis of hantavirus infection. Immunohistochemistry: Particularly, it is used for diagnosis in cases of death, when it was not possible to perform the serological diagnosis in vivo. Reverse transcription-polymerase chain reaction (RT-PCR): It is useful for identifying the virus and its genotype, being considered a complementary test. The IgG ELISA technique, although available in the public network, is used in epidemiological studies to detect previous viral infection in rodents or humans [13, 17, 18].

14  Hantavirus Infection and the Renal Syndrome

183

14.7.1  Nonspecific Laboratory Diagnosis HCPS laboratory findings, although not characteristic, may support the diagnosis of a suspected case of the disease. Data from complete blood counts obtained during the prodromal period, such as elevated hematocrit, presence of immunoblasts (atypical lymphocytes), and thrombocytopenia, may be the evidence that respiratory impairment can occur within hours, even if the chest X-ray results are normal [59, 60]. The most commonly found chest X-ray alterations are progressive bilateral interstitial infiltrate, hilar and peribronchial congestion, and pleural effusion; after 24–48 hours, air-space consolidation rapidly evolves and pleural effusion progressively increases; if the evolution is favorable, these radiological abnormalities disappear within a few days [61]. Other signs and symptoms have been reported, and in some cases, the disease may not progress from the prodromal stage or clinical symptoms may be completely absent [59]. Based on clinical symptomatology, early disease recognition is not easy and may be mistaken by endemic diseases prevalent in the same areas, such as dengue, leptospirosis, and influenza [18, 26, 54, 62].

14.7.2  Differential Diagnosis Diseases of infectious origin: leptospirosis, influenza and parainfluenza, dengue, Yellow fever and Rift Valley fever, Coxsackie virus infections, Adenovirus and Arenavirus (Lassa fever) infections, trichinellosis, malaria, pneumonia (viral, bacterial, fungal and atypical), septicemia, rickettsiosis, histoplasmosis, and pneumocystosis [18, 26, 54, 62]. Noninfectious diseases: acute abdomen of variable etiology, acute respiratory distress syndrome (ARDS), acute (cardiogenic) pulmonary edema, interstitial pneumonia by collagen disease (systemic lupus erythematosus, rheumatoid arthritis), and chronic obstructive bronchopulmonary disease (COBPD) [18, 26].

14.8  General Pathophysiology and Kidney Impairment In both HFRS and HCPS, viral infections start with the endothelial cells of the lung microvascularization. After viral replication, the virus disseminates through the lymphatic route to other organs and tissues. The pathogenetic mechanisms of hantavirus infections seem to originate from an autoimmune response, since they do not induce increased capillary permeability by themselves. The disease severity increases after the immune response. The viral infection triggers an immune response, with the activation of defense cells, including thymus-dependent cytotoxic lymphocytes (L-TCD8) [55].

184

S. V. de Oliveira and Á. A. Faccini-Martínez

Recognized as an infectious vasculitis, small vessel endothelium is a major target in hantavirus infection, producing endothelial activation, vascular dysfunction secondary to the immune response and inflammatory mechanism, thrombin formation, fibrinolysis, and increased platelet consumption [63]. In addition to being massively present in the lungs, defense cells are also found in peripheral blood as atypical lymphocytes. Once activated, these cells are capable of producing cytokines that will act directly on the vascular endothelium, as well as stimulating macrophages to produce more cytokines, such as interleukin 1 (IL-1), interferon gamma (IFN-γ), and the tumor necrosis factor (TNF). These substances, acting directly on the capillary, can lead to increased vascular permeability, which allows massive fluid leakage into the interstitial space and later into the alveoli, triggering pulmonary edema and acute respiratory failure in the case of HCPS [55]. In the kidneys, especially in the podocytes, glomerular endothelial cells, and tubular epithelial cells, hantaviruses join and enter via αvβ1 integrins and components of the complement system (CD55 and GC1qR/p32) [64]. Under basal conditions, β-integrins contribute to the regulation of the vascular integrity, endothelial cell permeability, through restriction of vascular endothelial growth factor (VEGF), and in platelet functions [63]. The viral infection inhibits normal regulation of β-integrins, inducing an increased endothelial cell response to VEGF and producing a significant increase in vascular permeability [63]. Additionally, there is redistribution and decrease in intercellular junctions, explaining the classical proteinuria in the acute phase of the disease [63]. Urinary loss of low molecular weight proteins (α1 and β2 microglobulins) suggests that tubular involvement also contributes to proteinuria [63]. Increased vascular permeability in different organs, including the kidneys, explains the typical characteristics of hantavirus infection: hemoconcentration, hypotension, shock, abdominal pain (due to retroperitoneal edema), and pleural effusion [63]. To date, the reasons why there are groups of hantavirus that trigger greater pathogenesis in the renal system in the case of HFRS, or in the lungs and heart in the case of HCPS, are unknown [18].

14.9  General Considerations and Findings on Renal Biopsy Hantavirus infections usually have little histopathological evidence of cell damage, and no pathognomonic lesions are found [62]. The lungs are the most frequently injured organs in HCPS, where pulmonary edema is described, with discrete hyaline membrane, interstitial lymphocyte infiltrate (immunoblasts), and activated macrophages [65, 66]. Renal hantavirus infection is typically described as acute tubulointerstitial nephritis [55]. Findings in the histopathological study include cell infiltrates (leukocytes, plasma cells, monocytes, macrophages, polymorphonuclear cells), edema and interstitial hemorrhages, medullary hemorrhages, alterations in the tubular

14  Hantavirus Infection and the Renal Syndrome

a

185

b

Fig. 14.4 (a) Endothelial cells of glomerular capillaries containing hantavirus antigens detected by immunohistochemical technique. (b) Endothelial cells containing hantavirus antigens detected by immunohistochemical technique in the renal medullary capillaries. (a, b) Mouse monoclonal A1C5 for hantavirus, Abcam, alkaline phosphatase conjugated polymer, and fast red substrate, counterstained with hematoxylin; 40×. (Courtesy of Silvia D’Andretta Iglezias, Pathologist at the Instituto Adolfo Lutz, Pathological Anatomy Center, São Paulo)

epithelium and lumen, generalized capillary damage with intratubular alterations and interstitial edema, and sporadically, glomerular involvement with hypercellularity and mesangial expansion (Fig. 14.4) [55, 56, 58]. The severity of acute renal failure is due to the level of tubulointerstitial and glomerular damage [55]; however, glomerulonephritis is a rare consequence of hantavirus infection [56]. A study published in 2015, carried out in France, characterized renal histopathological findings in 17 patients diagnosed with HFRS secondary to Puumala virus infection [67]. Interestingly, interstitial hemorrhage and acute tubular necrosis were commonly described, but interstitial nephritis was not frequent. Moreover, renal microvascular inflammation (presence of T cells and macrophages) was observed, with cortical peritubular capillaritis and in the medullary portion of the vasa recta.

14.10  Treatment There is no treatment with antiviral drugs specific for hantavirus. Any suspected case of hantavirus should be transferred to the intensive care unit (ICU) as soon as possible [18]. Unspecific/prodromal form: The treatment of patients with mild forms of the disease is symptomatic. Hydration, when necessary, should be carefully provided to avoid volume overload. Strict control of vital data regarding hemodynamic and ventilatory parameters is required to prevent triggering or worsening of the cardiorespiratory condition in the case of HCPS [18]. Severe form: In patients with more severe forms and worsening hemodynamic and ventilatory parameters, careful intravenous (IV) fluid infusion is recommended,

186

S. V. de Oliveira and Á. A. Faccini-Martínez

which, if excessive, may precipitate pulmonary edema. Adequate management of fluid intake is the main therapeutic element. Fluid balance is another parameter of great importance, requiring control of diuresis, bladder catheterization (not mandatory), and renal function. The volume of IV fluids should be sufficient to maintain the preload and ensure adequate renal plasma flow, maintaining a negative or at least zero fluid balance, so as not to increase pulmonary edema (maximum 2500 mL in 24 hours for adults). Colloidal and plasma solutions may be employed to achieve a negative or zero fluid balance, sufficient to optimize volemia with central venous pressure (CVP)