Tropical Infections Causing Acute Kidney Injury

Objectives

This chapter will:

1.
Provide an overview of tropical areas and tropical infections causing acute kidney injury (AKI).
2.
Describe epidemiology, clinical features, pathogenesis, and management of common tropical infections causing AKI, including leptospirosis, malaria, dengue, and hantavirus infection.
3.
Explain the role of renal support in limited resource areas, including tropical areas.
4.
Provide an example of long-term outcomes of AKI patients who recover from tropical infections causing AKI.

The tropics is an area of the Earth around 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 includes 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, South Asia, almost all of Africa, Central American and, South America.

The tropics currently contain nearly 150 countries and account for 40% of the world's population. It is predicted that by 2050 approximately 55% of the world's population will live in the region. Indeed, most of the countries in this region have been grouped by the World Bank into low to low-middle income countries and have limited access to many services, including healthcare.

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

Tropical Infections Associated With Acute Kidney Injury and “One Health” Perspective

The predominant cause of AKI in developing countries is community-acquired acute kidney injury (AKI), one of the major causes of which is tropical infectious diseases. This is in contrast to AKI in developed countries, where hospital-acquired AKI is a predominant cause of AKI.

Therefore prevention by using the “One Health” perspective is the key to success in controlling infection-related AKI in the tropics. The “One Health” perspective comprises the aspects of human, animal (reservoir), and environment factors. 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, in which the relationship between humans, animals, and ecosystems is studied to improve knowledge on a disease and to enhance collaborative intersectoral 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 water and sanitation, and poor housing conditions. Heavy rains or floods have been linked to a higher number of cases of leptospirosis. Alkaline and neutral soil are suspected of promoting a longer survival of this bacteria. Leptospirosis also is considered as 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 mosquito bite. Data from systematic review 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.

Indeed, to compete with these types of zoonosis diseases, the current gaps in scientific and technologic knowledge that may delay the detection of cases 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 are not available at this time.

Overview of Tropical Infections Causing Acute Kidney Injury

Tropical infection is one of the common causes of AKI and is recognized as community-acquired renal emergency in tropical countries. Not only infection-related but also non–infection-related causes such as snake bite toxins, plant toxins, and chemical toxins are common causes of AKI in tropical areas. There are only a few reports that have studied the impact of tropical infection causing AKI on a multinational level. A recent major report from 0by25 Global Snapshot team revealed that from a total of 4105 AKI cases, 50% came from tropical areas (13% from Africa, 14% from Latin American/Caribbean, 4% from Oceania/southeast Asia, and 19% from 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). Although dehydration was the leading cause of AKI (nearly 50%), sepsis, pregnancy-related AKI, and envenomation were more common in LLMIC than other income areas.

The causes of tropical infections causing AKI in tropical countries can be divided broadly into those caused by viruses, bacteria, and parasites ( Box 85.1 ). The leading causes are leptospirosis, malaria, dengue virus, and hantavirus. Distribution of these infections also varied by geographic 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 ( Fig. 85.1 ).

Box 85.1

Specific Infections in Tropical Infections Causing Acute Kidney Infection

Viral Infections

Dengue virus ^a

a Common cause.
Hantaan virus

Bacterial Infections

Leptospirosis ^a
Burkholderia pseudomallei
Orientia tsutsugamushi (scrub typhus)
Salmonella
Shigella

Parasitic Infections

Plasmodium falciparum ^a , Plasmodium vivax, Plasmodium knowlesi
Wuchreria bancrofti
Brugia malayi, Brugia timori
Leishmania donovani (kala-azar)

FIGURE 85.1, Prevalence estimates of major tropical infection causing acute kidney injury (AKI). 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 and 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.

Clinical Features, Pathogenesis, and Management of Common Tropical Infections Causing Acute Kidney Injury

Leptospirosis and Acute Kidney Injury

Epidemiology.

Leptospirosis is an important zoonosis, especially in tropical areas. However, with the impact of world globalization, there are also reports of this disease as sporadic cases in developed countries. A recent report has shown that the endemic area of leptospirosis includes the Caribbean and Central and South America, as well as southeast Asia and Oceania. Kidney injury with hyperbilirubinemia represents a severe form called Weil syndrome.

AKI is one of the most serious complications of leptospirosis. The incidence of AKI in leptospirosis by using the standard AKI criteria was up to 84%. This is approximately two times higher than the AKI incidence in the intensive care unit (ICU). This specific setting injures the kidney by direct effect, direct invasion, and indirect effect, such as dehydration, rhabdomyolysis, and bleeding.

Clinical Features.

Renal manifestations of leptospirosis-associated AKI can vary from mild AKI to severe AKI, requiring renal replacement therapy (RRT). Not only kidney injury but also tubular dysfunction, mainly at the proximal tubule, are the common features of leptospirosis-associated AKI.

Hypokalemia is one of the most unique features of renal tubular dysfunction in leptospirosis and is found in nearly 50% of cases. Leptospirosis-associated AKI is usually nonoliguric. This finding is independent from its severity, hypercatabolism, rhabdomyolysis, and acidosis. Kositseth et al. reported that 75% of leptospirosis patients had hypermagnesuria, whereas 50% of patients had decreased the threshold of tubular reabsorption of phosphate. These abnormal findings were improved significantly within 2 weeks after admission. Alterations such as bicarbonaturia, glycosuria, and reductions in proximal reabsorption of sodium, uric acid, and phosphate excretion have been observed. Moreover, a defect in the urinary concentration can persist for a prolonged period.

Mild active urinary sediments (pyuria, hematuria, bile pigment, and granular cast) and mild proteinuria (less than 1 g/day) usually are observed in the urinalysis.

AKI usually develops at the early phase of infection. A recent report by Srisawat et al. indicated that most of the patients had AKI on the first day of admission.

Pathogenesis

Direct kidney damage: acute interstitial nephritis.

Leptospira in the renal tissue triggers a process of acute interstitial nephritis, the key mechanism of AKI in leptospirosis. A study in the past showed the evidence of higher leptospiral load in kidney than other organs.

Study of Leptospira in kidney rats has shown that Leptospira penetrate capillary lumen on the second day and then enter in the renal interstitial tissue, causing interstitial edema at the end of first week. After that, Leptospira adhere to the renal tubular epithelial surface and cross to the tubular lumen in the second week. The outer membrane of Leptospira contains antigenic components, including lipoproteins, lipopolysaccharides and peptidoglycans, and endotoxins that can account for kidney injury, leading to tubular dysfunction and inflammation. Several outer membrane proteins (OMPs), such as lipL32, Loa22, LipL41, Lig family, LipL36, LipL21, and LipL46 of pathogenic species, have been identified at the proximal tubule and interstitium of infected animals. Among them, LipL32 is one of the most important OMPs. The LipL32 will bind to Toll-like receptor 2 (TLR2), not TLR4, leading to activation nuclear factor kβ (NF-kβ). This will stimulate the production of proinflammatory cytokines and chemokines, such as tumor necrosis factor-alpha (TNF-α), inducible nitric oxide, monocyte chemotactic protein-1, T cells (RANTES), and CXCL2/MIP-2 for recruiting inflammatory cells. TNF-α is the most investigated cytokine in leptospirosis. It is an inflammatory cytokine produced after TLR4 stimulation ( Fig. 85.2 ).

FIGURE 85.2, Pathogenesis of leptospirosis-associated acute kidney injury.

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