**3. Dengue and other endemic arbovirosis**

animals, and also facing difficulties to access health-care facilities. The 2018 WHO list of neglected tropical diseases includes Buruli ulcer, Chagas disease, dengue, chikungunya, dracunculiasis, echinococcosis, foodborne trematodiases, human African trypanosomiasis, leishmaniasis, leprosy, onchocerciasis, rabies, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminthiases, snakebite envenoming, taeniasis/cysticercosis, trachoma, yaws, lymphatic filariasis, mycetoma, chromoblastomycosis, and other deep mycoses [1]. The kidneys are frequently affected in these diseases, and in some cases, the complications increase the risk of death. In this chapter, we discuss the main neglected tropical diseases,

Chagas disease (or American trypanosomiasis) is the infection caused by the flagellated protozoan *Trypanosoma cruzi* and transmitted by insects of the family Triatominae, the *Triatoma infestans*, known as "kissing bugs" (in Brazil: "barbeiro"; in Argentina, Bolivia, Chile, and Paraguay: "vinchuca"; in Colombia: "pito"; in Venezuela: "chipo"; and in Central America: "chinche") [2]. The transmission occurs through the inoculation of *T. cruzi* in the blood of the host, through the insect stool left next to the site of the bites. The infection can also occur through the ingestion of the infected insects (contaminated food), blood transfusion, organ donation, or vertical transmission [3]. Kidney involvement in Chagas disease is seldom

The disease is endemic in 21 Latin American countries, and the highest prevalence is registered in Bolivia, Argentina, Paraguay, Ecuador, El Salvador, and Guatemala [3]. In Brazil, there was a significant decrease in incidence due to the vector control program, and now the disease is predominantly seen as chronic cases with cardiac or gastrointestinal manifestations

Clinical manifestations of Chagas disease can be divided into acute and chronic phase [3, 4]. The acute phase manifests with fever, signs of inflammation at the inoculation site, unilateral palpebral edema (Romaña sign), lymphadenopathy, and hepatosplenomegaly [3]. Severe acute Chagas infection is rare and occurs in less than 5% of the cases, manifesting with acute myocarditis, pericardial effusion, and meningoencephalitis [3]. The chronic phase develops in 10–30% of infected individuals and is characterized by heart disease and gastrointestinal

*T. cruzi* has the ability to act as a parasite to a great variety of cells, including kidney cells [4]. There is evidence of functional and structural kidney abnormalities after *T. cruzi* infection, associated with reduction in renal blood flow, proximal tubular damage, and inflammatory interstitial infiltrate. An observation is made of an increased production of pro-inflammatory cytokines and nitric oxide, as well as renal function loss associated with high parasitic load [9–12]. In the acute phase, the renal lesion is related to cardiovascular dysfunction, due to a transitory decrease in renal blood flow, which was demonstrated in experimental models [11, 13]. Glomerulonephritis is reported in *T. cruzi* infection and also demonstrated in

which complicate matters with kidney involvement.

32 Current Topics in Tropical Emerging Diseases and Travel Medicine

**2. Chagas disease**

described and rarely studied [4].

disease (megaesophagus and megacolon) [7, 8].

[5, 6].

Dengue is the most common arbovirosis in the world, there are more than 2 billion people living in endemic areas [18], and it is the second most common disease transmitted by mosquitoes, following malaria [19]. Tropical countries face repeated outbreaks of the disease. In Brazil, the most recent outbreaks have affected millions of people [20, 21]. In recent years, other arbovirosis has caused epidemics in the Caribbean region and Latin America: chikungunya fever and Zika virus infection, and renal involvement has already been reported [22–27].

Clinical manifestations vary according to patients' age, and the incubation period varies from 3 to 14 days. The majority of patients are asymptomatic or have a mild disease characterized by fever, headache, myalgia, arthralgia, retroorbital pain, and maculopapular rash, which has been known as dengue fever [19, 28]. Severe forms of the disease, characterized by coagulation disturbances, increased vascular permeability, and hemorrhagic manifestations, are classically known as dengue hemorrhagic fever and can evolve to dengue shock syndrome [19]. There is evidence that severe cases of dengue are increasing, complicating with organ damage, including kidney involvement [14, 18].

Renal abnormalities in dengue include hydroelectrolyte disturbances, acute kidney injury (AKI), and, less frequently, glomerulonephritis, rhabdomyolysis, and hemolytic uremic syndrome [18, 29–31]. AKI seems to be more frequent in adults than in children with dengue and is associated with hypotension, sepsis, multiple organ dysfunction, and use of vasoactive drugs [30–37]. Direct kidney damage caused by dengue virus is described through cytopathic effect of viral proteins on glomerular and tubular cells, associated with immunological mechanisms mediated by viral antigens deposited on glomerular structures and tissue damage by immune complex deposition [18, 31, 38]. Other factors that mediate renal lesions in Dengue are hemodynamic instability, hemolysis, rhabdomyolysis, and nephrotoxic drug use. Autopsy studies show evidence of acute tubular necrosis, predominantly in the proximal tubules, hemorrhage, and edema, more accentuated in the medullary region [29, 38]. Dengue-associated AKI usually has a favorable outcome, with recovery in around 2 weeks [18]. Among patients with chronic kidney disease, dengue is associated with high mortality [18]. Among renal transplant patients, dengue fever also presents favorable outcomes and does not significantly affect the allograft function [39].

The disease can be asymptomatic or manifest as a localized disease in the skin (cutaneous leishmaniasis) or affect different organs (visceral leishmaniasis, also known as kala-azar or black fever). Incubation period can vary from few weeks to years, and the main symptoms and signs include insidious low-grade fever, pallor, splenomegaly, hepatomegaly, fatigue, weakness, hyporexia, and weight loss [42, 47]. In endemic areas, such as northeast of Brazil, the most affected individuals with visceral leishmaniasis are children [28]. Laboratory abnormalities are common and are typically characterized by pancytopenia, associated with hyper-

Neglected Tropical Diseases with an Impact on Kidney Function

http://dx.doi.org/10.5772/intechopen.78981

35

Kidney involvement in visceral leishmaniasis has been studied in both cutaneous form of leishmaniasis (American cutaneous leishmaniasis), in which tubular dysfunction predominates [48], and visceral leishmaniasis, in which renal lesions seem to be more frequent and severe [49]. Immunological mechanisms seem to be the key components of kidney injury in leishmaniasis, with immune complex deposition, T cell activation, and inflammatory process, leading to glomerulonephritis and interstitial nephritis [49–51]. Clinically, renal involvement in visceral leishmaniasis can manifest with acute kidney injury (AKI), mild-to-moderate proteinuria, hematuria, leukocyturia, hydroelectrolyte disturbances, and tubular defects—urinary concentration and acidification defects, which can persist even after specific treatment [52–54]. Glomerular disease in leishmaniasis is characterized to be mesangial proliferative, with immune complex deposition, and can complicate with rapidly progressive glomerulonephritis [55, 56]. Microalbuminuria is the most frequent renal abnormality found in patients with visceral leishmaniasis (around 40%), evidencing important glomerular filtration barrier defect caused by the infection process [57, 58]. AKI has also been reported in a considerable number of patients (more than 30%); it seems to be more frequent and severe in adults and is associated with hypokalemia, leukopenia, and use of amphotericin B [53, 59]. AKI was also associated with hyponatremia, hypoalbuminemia, hyperglobulinemia, and secondary infections in children with visceral leishmaniasis [60]. New biomarkers are under investigation aiming to detect early kidney injury in tropical diseases, including leishmaniasis. The most studied by now are the neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and monocyte chemotactic protein-1 (MCP-1) [61–63]. NGAL has been associated with AKI in visceral leishmaniasis, presenting good accuracy for the early diagnosis of AKI, and is a promisor tool for the identification of patients at risk of developing severe

Treatment consists of anti-Leishmania drugs, and the standard treatment is pentavalent antimonials [42, 43]. The most commonly used drug is meglumine, but the biggest problem is its toxicity (cardiotoxicity). The second choice is amphotericin B, which has nephrotoxicity as the

Leprosy is a chronic disease caused by the *Mycobacterium leprae*, an acid-fast bacillus, characterized to be incapacitating and to cause organ failure in some cases, including kidney disease

globulinemia and hypoalbuminemia [28].

disease [64].

**5. Leprosy**

main adverse effect [42, 43].

Chikungunya infection is another arbovirosis that has been responsible for large epidemic in recent years, causing self-limited disease in most cases, with predominant symptoms being fever and arthralgias [22, 23], but renal involvement has been reported in fatal cases [22, 24]. A series of 10 autopsies from Colombia evidenced that renal involvement is frequent, with serum creatinine at admission varying from 1.2 to 8.9 mg/dl (median 2.8 mg/dl), and the main histopathological findings were glomerular involvement (glomerular edema, nephrosclerosis, and membranoproliferative glomerulonephritis) and acute tubular necrosis [22, 24]. Similar to what is seen in dengue infection, transplanted patients who acquire Chikungunya infection seem to have a milder disease, with less severe arthralgia, and this could be due to immunosuppressant drug effects [25]. The acute viral infection also seems not to significantly affect the renal allograft [25].

Zika is another arbovirosis that usually causes a mild infection, which is predominated by fever, arthralgias (milder than in dengue and chikungunya), and a typical rash with pruritus, which was brought to the attention of the Public Health authorities in 2015—the outbreak occurred in Brazil affecting a large number of people and causing neurologic disturbances in newborns, including microcephaly [26, 27]. Renal involvement has been recently described in experimental studies, which demonstrated that the Zika virus has the potential to infect different types of kidney cells, including podocytes, endothelial and mesangial cells, and the virus can also be detected in the urine, which is an evidence of the kidneys as reservoirs of the virus and a potential source for the transmission [26, 27]. These findings also suggest that patients infected with Zika virus are at risk of developing glomerulonephritis, as expected in the other arbovirosis.

There is no specific treatment for dengue, as well as for the other arbovirosis, so it consists in supportive measures and depends on clinical manifestations [40]. Treatment basis include hydration (oral or venous, depending on disease severity), resting and symptomatic medication (antipyretics, analgesics), and avoiding the use of anti-inflammatory drugs. Correction of metabolic and electrolyte disturbances is crucial and if instituted early can prevent complications [18]. Dengue vaccines are under research and the available ones present good results in individuals with previous exposure to the virus [41].
