Review Article - (2017) Volume 8, Issue 3

Renal Disfunction in Chagas Disease

Camila Botelho Miguel1,2*, Daniel Mendes Filho3,4, Niege Silva Mendes5, Patrícia De Carvalho Ribeiro6, Ricardo Cambraia Parreira4,7 and Wellington Francisco Rodrigues1
1Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brasil
2Laboratório Morfofuncional, Centro Universitário de Mineiros, Mineiros, GO, Brasil
3Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brasil
4Instituto Nanocell, Divinópolis, MG, Brasil
5Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
6Laboratório de Imunologia e Transplante Experimental, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brasil
7Pós-Graduação em Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
*Corresponding Author: Camila Botelho Miguel, Pós-Graduação em Ciências da Saúde, Universidade Federal Do Triângulo Mineiro, Uberaba, MG, Brasil, Tel: +55 34 99667-7248 Email:

Abstract

Background: Chagas’ disease has a wide distribution in South America, having several forms of transmission. The disease’s evolution varies according to the parasite/host relationship, presenting diversified progression through the acute, indeterminate and chronic forms. In the cardiac form, there are several clinical and laboratory alterations due to the involvement of several organs, including the kidneys. Actually, a lot of mechanisms are employed for the control and detection of renal damage. It has been proven that before the cardiac inflammatory changes were established, alterations in renal function could be observed due to elevated levels of urea, creatinine and other alterations compatible with the clinical picture of uremia. As well it was possible to verify an anemic state in laboratory animals, thus, it could be a condition known as cardio-anemic-renal syndrome described in patients with heart failure. Although there are studies correlating clinical and laboratory findings of renal dysfunction in Chagas’ disease, there is still a need to elucidate some pathways of interaction between chagasic physiopathogeny and renal function.

Aim: The present study addresses a review of articles from the current and classical scientific literature, correlating the function and/or loss of renal function with Chagas’ disease.

Conclusion: The information base of renal pathophisyology is crucial in order to better understand this problem of public health that involves several countries and populations.

Keywords: Chagas’ disease; Neglected diseases; Trypanosomiasis; Trypanosoma cruzi ; Kidney; Nephritis

Introduction

Chagas’ disease is a disorder of wide distribution in South America and it is caused by the protozoan Trypanosoma cruzi (T. cruzi ) [1]. For many years, the primary means of transmission was through the triatomine hematophagous vector; however, other pathways of infection such as blood transfusion, organ transplantation, transplacental and oral infection are more frequent [2-4].

This parasitosis is characterized by an initial acute phase that later becomes chronic, and it may evolve to myocarditis and affect other organs, such as the kidney [5-7]. There are few reports correlating the involvement of renal function with the pathophysiology of Chagas' disease, and most of them involve organ transplantation or the reactivation of the disorder [8,9]. A study by Lenzi [10] demonstrated the relationship between the disseminated form of infection, tissue damage in the acute phase and the presence of the parasite in the tissue. Other authors have also described the relationship between T. cruzi parasitism and acute infection in other organs, such as the kidney and intestines [11-13].

Inflammatory response is important for the pathogenicity of renal injury, along with other factors such as impairment of endothelium, which releases reactive oxygen species (ROS), and produce mediators of damaged tubular cells [14]. This dysfunction involves increased production of nitric oxide (NO), reactive oxygen species (ROS) and endothelin, as well as decreased vascular smooth muscle sensitivity to NO and prostacyclin. Under these conditions, endothelial cells lose the ability to regulate vascular tone, perfusion, permeability, inflammation and cell adhesion [15]. In summary, several mechanisms may be involved with tissue aggression in Chagas' disease (whether local or systemic), which would interfere with renal physiology.

Development

Etiologic agent and evolutionary cycle

Chagas' disease is one of the most widespread diseases in the Americas and its vectors was already found from the southern United States to Argentina. For many years, the transmission of T. cruzi was primarily through triatomine vectors, which proliferate in abundance in precarious housing conditions environments [16]. This phenomenon limited the incidence of the disorder to certain countries and social classes. Due to the other transmission routes - blood, transplacental (congenital) and oral [4,7] for example, - Chagas’ disease also affects individuals under better socioeconomic conditions.

T. cruzi performs its biological cycle in both invertebrate and vertebrate hosts, which leads to several evolutionary forms. In their cycle in humans, trypomastigotes eliminated in the feces and urine of the invertebrate vector penetrate the site of the bite and interact with macrophages of the skin or mucosa, differentiating in amastigotes, and multiplying in this place by simple binary division. Sequentially, the differentiation of the amastigotes into trypomastigotes occurs and they are released into bloodstream, reaching other cells of any tissue or are destroyed by immunological mechanisms of the host.

The triatomine vectors become infected by ingesting trypomastigote forms present in the bloodstream of vertebrate host; in the insect's stomach they differentiate into rounded epimastigote forms. In the middle intestine, epimastigotes are multiplied by simple binary division, being responsible for the maintenance of infection in the vector. In the rectum, epimastigotes differentiate into metacyclic trypomastigotes, being eliminated in feces or urine [17,18].

Evolution of Chagas' disease and the related immune response

The onset of chagasic infection in humans is marked by the acute phase, in which parasites are detected in a direct blood test, lasting one to two months. At this stage, a non-specific inflammatory process may occur, the chagoma of inoculation or Romaña sign (a typical manifestation of ocular infection with unilateral bi-palpebral edema and lymph node infarction) [16]. However, in most individuals the acute phase is asymptomatic and may have some nonspecific symptoms such as malaise and fever [19]. At this stage, the immune response is essential both in chronifying the disease and in reducing parasitaemia [20].

In the bloodstream, the interaction of trypomastigotes with host cells initiates an immune response based on the induction of Natural Killer cell activation and subsequent lymphocyte T cell expansion. First, the parasite is phagocytosed by macrophage and then begins the multiplication of amastigote forms within this cell, inducing the inflammatory response, leading to the production of cytokines such as TNF-α and IL-12, in addition to nitric oxide, generating macrophagic enhancement. These cytokines activate Natural Killer (NK) cells, which are important sources for the synthesis of other cytokines, such as IFN- γ and TNF-α, responsible factors for the activation of macrophages and consequent destruction of intra- and extracellular microorganisms [20-22]. On the other hand, the production of IL-4 and IL-10 inhibits the activation of macrophages and the differentiation of Th1 cells, inducing differentiation of Th2 cells, more commonly observed in bacterial infections [23,24].

Following macrophage activation, the antigens are exhibited on the macrophage membrane, initially for CD4+ T lymphocytes (produced by Th0 differentiation in Th1), which also release type I cytokines (IFN-γ and TGF-β), in order to eliminate the parasite and produce a cytotoxic TCD8+response. Finally, the activation of T lymphocytes generates IgG antibodies [20,25,26].

The evolution from the acute phase to the chronic one is perceived through diminution of the sanguine parasitism and the intensity of inflammatory process. This parasitism persists for the whole life of the host, and no cases of spontaneous cures have been known so far [27]. At first in the chronic phase, the individual may not present clinical signs and symptoms, which characterizes the indeterminate form of Chagas' disease. However, there are other patients who may manifest symptoms during the chronic phase and these will determine distinct anatomic-clinical forms (cardiac, digestive, cardiac and digestive, nervous, reactivation of Chagas disease, cardio-anemic-renal syndrome [28-31].

Chagas disease and renal damage

The cardiac form is the most serious clinical manifestation of the disease. The most common symptoms are: palpitations (tachycardia) and out-of-rhythm heart beats (extra-systoles and arrhythmias), dizziness, chest pain, shortness of breath in physical exertion, and progressive heart failure [32].

In an experimental study, Oliveira et al. [33] demonstrated that before the cardiac inflammatory alterations were established, alterations in renal function were already observed by the increase of urea and creatinine. Further study of renal function showed the presence of leukocyturia and high concentrations of urobilinogen in the urine, besides oliguria and polaciuria (compatible clinical picture of uremia). It was also possible to verify an anemic state in laboratory animals, leading to the establishment of cardio-anemic-renal syndrome described in patients with heart failure [33]. Such anemic state may be related to a deficit in renal function which results in a lower release of the renal hormone erythropoietin, which stimulates erythrocytic production in the bone marrow.

Before cardiac lesions were established, rats infected with T. cruzi showed renal inflammatory infiltration. This inflammatory process, in addition to kidney damage, caused ischemic/reperfusion injury due to the increase of pro-inflammatory cytokines and NO. In addition, it was seen that in the absence of Fas-L (binding proteins of tumor necrosis factor (TNF)), there was a lower cardiac inflammatory infiltration, but a higher systemic inflammatory response and renal injury. These data suggest that the damage of renal tissue leads to an irreversible dysfunction of renal and cardiac function, promoting death, even after blockade of the renin-angiotensin system (RAS) [34-36].

In relation to morphometry, Peña et al. [37] described the application of the stereological method in the evaluation of some parameters, such as the number and volume of glomeruli per mm3 and the results obtained showed the variation of this compartment in relation to age and also to several diseases. Such analysis could be applied in renal biopsies of nephropathic patients in order to reach the estimation not only of the risks but also the prognosis of renal damage in chagasic patients [38]. Similarly, human experimental studies have been performed, being possible analyse several organs [39-41], including heart [42,43] and kidney [37]. These studies demonstrated important structural changes in the architecture of each tissue in Chagas' disease.

The cytokines involved in the inflammatory process are responsible for the morphological changes found in the damage tissue. In this sense, the role of polymorphonuclear cells (PMN) in the renal injury process has been discussed, since in cases of Ischemic Renal Insufficiency, PMN are not observed histologically in the tissue even with increased activity of Myeloperoxidase (MPO). The MPO enzyme is present in the PMN cytoplasm and is directly related to the oxygendependent bactericidal mechanisms, acting as a catalyst protein in the formation of highly reactive radicals such as hypochlorous acid (HCLO), from H2O2 and halogen ions [44]. This enzime represents an important defense mechanism against pathogenic microorganisms, like T. cruzi [44]. Thus, intense recruitment of these cells into renal tissue is expected to explain the elevation of enzyme activity, degranulation of PMN and consequent release of intracellular stocks of MPO, which would remain bound to the cellular membranes of renal tissue [45].

Another way of assessing kidney damage in Chagas' disease is based on biochemical parameters measured in both blood plasma and urine. Rosa [46] and other studies have shown that male Wistar rats infected with T. cruzi have hidroelectrolytes disorders in response to water deprivation for a period of 8 h. These alterations were represented by a lower conservation and a higher excretion of water and sodium, which indicated a decreased rate of glomerular filtration. In addition, creatinine excretion was lower in infected rats than controls, which corroborates to the reduced rate of glomerular filtration.

Conclusion

The pathophysiology of Chagas’ disease is complex and involves several mechanisms in response to the presence of the parasite. The innate immunity of the host plays a crucial role in such response, through the action of NK cells that limits parasite growth, as well as promotes the development of acquired cellular immunity. Infection of macrophages by T. cruzi can induce IL-12 secretion, which leads to increased production of IFN-γ and TNF-α, resulting in parasitemia and mortality control. On the other hand, the development of this effective response against parasitic dissemination (depending on the parasite / host relationship) can provide tissue damage.

Chagas' disease, in its chronic phase, may compromise tissue physiology, as well as loss of function (cardiac and/or digestive). In addition, in its cardiac manifestation (Chagas' heart disease), systemic decompensation is observed, leading to injury of several organs.

There are some studies that investigate the function/loss of renal function due to T. cruzi infection. Most of these studies involve renal lesions (correlating them with cardiac lesions) or are aimed at infection or reactivation of the disease in renal transplantation, with scarce literature involving renal pathophysiology in Chagas' disease.

It is important to note that although there are studies correlating clinical and laboratory findings of renal dysfunction in Chagas' disease, this relationship is still poorly studied. Therefore, it’s necessary to elucidate some routes of interaction between the disease and renal dysfunctions.

Conflict of Interest

None

Acknowledgements

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and by the Fundação de Amparo à Pesquisa do estado de Minas gerais (FAPEMIG).

References

  1. Chagas C (1909) Nova tripanosomíase humana. Estudos sobre a morfologia e o ciclo evolutivo do Schyzotripanum cruzi n. gen., n. sp., agente etiológico de nova entidade mórbida do homem. Mem Inst Oswaldo Cruz 1: 1-59.
  2. Moncayo A (2003) Chagas’ disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries Mem Inst Oswaldo Cruz 98: 577-591.
  3. Barreto-de-Albuquerque J, Silva-dos-Santos D, Pérez AR, Berbert LR, de Santana-van-Vliet E, et al. (2015) Trypanosoma cruzi Infection through the Oral Route Promotes a Severe Infection in Mice: New Disease Form from an Old Infection? PLoS Negl Trop Dis 9: e0003849.
  4. Campos FP, Pansard HM, Arantes LC, Rodrigues AT, Daubermann MF, et al. (2016) A case of Chagas' disease panniculitis after kidney transplantation. J Bras Nefrol 38: 127-131.
  5. Coura JR (2007) Chagas’ disease: what is known and what is needed—a background article. Mem Inst Oswaldo Cruz 102: 113-122.
  6. Higuchi Mde L, Benvenuti LA, Martins Reis M, Metzger M (2003) Pathophysiology of the heart in Chagas’ disease: current status and new developments. Cardiovasc Res 60: 96-107.
  7. Moncayo A, Silveira AC (2009) Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy. Mem Inst Oswaldo Cruz 104: 17-30.
  8. Arias LF, Duque E, Ocampo C, Henao J, Zuluaga G, et al. (2006) Detection of amastigotes of Trypanosoma cruzi in a kidney graft with acute dysfunction. Transplant Proc 38: 885-887.
  9. Márquez E, Crespo M, Mir M, Pérez-Sáez MJ, Quintana S, et al. (2013) Chagas' disease and kidney donation. Nefrologia 33: 128-133.
  10. Lenzi HL, Oliveira DN, Lima MT, Gattass CR (1996) Trypanosoma cruzi: paninfectivity of CL strain during murine acute infection. Exp Parasitol 84: 16-27.
  11. Lemos JR, Rodrigues WF, Miguel CB, Parreira RC, Miguel RB, et al. (2013) Influence of parasite load on renal function in mice acutely infected with Trypanosoma cruzi. Plos one 8: e71772.
  12. Vazquez BP, Vazquez TP, Miguel CB, Rodrigues WF, Mendes MT, et al. (2015) Inflammatory responses and intestinal injury development during acute Trypanosoma cruzi infection are associated with the parasite load. Parasit Vectors 8: 206.
  13. Barbosa Md, Ferreira JM, Arcanjo AR, Santana RA, Magalhães LK, et al. (2015) Chagas’ disease in State of Amazonas: History, epidemiological evolution, risks of endemicity and future perspectives. Rev Soc Bras Med Trop 1: 27-33.
  14. Boneventre J, Zuk A (2004) Ischemic acute renal failure: an inflammatory disease? Kidney Int 66: 480-485.
  15. Molitoris BA, Sutton TA (2004) Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 66: 496-499.
  16. De Sousa W (2002) From the cell biology to the development of new chemotherapeutic approaches against trypanosomatids: dreams and reality. Kinetoplastid Biol Dis 1: 3.
  17. Lana M, Tafuri WL (2003) Trypanosoma cruzi e Doença de Chagas. In: Neves DP. Parasitologia Humana 10th edn. São Paulo: Atheneu.
  18. Teixeira AR, Nascimento RJ, Sturm NR (2006) Evolution and pathology in chagas disease--a review. Mem Inst Oswaldo Cruz 101: 463-491.
  19. Brener Z (2000) Terapêutica experimental na doença de Chagas. In: Brener Z, Andrade Z, Barral-Netto M (eds), Trypanosoma cruzi e Doença de Chagas, 2nd edition. Rio de Janeiro: Guanabara Koogan.
  20. Scott P, Trinchieri G (1995) The role of natural killer cells in host-parasite interactions. Curr Opin Immunol 7: 34-40.
  21. Gil-Jaramillo N, Motta FN, Favali CB, Bastos IM, Santana JM (2016) Dendritic Cells: A Double-Edged Sword in Immune Responses during Chagas’ Disease. Front Microbiol 7: 1076.
  22. Brodskyn IC, Barral-Neto M (2000) Resposta Imune Humana na Doença de Chagas. In: Trypanosoma cruzi e Doença de Chagas. Brener Z, Andrade Z, Barral-Neto M. 2nd edn. Rio de Janeiro: Guanabara Koogan.
  23. Cunha-Neto E, Nogueira LG, Teixeira PC, Ramasawmy R, Drigo SA, et al. (2009) Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas’ disease cardiomyopathy. Mem Inst Oswaldo Cruz 1: 252-258.
  24. Basso B (2013) Modulation of immune response in experimental Chagas’ disease. World J Exp Med 3: 1-10.
  25. Pinazo MJ, Thomas MC, Bustamante J, Almeida IC, Lopez MC, et al. (2015) Biomarkers of therapeutic responses in chronic Chagas’ disease: state of the art and future perspectives. Mem Inst Oswaldo Cruz 110: 422-432.
  26. Brener Z (1979) Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the Western Hemisphere. Pharmacol Ther 7: 71-90.
  27. Lopes ER (2000) Doença de Chagas. In: Brasileiro-Filho G. Bogliolo Patologia, 6th edn, Rio de Janeiro: Guanabara Koogan.
  28. Córdova E, Maiolo E, Corti M, Orduña T (2010) Neurological manifestations of Chagas’ disease. Neurol Res 32: 238-244.
  29. Kransdorf EP, Zakowski PC, Kobashigawa JA (2014) Chagas’ disease in solid organ and heart transplantation. Curr Opin Infec Dis 27: 418-424.
  30. Dávila DF, Angel F, Arata de Bellabarba G, Donis JH (2002) Effects of metoprolol in chagasic patients with severe congestive heart failure. Int J Cardiol 85: 255-260.
  31. Oliveira GM, Batista W, Mahatma T (2008) Importância do uso de parâmetros não-invasivos para a avaliação clínica e laboratorial em camundongos. Revista Controle de Contaminação.
  32. De Oliveira GM, Diniz RL, Batista W, Batista MM, Correa CB, et al. (2007) Faz ligand dependent inflammatory regulation in acute myocarditis induced by Trypanosoma cruzi infection. Am J Pathol 171: 79-86.
  33. de Oliveira GM, da Silva TM, Batista WS, Franco M, Schor N (2009) Acute Trypanosoma cruzi experimental infection induced renal ischemic/reperfusion lesion in mice. Parasitol Res 106: 111-120.
  34. de Oliveira GM, Yoshida N, Higa EM, Shenkman S, Alves M, et al. (2011) Induction of proinflammatory cytokines and nitric oxide by Trypanosoma cruzi in renal cells. Parasitol Res 109: 483-491.
  35. Peña CE (2006) Determinación de parámetros estereológicos en el riñón de conejo (Oryctolagus cuniculus). Int J Morphol 24: 331-334.
  36. Mandarim-de-Lacerda CA (2000) Fisiologia e Fisiopatologia: Estereologia do rim: determinação do Vv, Nv e volume médio do glomérulo. J Bras Nefrol 22: 103-110.
  37. Han M, Schottler F, Lei D, Dong EY, Bryan A, et al. (2006) BcL-2 over-expression fails to prevent age-related loss of calretinin positive neurons in the mouse dentate gyrus. Mol Neurodegener 1: 9.
  38. Lopes-Paulo F (2002) Emprego da estereologia em pesquisas colorretais. Rev Bras Coloproct 22: 73-76.
  39. Herculano-Houzel S, Lent R (2005) Isotropic fractinator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci 25: 2518-2521.
  40. Aguila MB, Mandarim-De-Lacerda CA, Apfel MIR (1998) Estereologia do miocárdio de ratos jovens e idosos. Arq Bras Cardiol 70: 105-109.
  41. Pereira LMM, Vianna GMM, Mandarim-De-Lacerda CA (1998) Morfologia e estereologia do miocárdio em ratos hipertensos Correlação com o tempo de inibição da síntese de óxido nítrico. Arq Bras Cardiol 70: 397-402.
  42. Pereira CC, Laranja da Fonseca LF, Veiga dos Santos M, Mazza Rodrigues PH, Borelli P (2015) Avaliação da atividade da mieloperoxidase neutrofílica em bovinos da raça Holandesa e sua correlação com níveis plasmáticos de ácido ascórbico. Rev Bras Ciên Vet 7: 148-152.
  43. Quintaes PSL, Noronha IL (1998) Revisão/atualização em Insuficiência renal aguda: papel dos neutrófilos e moléculas de adesão na fisiopatologia da insuficiência renal isquêmica. J Bras Nefrol 20: 74-77.
  44. Rosa TT, Junqueira Júnior LF, Mangia FJ, Veiga JP, Pádua FV (1995) Effects of water deprivation on renal hydroelectrolytic excretion in chronically Trypanosoma cruzi infected rats. Rev Soc Bras Med Trop 28: 7-11.
Citation: Miguel CB, Rodrigues WF, Filho DM, Mendes NS, Ribeiro PDC, et al. (2017) Renal Disfunction in Chagas Disease. J Bacteriol Parasitol 8:313.

Copyright: © 2017 Miguel CB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.