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Malarial Acute Renal Failure
... The pathogenesis of acute kidney injure in malaria has not been fully, however, it is believed that it covers a wide range of mechanisms: hemodynamic (mechanical), immune-mediated and metabolic, which form a complex combination of factors leading to acute renal failure [7][8][9][10][11]. ...
... Free hemoglobin is the cause of oxidative stress [20]. Another mechanic factor of kidney injure is myoglobin, which enters the bloodstream due to rhabdomyolysis caused by malarial sequestration [11]. In additional probable mechanical factor of the damage is thrombotic microangiopathy of kidneys as consequents of systemic coagulopathy or hemolytic-uremic syndrome. ...
... Th1 proliferation with the relies of appropriate anti-inflammatory cytokines enhances kidney hipoperfusion, which leads to the development of acute interstitial nephritis. Stimulation of Th2 causes the activation of complement with subsequent deposition of immune complexes and development of glomerulonephritis [3,11]. Histopathological samples showed proliferation of mesangial cells, which leads to glomerular edema. ...
We have described two clinical cases of severe malaria caused by different pathogens: Pl. falciparum and Pl. malaria, common to which there was a severe course, complicated by acute renal failure and hemolytic anemia. In a detailed analysis of both clinical cases, Patient 1 had acute kidney damage arose after the increase of anemia and thrombocytopenia, in combination with hemoglobinuria. This shows that the leading mechanism of kidney injure in this case is acute tubular necrosis, due to the toxic effects of free hemoglobin and sequestration in the capillaries of the glomerulus. A Patient 2 had a significant increase of anemia after appears of acute kidney damage; there was no hemoglobinuria, however, significant leukocytosis was observed. It seems, that the leading mechanism in this case is immune-mediated kidney injure or due to hypoperfusion of kidney tubules with the development of acute interstitial nephritis or immune complex glomerular injure with the development of glomerulonephritis, or a combination of them. A detailed analysis of the described two clinical cases of severe malaria caused by Pl. falciparum and Pl. malaria, respectively, and complicated by acute renal failure and hemolytic anemia, suggests that the pathogenetic mechanisms and severity of kidney damage depend on the type of malaria.
... This results in the formation of rosettes that can impede the microcirculation of internal organs. This occurs with all types of plasmodium but mainly occur with falciparum malaria, where it has been associated with 14,15 serious sequelae. The endothelial cytoadherence, sequestration, increase whole blood viscosity and capillary lumen obstruction by sticky cell aggregates together contributes to renal ischemia and acute 2,14,15 renal failure. ...
... This occurs with all types of plasmodium but mainly occur with falciparum malaria, where it has been associated with 14,15 serious sequelae. The endothelial cytoadherence, sequestration, increase whole blood viscosity and capillary lumen obstruction by sticky cell aggregates together contributes to renal ischemia and acute 2,14,15 renal failure. ...
... Hypovolemia, also contribute to RF. The associated endothelial activation leads to the release of several vasoactive cytokines and mediators which leads to decreased systemic vascular resistance and reduction in renal blood ow and lead to renal 15 ischemia. ...
BACKGROUND: Wide spectrum of kidney and kidney-related disorders, ranging from urinary abnormalities like proteinuria (< 1gm/24 hour) to kidney failure, can be caused by plasmodium falciparum. Falciparum malaria causes more frequently renal failure. Renal failure incidence by falciparum is variable between 1-4%.2,3. Renal failure is uncommon in vivax malaria. METHODS: It is an observational cross-sectional study of 266 cases of malaria through biochemical and hematological analysis of the blood of patients suffering from malaria infections between Jan 2018 to July 2022. RESULTS: Out of 266 cases of malaria in the age group 14-80 years, acute renal failure was seen in 20 cases (7.5%). Out of 20 renal failure cases, the maximum cases were 15 (75%) caused by plasmodium falciparum then, 3 (15%) cases by plasmodium vivax, and 2(10%) cases by mix (PF & PV). The presenting feature were fever (75%), jaundice (20%), and splenomegaly (20%). The probable contributing factors for renal failure were hyperbilirubinemia 9 (45%), hemolysis 9 (45%) hypotension 1 (5%), and oliguria present in 8(40%). Haemodialysis is required in 7 (35%) patients. Mortality was noted in 5% (1/20) of patients. CONCLUSIONS: Acute renal failure is caused more commonly by plasmodium falciparum than plasmodium vivax malaria. Acute tubular necrosis due to renal ischemia is the dominant pathogenic mechanism. The malarial parasites are commonly associated with jaundice, hemolysis, thrombocytopenia, and hypotension. The prognosis of renal failure is better in P. vivax than in P. falciparum.
... 4,5 The mechanism of AKI in severe malaria is multifactorial and poorly understood. 6 The pathogenesis of kidney injury in severe malaria includes mechanical obstruction of kidney microvasculature from parasitized red blood cells, immune dysregulation, and oxidative stress from intravascular hemolysis with resultant hypoperfusion, sequestration, and acute tubular necrosis. [6][7][8] The incidence of AKI in malaria varies from 2-39%, with a mortality rate as high as 15-45%. ...
... 6 The pathogenesis of kidney injury in severe malaria includes mechanical obstruction of kidney microvasculature from parasitized red blood cells, immune dysregulation, and oxidative stress from intravascular hemolysis with resultant hypoperfusion, sequestration, and acute tubular necrosis. [6][7][8] The incidence of AKI in malaria varies from 2-39%, with a mortality rate as high as 15-45%. [6][7][8] However, the actual burden of AKI associated with malaria in children remains underestimated because of varying criteria used in defining AKI in malaria. ...
... [6][7][8] The incidence of AKI in malaria varies from 2-39%, with a mortality rate as high as 15-45%. [6][7][8] However, the actual burden of AKI associated with malaria in children remains underestimated because of varying criteria used in defining AKI in malaria. For example, the World Health Organization (WHO) criteria uses an absolute creatinine cut-off value of 3 mg/dL. ...
Background Acute kidney injury (AKI) is an underrecognized complication of severe malaria and an independent risk factor for mortality among children.
Objective To determine the incidence and factors predictive of AKI as defined by the pediatric risk, injury, failure, loss, and end-stage (pRIFLE) criteria in children with severe malaria and to assess in-hospital mortality rates in malarial AKI (MAKI).
Methods This was a prospective cohort study in 170 children aged 0.5 to 14 years with confirmed Plasmodium falciparum on peripheral blood smears and clinical and/or laboratory features of severe malaria. Serum creatinine was determined using the Jaffe method and glomerular filtration rate (eGFR) was estimated using the Schwartz equation. The primary outcome was the incidence of AKI as defined by the pRIFLE criteria. Secondary outcomes included in-hospital mortality comparison between AKI and non-AKI groups, as well as factors predictive of AKI.
Results The incidence of MAKI was 61.2% (104/170) and was comparable between males (66.7%) and females (70.6%). Mean eGFR was lower among children with AKI than those without [42.00 (SD 22) vs. 98.7 (SD 3.9) mL/min/1.73m2, respectively; P=0.005]. Children with MAKI were categorized as having risk (47/104; 45.2%), injury (33/104; 31.7%), or failure (24/104; 23.1%). Mortality rates in AKI and non-AKI subjects were comparable (4.8% vs. 4.6%; P=0.888). Predictors of MAKI were hemoglobinuria [adjusted OR (aOR) 3.948; 95%CI 1.138 to 8.030], deep acidotic breathing (aOR 2.991; 95%CI 3.549 to 66.898), and longer hospital stay (aOR 2.042; 95%CI 3.617 to 12.156). Children with MAKI were more likely to have a longer hospital stay by a mean of 2.5 days.
Conclusion AKI is a common complication in children with severe malaria. MAKI has a low mortality rate comparable to those with severe malaria but without AKI. Hemoglobinuria, deep acidotic breathing, and longer hospital stay were predictive of MAKI.
... Pathogenesis of malaria is complex and involves various independent and overlapping pathways and is summarized in Figure 2. While severe malaria may involve different organs, renal involvement is a frequent complication and is recognized as an independent risk factor for death [48]. Within the kidney, different underlying mechanisms that culminate in kidney injury and disease have been proposed. ...
... Within the kidney, different underlying mechanisms that culminate in kidney injury and disease have been proposed. Notably, malaria has been recognized to damage virtually all segments of the nephron, namely glomeruli, tubules and interstitium [48,49]. These findings have been corroborated in histopathological samples [50,51]. ...
... Although rare, cases of nephrotic syndrome have also been reported [52]. Overall, AKI, likely resulting from overt acute tubular necrosis, is the predominant finding when kidneys are affected [48,53,54]. While the precise mechanisms that culminate in the pathogenesis of malaria-induced kidney disease are not fully described, multiple pathways and mechanisms have been demonstrated to have fundamental significance in this context. ...
With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.
... Both Na + and K + are important regulators of nerve impulses in the membrane of neurons and muscle fibers. Electrolyte abnormalities seem to be frequent in malaria-associated acute kidney injury (Barsoum, 2000). Hyponatremia is a common feature in both malaria infections and kidney diseases (Barsoum, Ameliorating effects of ethanol extract of root bark of Salacia nitida on blood electrolyte and renal perturbations in Plasmodium berghei-infected mice 2000), as a result of depletion in blood volume, renal loss due to increased vascular permeability, acute renal tubular failure, or renal tubular acidosis (Pohl, Wheeler, Murray, 2013). ...
... The mechanism responsible for renal failure in malaria infection might be due to a reduction in renal blood f low resulting from intravascular rosettes and parasite cytoadherence that may impede microcirculation, hypovolemia, the release of chemical mediators that increase vascular permeability, renal tubular cell membrane derangements due to ischemiaperfusion syndrome caused by the malaria parasite, intravascular coagulation, increased plasma viscosity due to malaria parasite, or inflammation due to increased vascular permeability. Other factors of kidney injury in malaria infection are hemolysis, and hepatic dysfunction with jaundice, resulting in hyperbilirubinemia, cast nephropathy, and acute kidney disease (Barsoum, Sitprija, 1996;Barsoum, 2000;Mehta et al., 2001). ...
... Presence of raised bilirubin in these patients not only indicates haemolysis but liver dysfunction were also responsible to the raised serum bilirubin. ARF complicates falciparum malaria in less than 1 to 4.8% of native patients in endemic areas, yet it is much more frequent in non immune Europeans; reported figures usually are 25 to 30% [21].In our study we found acute renal failure were more common in >5 age group of children, (10% of total cases); results were comparable with the otherstudies [9,10]. ...
... High degree of suspicion should be maintained to differentiate these complications so that by early detection and prompt management morbidity and mortality can be reduced. It was significantly associated with mortality (p value <0.05).The study done by Rashid SB[21] have reported renal failure in 5.9% of cases, Kaushik et al[15] reported 8.9%.Hypoglycemia was present in 36% of total cases.Similar observation was made in study done by N.J .White et al[23] ...
Introduction: Malaria is one of the oldest recorded diseases of world, it has infected humans since last 50,000 years .Pediatric population is especially vulnerable to this preventable illness. This study has been undertakento ascertain the incidence of common clinical features of falciparum malaria so that to improve the insight into this highly prevalent disease and to evaluate prognostic indicators of falciparum malaria. Materials and Methods: The study has been conducted in Department of Pediatrics ,Gandhi Medical College Bhopal (MP),over a period of one year.150 cases of slide positive falciparum malaria were studied thoroughly using a preformed proforma. Clinical features, biochemistry, course during stay, response to treatment and outcome were recorded in all the study patients. Results: Majority of our cases were males of more than five years. Fever was presenting symptom in 98% of patients. Vomiting, altered sensorium, convulsions, breathlessness, headache, bleeding were the other symptoms recorded in that order. Pallor was the most common clinical sign (96%) followed by hepatomehaly & splenomegaly(57 & 65%), hypotension(30%), dehydration(25%) and icterus(28%). Serum creatinine value of >3 gm/dl (10%)and Hemoglobin level of <5gm/dl was significantly associated with mortality(p value <0.05).Incidence of severe falciparum malaria was 36% in our study out of which 29% expired. Conclusions: Severe anaemia and cerebral malaria are the most common presenting features in the pediatric population as per our study. Serum creatinine levels of > 3 gm/dl and haemoglobin levels of <5gm/dl were significantly associated with mortality. The signs significantly associated with mortality were; Glasgow Coma Scale <8, splenomegaly, neck rigidity.
... 28 Asymptomatic hyponatremia is usually observed in 25%-67% of patients and is caused by haemodilution and sodium wasting. 131,132 This is related to the severity of malaria and resolves within a few days after treatment. 131 Hypernatremia is uncommon but associated with unfavourable prognosis. ...
... 131,132 This is related to the severity of malaria and resolves within a few days after treatment. 131 Hypernatremia is uncommon but associated with unfavourable prognosis. Hypokalaemia secondary from respiratory alkalosis occurs in F I G U R E 2 Pathogenesis of malaria-associated AKI. ...
The tropics are a region consisting of more than 125 countries, accounting for 40% of the world’s population. The region’s population is expected to increase up to 60% in the coming decades. Many tropical countries continue to experience public health problems such as high rates of infectious diseases, lack of sanitation, climate change impacts, poor regulation of herbal medicines, and low access to healthcare. These conditions produce the unique problem of tropical acute kidney injury (AKI), which is associated with high morbidity and mortality. Tropical infections such as leptospirosis, dengue, and malaria have varied mechanisms of AKI, including both direct kidney invasion and indirect effects, depending on the disease characteristics. Animal toxins from snakebites and arthropods along with plant toxins, such as djenkol beans, starfruit, and herbal medicine, are characterized by a harmful renal effect from each toxic substance. Environmental factors such as heat stress, natural disasters, and chemical compounds also lead to AKI and have a systemic effect from their own pathogenesis. The long‐term kidney prognosis varies among these etiologies depending on the cause and severity of disease. However, all these conditions are potentially preventable and treatable. Prompt management and good preventive approaches are needed. This article will focus on the epidemiology, pathogenesis, and management of AKI associated with tropical infections, toxins, and environment impacts.
... Inside the liver cells, the parasites multiply asexually, until they reach mature schizont, and finally, a large number of merozoites produce and enter the bloodstream after infecting hepatocyte burst. e infected hepatocytes causing liver damage due to the rupture of infected hepatocytes and merozoites enter the bloodstream and start the erythrocytic cycle in the red blood cells [27,28]. Damage that occurs in the liver cells can increase the enzymes that work on liver function, especially transaminase enzyme and morphological changes in the appearance of liver [29,30], such as hepatomegaly. ...
... e infection of P. falciparum produces acute manifestations, ranging from asymptomatic, up to urinary disorders, and mild electrolyte disturbances for acute renal failure (ARF) or acute kidney injury (AKI) that require dialysis support [27,37]. e cases of AKI in the complication of malaria are known to contribute to a high mortality rate, which is about 75% of cases. ...
Currently, the presence of antimalarial drug resistance has become a major obstacle in the treatment of malaria. To overcome the problem, a series of studies are needed to find new antimalarial drugs from plants. Previously, 90% ethanolic extract of Cassia spectabilis DC (EECS) leaves have been reported to have antimalarial activity in vitro against Plasmodium falciparum and in vivo against Plasmodium berghei ANKA. The research is conducted to find out the toxicity and protective effects of EECS on the liver and kidneys of mice infected with P. berghei ANKA. The acute and subacute toxicity tests were carried out on healthy mice that were given EECS at a dose of 150 mg/kg BW. An antimalarial activity test was carried out at doses of 150 and 200 mg/kg BW in P. berghei-infected mice. Regarding hepatomegaly, further plasma levels of hepatic enzyme were analyzed, as well as histopathological observation of the liver to determine the effect of the extract on liver. The kidney was observed histopathologically as well. The acute toxicity test of EECS showed that there was no mouse died at the highest dose, indicating safe for the mice. The subacute toxicity based on the histology data showed no significant difference in the liver and kidney of mice between the tested group and the healthy group. The histological and enzymatic effect of EECS in mice infected with P. berghei showed the histological and enzymatic effect that improved liver function and the histopathological effect on kidneys with the highest activity at a dose of 200 mg/kg BW compared with the negative control. The results showed the EECS was not toxic in mice and repaired the liver and kidney functions of P. berghei ANKA-infected mice, indicating a good candidate for antimalarial drug development.
... L'incidence de l'IRA associé e au paludisme est trè s varié e et se trouve être é levé e dans les zones non endé miques [3]. Le mé canisme physiopathologique de l'atteinte ré nale n'est pas clairement connu, mais des hypothè ses ont é té proposé es telles que l'obstruction mé canique par les hé maties parasité es et l'exagé ration des ré ponses immunitaires de l'hôte [4,5]. Les principales lé sions anatomopathologiques rencontré es sont la né crose tubulaire aiguë , la né phrite interstitielle, la glomé ruloné phrite et l'atteinte vasculaire [6,7]. ...
... L'ané mie é tait sé vè re dans 12,62 % des cas concordant aux ré sultats des é tudes, avec une variation de 10 à 20 % [4]. Nous avons retrouvé une hyponatré mie dans 55,34 % des cas similaire aux donné es de la litté rature, avec une variation de 25 à 60 % [5]. L'hypernatré mie est rare, aussi bien dans la litté rature que dans le pré sent travail, et elle est surtout observé e au cours d'un neuropaludisme associé à une dé shydratation sé vè re [23]. ...
Introduction
L’insuffisance rénale aiguë est l’un des critères du paludisme grave avec une incidence variée. Nos objectifs sont de déterminer la prévalence de l’insuffisance rénale aiguë associée au paludisme et rapporter les caractéristiques des patients avec l’évolution des cas.
Patients et méthode
Il s’agit d’une étude descriptive rétrospective de 5 ans, menée du 1er janvier 2015 au 31 décembre 2019 dans le service des maladies infectieuses du Centre hospitalier universitaire de Befelatanana Antananarivo. Parmi 379 patients diagnostiqués, 103 patients, soit 27,18 %, présentant une insuffisance rénale aiguë associée étaient inclus. Nous avons utilisé les critères du groupe Kidney Disease Improving Global Outcomes pour définir l’insuffisance rénale aiguë.
Résultats
La prévalence de l’insuffisance rénale aiguë était de 27,18 %. L’âge moyen des patients était de 34,92 ans et le sex-ratio était de 3,68. Le Plasmodium falciparum était l’agent causal dans 98,06 % des cas, suivi par le Plasmodium vivax. La diurèse était conservée dans 69,86 % des cas. L’ictère était le principal signe de gravité associé (49,51 %). La créatininémie moyenne était de 466,93 μmol/L. L’évolution était favorable sous antipaludéen et la réhydratation. La dialyse était requise dans 25,24 % des cas. Treize patients étaient décédés, soit un taux de 12,62 %, parmi lesquels 8 patients (61,54 %) avaient présenté des critères de dialyse mais n’avaient pas été épurés pour des raisons économiques.
Conclusion
L’insuffisance rénale aiguë est une complication fréquente du paludisme. Elle est responsable d’une mortalité non négligeable malgré l’amélioration des soins dans la lutte contre le paludisme.
... The kidneys are pair bean-shaped organs in all vertebrates, and are located at the back of abdominal cavity, one on each side of spine [1]. Due to the asymmetry caused by the liver the left kidney is slightly smaller than the right. ...
... Inside the kidneys are numbers of pyramid shaped tubes, each consist of an outer-renal cortex and inner renal medulla. Following between these sections are nephrons, the urine producing structure of kidneys [1]. Blood enters the kidney through the renal veins. ...
Plasmodium falciparum (P. falciparum) is a specie of Plasmodium parasite responsible for the pathogenicity of malaria, a disease with several complications reported as the leading cause of over 1 million deaths worldwide. In this study, the effects of malaria on the kidney (Renal) histo-architecture was studied ex-vivo in albino mice rats. Twenty one (21) albino mice rats of between 30-35g weights were procured, acclimatized for two weeks in the animal unit of the Ambrose Alli University, Ekpoma, Edo State. They were then grouped into three (3) of seven (7) mice each, following which group I received standard rat diet and water ad libitum (control). Using the 2ml syringe, Groups II and III were inoculated with 0.2 ml of the malaria parasite Plasmodium berghei each intra-peritoneally. While group II mice were left untreated for 7 days, group III (infested) mice were administered with 5.7 mg/kg body weight of Coartem (an anti-malaria), morning and evening for 1 week. Following period of administration of substances, kidneys were harvested, rid of adherent tissues, and subjected through histological scrutiny to ascertain the changes in renal histo-morphology across groups. For each group, body weight changes were also noted within test duration and compared between groups with the one way analysis of variance. Where differences exist, the tukey (Post Hoc) test was used to ascertain the cause of the differences in body weight due to P. berghei. From the result, a statistically significant decrease (p > 0.05) in body weight was observed in P. berghei infested mice (Groups II and II) compared with control (group I). Body weight however recovered in Group III mice treated with coartem, proving to have increased significantly (p < 0.05) compared to control group. Renal histo-architectural changes revealed glomerulosclerosis, interstitial oedema and congested vessels in group II mice compared to control. We recommend similar study in other tissues other than the kidney for reference purposes
... Nuclear factor-kappa Beta (NF-kβ) also increases the secretion of adhesion molecules such as ICAM-1. [4,19,24] Loss of NF-kβ function causes various levels of immunodeficiency, thus causing various immune and inflammatory responses and deficiency of several antibodies. [5,23] Monotherapy injection of artesunate provides an improvement in tubular degeneration on the 7 th and 14 th day of postinfection, this is caused by the mechanism of antiparasitic in vitro through cutting the endoperoxide chain followed by position changes which results in carbon-centered radicals that alkalize and damage macromolecules in parasites. ...
... NFkβ activation plays an important role in the pathogenesis of severe malaria through important mediators, such as Toll-like receptors (TLR) will cause activation of the inflammatory response either through cellular immunity (TH1) which will release TNFα, IL-1, IL-6, IL-12, IL-18, INF-y and cellular immunity (TH2) which will release IL-4 and IL-10. [23,24] Meanwhile, nitric oxide and adhesion molecules such as ICAM-1, CD-36, all of which cause cytoadherence and parasite sequestration which will clog blood flow capillaries and cause interference with the microcirculation that cause anoxia in tubular cells resulting in acute tubular necrosis and kidney disorders. [6,19,21,22] ...
Brotowali (BR) extract (Tinospora crispa) can be used as an antimalarial. Aim: to determine the effect of BR extract in histopathological and expression of NFκB in mice tubules infected by Plasmodium berghei treated by artesunate (AR). Method: we used 42 C57BL / 6J strain mice as experimental animals, which were randomly divided into 7 groups : negative control (NC), positive control (PC), treatment group consist of AR 32 mg/kb (group 1); BR 70 mg/kg (group 2), combination of AR+BR 50 mg/kg (group 3), AR+BR 60 mg/kg (group 4), and AR+BR 70 mg/kg (group 5). Histological examination (hematoxylin-eosin (HE) staining) and expression of NFKB (immunohistochemical staining) in the kidneys were performed on 7th and 14th. Result: compared to PC group, BR with doses of 70 mg until 14th day, improved the degree of tubular necrosis, interstitial fibrosis, tubular degeneration, and inflammatory cell infiltration (p <0.001) but did not reach NC group (p <0.05). The combination of AR+BR until the 14th day with dose of 50, 60, 70 mg all of dose improves significantly in-term of degree of tubular cell necrosis and inflammatory cell infiltration. The degree of interstitial fibrosis on 14th day only improved in group 4 and 5 (p<0.001 and p=0.003). The level of NF-kB expression on day 7 and day 14 was reduced in group 2, group 4, and group 5 compared to PC group. There was positive correlation on 7th and 14th between NF-kβ expression and tubular degeneration, tubular cell necrosis, inflammatory cell infiltration, and interstitial fibrosis. Conclusion: the combination of AR+BR extract can improve histopathological features and reduce NF-kβ expression in mice tubules infected by Plasmodium berghei with an optimal dose was 60 mg/day for 7-14 days or 70 mg for 7 days.
... Poor prognostic factors associated with malarial AKI includes a delayed referral, high parasite load, multi-system involvement, younger age, severe jaundice, hypotension, severe anemia, and oliguria. 3 The same factors accounted for poor prognosis in our series as well where in the the patient C who landed up in ESRD was the youngest of the three, had kidney and liver involvement, severe anemia and was anuric on presentation. ...
... The WHO numbered about 219 million of malaria cases worldwide, with global death estimated at 435 000, predominantly in young children in sub-Saharan Africa [1] . Malaria stands out among the systemic infectious diseases of humans, presenting with multiple manifestations including intense fever, headache, and muscular pain and sometimes accompanied by potentially fatal symptoms such as severe anaemia, coagulation disturbances, microcirculation impairment that contribute to liver and renal failure and could induce major cerebral pathology [2,3] . These symptoms are caused by parasitized red blood cells (RBCs) adhering to the endothelium surface, obstructing blood flow and causing regional oxygen deprivation and haemorrhage [4] . ...
Anthocleista liebrechtsiana is a plant used in traditional medicine in Cameroon to treat sexual asthenia and male infertility. In order to evaluate the effects of Anthocleista. liebrechtsiana hydroalcoholic extract leaves on ethanol-induced sperm disorders in rats, adult male rats were divided into 4 groups of five rats each. The experimental period lasted 75 days. It was divided into two phases: an oligospermia or azoospermia induction phase (21 days) during which all the animals were intoxicated with 40 ° ethanol at a dose of 6 g/kg except the normal control group, and the treatment phase which lasted 54 days. During the latter phase, the animals of the negative control group received ethanol and distilled water per os; those of test groups A and B received ethanol and hydroalcoholic extract at doses of 150 and 300 mg/kg, respectively. At the end of this period, the animals were anesthetized and then sacrificed. Reproductive organs and annex glands were removed and weighed; arteriovenous blood was collected in tubes for testosterone assay. Sperm count, motility, sperm vitality was determined, and histopathological analysis of the testis, epididymis and prostate was performed. The results of the study showed that treatment of rats with 40° ethanol has significantly reduced body weight, relative weight of reproductive organs and the annex glands, the number of spermatozoa, their mobility and vitality, and the level of testosterone compared to the normal group. The treatment with the hydroalcoholic extract of Anthocleista liebrechtsiana significantly corrected the weight of the reproductive organs and annexed glands, and the number, mobility and vitality of spermatozoa. These results indicate the ability of the hydroalcoholic extract of Anthocleista. liebrechtsiana to correct the deleterious effects of ethanol on sperm parameters. These results thereby justify the use of Anthocleista. liebrechtsiana leaves in the management of male infertility in the traditional pharmacopoeia.
... Kidney disease in malaria is primarily due to erythrocyte abnormalities. Parasitized red cells tend to adhere to healthy erythrocytes, blood platelets, and capillary endothelium, leading to formation of rosettes and clumps, which impair microcirculation [4], and these events are probable contributing factors for kidney injury, in association with hemodynamic instability, including hypovolemia and shock. Endothelial activation leads to the release of several cytokines, including thromboxane, catecholamines, endothelin, and other inflammatory mediators that are also implicated in the pathogenesis of malaria-associated kidney injury [5]. ...
Background:
Malaria remains one of the leading health problems of the developing world, and acute kidney injury (AKI) is a well-recognized complication of severe malaria in adults; but the clinical importance of AKI in paediatric severe malaria is not well documented. Knowledge of the prevalence and factors associated with AKI among children with severe malaria is among the key strategies, which can help to reduce the burden of AKI among this vulnerable group. Methodology. A hospital-based prospective cross-sectional descriptive and analytic study of children with severe malaria was carried out at Kiryandongo General Hospital. The study involved 350 children with severe malaria attending the study site from August to October 2021. Questionnaires were administered to caretakers to obtain sociodemographic characteristics. Medical data were obtained through physical examination followed by laboratory tests. Blood samples were tested for creatinine and blood smear for malaria. Data were analyzed using binary logistic regression (bivariate and multivariate) to assess for the factors associated with AKI. A p value < 0.05 was considered statistically significant.
Results:
The mean age of children with severe malaria was 7.0 ± 3.8 years, and 54.3% of them were male. Of the 350 children enrolled, 167 had AKI, giving an overall AKI prevalence of 47.7% (95% CI: 42.5-53.0). The factors that were significantly associated with AKI among children with severe malaria included caretaker with no formal education (aOR = 21.0, 95% CI: 1.68-261.18, p = 0.018), caretaker with primary education level (aOR = 4.5, 95% CI: 1.41-14.12, p = 0.011), age of child < 5 years (aOR = 1.8, 95% CI: 1.07-2.88, p = 0.025), history of receiving NSAIDs (aOR = 5.6, 95% CI: 2.34-13.22, p < 0.001), moderate anemia (aOR = 3.1, 95% CI: 1.39-6.94, p = 0.006), and severe anemia (aOR = 3.8, 95% CI: 1.66-8.55, p = 0.002).
Conclusion:
The prevalence of AKI was high among children with severe malaria in Kiryandongo General Hospital. Acute kidney injury among children with severe malaria was associated with low level of education of caretakers, age of children less than 5 years, history of receiving NSAIDs, and anemia. The management of severe malaria should include screening for AKI especially in children under five years of age, anemic, and those who have received NSAIDs.
... 24 Volume depletion due to severe vomiting and hypotension may also have a significant role to play in the development of ARF in malaria. 25 One of the patients with vivax malaria developed thrombocytopenia. Recently there are several reports suggesting that vivax malaria is no longer considered to be as mild, many severe complications especially thrombocytopenia and hepatic dysfunction can develop in vivax malaria. ...
... Malarial acute kidney injury can develop as a solitary complication or as part of a multiorgan disorder [11]. In the majority of cases, malarial acute kidney injury shows clinically and pathologically as acute tubular necrosis and are associated with jaundice in around 75% of cases, as observed in our patient [12]. Jaundice is typically "biphasic," with high levels of conjugated and nonconjugated bilirubin caused by cholestasis and hemolysis, respectively [13]. ...
Acute kidney injury is a complication of severe malaria that is relatively uncommon. It has clinical importance associated with substantial morbidity and mortality in malaria-endemic regions. We report a young patient who developed acute renal injury as a result of severe malaria. In this case, malaria diagnosis was confirmed using the malaria rapid screening test and microscopic inspection of blood smears. Fever, nausea and vomiting, loss of appetite and jaundice were the clinical presentations. Treatment with artemether injection, volume expansion and antipyretics was given. He recovered well without needing hemodialysis. This is not always the case, and the prognosis is dependent on the time of presentation, the diagnosis, and the treatment received. Özet Akut böbrek hasarı, ciddi sıtmanın nispeten nadir görülen bir komplikasyonudur. Sıtmanın endemik olduğu bölgelerde morbidite ve mortalite ile ilişkili klinik önemi vardır. Şiddetli sıtma nedeniyle akut böbrek hasarı gelişen genç bir hasta olgusunu sunuyoruz. Bu olguda, sıtma tanısı sıtma hızlı tarama testi ve kan yaymalarının mikroskobik incelemesi ile doğrulandı. Klinik prezentasyonlar ateş, bulantı ve kusma, iştahsızlık ve sarılıktı. Artemeter enjeksiyon ile tedavi edilen hastaya volüm desteği ve antipiretik verildi. Hasta hemodiyaliz gereksinimi olmaksızın iyileşti. Olgularda durum her zaman böyle değildir ve prognoz başvuru zamanına, tanıya ve alınan tedaviye bağlıdır.
... Several studies have reported similar trend in serum electrolytes in patients with severe malaria, some with associated acute kidney injury. [36,37] Severe metabolic acidosis, hypermetabolic state and oligo-anuria are major manifestations of renal affectation and complications by Plasmodium falciparum parasitaemia. [38,39] This report is inkeeping with our findings in which metabolic acidosis is depicted by low serum bicarbonate and reduced blood pH in the parasitized untreated mice. ...
Background: Malaria, an endemic parasitic infection in Sub-Saharan Africa causes a huge human and economic burden to the region. Malaria complication is known to affect several body organs and systems. The kidney is one of the major organs that is affected by Plasmodium falciparum infection. Kidney involvement is one of the key criteria for classifying patient as having severe or complicated malaria. Our study evaluated the renoprotective potential of Eremomastax speciosa on Plasmodium berghei infected mice, treated with Artemether-lumefantrine.
Methodology: Thirty-five albino mice, whose weights ranged between 30 to 38g, were divided into 5 groups having 7 mice in each. The mice were inoculated with Plasmodium berghei from a donor mouse. An inoculum which consisted of 5 x 107 Plasmodium berghei infested erythrocytes per ml of blood was injected into each mouse by intraperitoneal route. The mice were kept for 7 days for the parasite to develop and parasitaemia was confirmed using standard procedure. A non-parasitized mice group served as normal control. About 300mg/Kg body weights of Eremomastax speciosa leaf extract, 3mg/kg body weight of Artemether and 18mg/kg body weight of Lumefantrine were administered concomitantly by oral routes to a mice group. A parasitized group was treated with Artemether-Lumefantrine only, and another with E. speciosa only. A parasitized and a non-parasitized group, given only normal saline, served as controls. All treatment lasted for six days. Serum were obtained from where electrolytes, creatinine, urea and blood pH were measured..
Results: Mice group treated with combination of Artemether-lumefantrine and E. speciosa leaf extract showed significant (P <0.05) increases in the serum electrolytes in comparison to the parasitized untreated mice. The levels of the electrolytes obtained the concurrent treatment were similar to that obtained for the non-parasitized normal control. The mice group concurrently treated with Artemether-lumefantrine and extract of E. speciosa showed significant decreases in creatinine and urea levels in comparison to the parasitized untreated group. These creatinine and urea levels were very similar to that obtained from non-parasitized normal mice group.
Conclusion: Concurrent administration of Artemether-lumefantrine with E. speciose leaf extract reversed Plasmodium berghei-induced metabolic acidosis, hyponatiaemia, hypokalaemia, hypochroraemia, and uraemia. This may be due to synergistic action of the Artemether-lumefantrine with some phytochemicals in the plant extract.
... Malaria was the first parasitic infection to be clearly associated with glomerular diseases in tropical areas [4]. Severe malaria can cause disease in glomeruli, tubules and in the interstitial region. ...
Malaria is an infectious disease that is transmitted through mosquito bites and is endemic especially in Sub-Saharan Africa. The current study aimed at evaluating the antioxidants and kidney function indices in albino mice infected with P. berghei and treated with sodium bicarbonate. Twenty mice were randomly divided into five groups of four mice each. Groups 1was the normal control, group 2 was infected with P. berghei, not treated groups (3, 4 and 5) were administered 84mg/kg b.w of sodium bicarbonate once, twice and thrice per day respectively for three days. Serum samples were collected and analyzed for MDA, GPx, SOD, CAT, GHS, Na + , K + , Cl-, HCO 3-, Urea and Creatinine following standard methods. MDA concentrations were significantly (p<0.05) higher in all the test groups compared to the control. GPx activity decreased significantly (p<0.05) in group 2 and increased significantly (p<0.05) in group 5 compared to the control group. SOD activity decreased significantly (p<0.05) in group 3 and increased significantly (p<0.05) in groups 2, 4 and 5 compared to the control. Catalase decreased significantly (p<0.05) in groups 2, 4 and 5 Original Research Article Haruna et al.; IJANR, 4(1): 82-91, 2021; Article no.IJANR.74351 83 compared to the control. GSH increased significantly (p<0.05) in all the test groups compared to the control. Sodium ion was significantly (p<0.05) higher in group 2,3 and 4 compared to the control. Potassium ion was significantly (p<0.05) higher in all the test groups compared to the control. Chloride ion increased significantly (p<0.05) in group 5 and decreased significantly (p<0.05) in group 3 and 4 compared to the control (75.37±0.707). Urea concentration increased significantly (p<0.05) in groups 2,4,5 and decreased significantly (p<0.05) in group 3 compared to the control (37.60±0.707). Similarly, creatinine increased significantly (p<0.05) in groups 2, 4 and 5 but decreased significantly (p<0.05) in group 3 compared to the control. This study revealed that infection of mice with P. berghei may have posed a massive metabolic stress on the kidney as indicated by elevated biochemical parameters although this could not be seen in the histological studies.
... Malaria was the first parasitic infection to be clearly associated with glomerular diseases in tropical areas [4]. Severe malaria can cause disease in glomeruli, tubules and in the interstitial region. ...
This review was tailored on the description, types and progression of diabetes mellitus. Diabetes is a non�infectious disease of sugar metabolism that is characterized by elevated blood glucose concentration above
normal level; referred technically as hyperglycaemia. It has been shown that excessive thirst, fatigue,
hunger, weight loss, blurry visions, frequent urination constitutes the symptoms of diabetes. The disease has
three broad classifications which include; type 1 diabetes mellitus, type 2 diabetes mellitus and gestational
diabetes mellitus depending on the underlying factors causing it. For the type 1 diabetes mellitus, insulin is
not produced at all duet to deformities of β cells present in the pancreas, in the type 2 diabetes, insulin is
produced but not sensitive to glucose which would have helped cells to internalize it while the gestational
diabetes is usually in women due to pregnancy. In any case, life-threatening complications may result. The
possible mechanisms for unabated diabetes progression may be due chiefly to oxidative-based stress due to
the accumulation and activities of reactive oxygen species-induced hyperglycaemia, activation of protein
kinase C (PKC), elevated inflow of bio-precursors and substrates in the pathway leading to hexosamine
biosynthesis, production of advanced glycation end-product (AGEs), altered polyol pathway flux and
altered gene expression leading to beta cell death and reduced insulin secretion. In order to detect and stop
its progression to unbearable complications, individuals should look out for these symptoms and go for early
medical check-ups and diagnosis so that diabetes mellitus and its attending complications may be averted.
... AKI may be associated with massive parasitemia, intravascular haemolysis, and rarely rhabdomyolysis. Acute lesions are transient, reversible and respond favourably to antimalarial drugs [63,65,68,69]. ...
Acute kidney injury (AKI) is a complex condition that can occur in both community and hospital settings and has many aetiologies. These aetiologies may be infectious, toxic, surgical, or related to the different management methods. Although it is a major public health problem worldwide, it must be emphasised that both its incidence and mortality rate appear to be very high in sub-Saharan African (SSA) countries compared to developed countries. The profile of AKI is very different from that of more developed countries. There are no reliable statistics on the incidence of AKI in SSA. Infections (malaria, HIV, diarrhoeal, and other diseases), nephrotoxins, and obstetric and surgical complications are the main aetiologies in Africa. The management of AKI is costly and associated with high rates of prolonged hospitalisation and in-hospital mortality.
... Malaria was the first parasitic infection to be clearly associated with glomerular diseases in tropical areas [4]. Severe malaria can cause disease in glomeruli, tubules and in the interstitial region. ...
Malaria is an infectious disease that is transmitted through mosquito bites and is endemic especially in Sub-Saharan Africa. The current study aimed at evaluating the antioxidants and kidney function indices in albino mice infected with P. berghei and treated with sodium bicarbonate. Twenty mice were randomly divided into five groups of four mice each. Groups 1was the normal control, group 2 was infected with P. berghei, not treated groups (3, 4 and 5) were administered 84mg/kg b.w of sodium bicarbonate once, twice and thrice per day respectively for three days. Serum samples were collected and analyzed for MDA, GPx, SOD, CAT, GHS, Na + , K + , Cl-, HCO 3-, Urea and Creatinine following standard methods. MDA concentrations were significantly (p<0.05) higher in all the test groups compared to the control. GPx activity decreased significantly (p<0.05) in group 2 and increased significantly (p<0.05) in group 5 compared to the control group. SOD activity decreased significantly (p<0.05) in group 3 and increased significantly (p<0.05) in groups 2, 4 and 5 compared to the control. Catalase decreased significantly (p<0.05) in groups 2, 4 and 5 Original Research Article Haruna et al.; IJANR, 4(1): 82-91, 2021; Article no.IJANR.74351 83 compared to the control. GSH increased significantly (p<0.05) in all the test groups compared to the control. Sodium ion was significantly (p<0.05) higher in group 2,3 and 4 compared to the control. Potassium ion was significantly (p<0.05) higher in all the test groups compared to the control. Chloride ion increased significantly (p<0.05) in group 5 and decreased significantly (p<0.05) in group 3 and 4 compared to the control (75.37±0.707). Urea concentration increased significantly (p<0.05) in groups 2,4,5 and decreased significantly (p<0.05) in group 3 compared to the control (37.60±0.707). Similarly, creatinine increased significantly (p<0.05) in groups 2, 4 and 5 but decreased significantly (p<0.05) in group 3 compared to the control. This study revealed that infection of mice with P. berghei may have posed a massive metabolic stress on the kidney as indicated by elevated biochemical parameters although this could not be seen in the histological studies.
... Malaria was the first parasitic infection to be clearly associated with glomerular diseases in tropical areas [4]. Severe malaria can cause disease in glomeruli, tubules and in the interstitial region. ...
Malaria is an infectious disease that is transmitted through mosquito bites and is endemic especially in Sub-Saharan Africa. The current study aimed at evaluating the antioxidants and kidney function indices in albino mice infected with P. berghei and treated with sodium bicarbonate. Twenty mice were randomly divided into five groups of four mice each. Groups 1was the normal control, group 2 was infected with P. berghei, not treated groups (3, 4 and 5) were administered 84mg/kg b.w of sodium bicarbonate once, twice and thrice per day respectively for three days. Serum samples were collected and analyzed for MDA, GPx, SOD, CAT, GHS, Na + , K + , Cl-, HCO 3-, Urea and Creatinine following standard methods. MDA concentrations were significantly (p<0.05) higher in all the test groups compared to the control. GPx activity decreased significantly (p<0.05) in group 2 and increased significantly (p<0.05) in group 5 compared to the control group. SOD activity decreased significantly (p<0.05) in group 3 and increased significantly (p<0.05) in groups 2, 4 and 5 compared to the control. Catalase decreased significantly (p<0.05) in groups 2, 4 and 5 Original Research Article Haruna et al.; IJANR, 4(1): 82-91, 2021; Article no.IJANR.74351 83 compared to the control. GSH increased significantly (p<0.05) in all the test groups compared to the control. Sodium ion was significantly (p<0.05) higher in group 2,3 and 4 compared to the control. Potassium ion was significantly (p<0.05) higher in all the test groups compared to the control. Chloride ion increased significantly (p<0.05) in group 5 and decreased significantly (p<0.05) in group 3 and 4 compared to the control (75.37±0.707). Urea concentration increased significantly (p<0.05) in groups 2,4,5 and decreased significantly (p<0.05) in group 3 compared to the control (37.60±0.707). Similarly, creatinine increased significantly (p<0.05) in groups 2, 4 and 5 but decreased significantly (p<0.05) in group 3 compared to the control. This study revealed that infection of mice with P. berghei may have posed a massive metabolic stress on the kidney as indicated by elevated biochemical parameters although this could not be seen in the histological studies.
... These mechanisms of damage do not stop here and from endothelial activation resulting in release of various cytokines and local mediators that may enhance peripheral capillary damage. 6 We hereby report a case of P. vivax malaria complicated with acute kidney injury (AKI) and severe microangiopathy causing gangrene of feet and tip of nose. ...
Malarial infestation is common in Pakistan and Plasmodium vivax is a common causative organism. Although it has been managed successfully with usual antimalarials and complications are rare, yet occasionally severe complications are observed including Acute kidney injury. We present her a case of AKI secondary to plasmodium vivax along with gangrene of bilateral feet.
... Parasitized red cells tend to adhere to healthy erythrocytes, blood platelets, and capillary endothelium, and this in turn leads to formation of rosettes and clumps, which impair microcirculation [41]. ...
Extracts of Alstonia boonei and Carica papaya are used in herbal medicine for the treatment of malaria. is work investigated the phytochemical, antioxidant, and antimalarial effects of hydromethanolic extracts of Alstonia boonei and Carica papaya. A four-day chemosuppressive test was conducted to assess the ability of the extracts to prevent establishment of infection. ree doses of the extracts were administered-100, 200, and 400 mg/kg bw-prior to Plasmodium berghei challenge. Change in body weight, par-asitemia, packed cell volume (PCV), and mean survival time was determined. A three-day curative test was also carried out on Plasmodium berghei-infected mice to determine the effects of the plant extracts (200 mg/kg bw) on parasitemia and biochemical indices of liver and kidney functions, lipid metabolism, and oxidative stress. e study revealed that the extracts possessed phenolic compounds (34.13 ± 1.90 mg GAE/g for Alstonia boonei and 27.99 ± 1.46 mg GAE/g for Carica papaya) and flavonoids (19.47 ± 1.89 mg QE/g for Alstonia boonei and 18.24 ± 1.36 mg QE/g for Carica papaya). In vitro antioxidant activity measured as total antioxidant power, total reducing power, and DPPH radical scavenging activity showed that the extracts possessed higher antioxidant activity than the reference compounds. e outcome of the chemosuppressive test revealed that whereas Plasmodium berghei-infected mice had high parasitemia, decreased mean survival time, exhibited loss of weight, and had low PCV, treatment with the extracts reversed the effects in a concentration-dependent manner. Similarly, the curative test revealed that the extracts significantly suppressed parasitemia compared with the malaria negative control group. is was mirrored by reversal of indices of hepatic toxicity (AST, ALT, and ALP levels), nephropathy (urea and creatinine levels), oxidative stress (SOD, CAT, GPx, GSH, and lipid peroxides), and dyslipidemia (TC, HDL, and TG levels and HMG-CoA reductase activity) in infected but treated mice compared with negative control. Put together, the results of this study demonstrate that the extracts of Alstonia boonei and Carica papaya possess antimalarial properties and are able to ameliorate metabolic dysregulations that characterize Plasmodium berghei infection. e phytoconstituents in these extracts are believed to be responsible for the pharmacological activity reported in this study.
... The parasite density is always low compared to Plasmodium falciparum and it produces clinical relapses due to the asexual forms that persist in the host's blood [17]. Symptoms include nephropathies [19][20][21][22][23], a long asymptomatic persistence of several years before access to recrudescence [24] that may induce transfusional malaria [25], genetic polymorphism [26][27][28][29], transmission by palearctic or tropical vectors [30,31], and due to its possibility to infect human and simian subjects [32], it was considered as an anthropozoonosis. ...
Background: A long-term village scale vector control program was implemented in eight villages around the Balombo town (Benguela Province, Angola) to compare the efficacy of four methods of vector control inside houses including long-lasting deltamethrin insecticide treated nets (PermaNet© 2.0 model or P.2.0); association of P.2.0 and deltamethrin Insecticide Treated Plastic Sheeting (ITPS)-Zero Fly© model; deltamethrin ITPS-Wall Lining model alone; and 2 rounds of lambdacyhalothrin Inside Residual Spraying followed by installation of ITPS.
Methods: Cross sectional parasitological surveys (CSS) were done every two months. Thick blood films (TBF) were microscopically examined at the Medical Department of the Angolese Sonamet company in Lobito and a sample of them were double-checked in Yaoundé. Plasmodium species determination, parasitaemia and gametocytes presence, and evolution in time were analyzed.
Results: A total of 190 CSS was done between 2007 and 2011, Plasmodium spp. were observed in 5,431 of the 21,804 TBF done. Plasmodium malariae alone was observed in 22 TBF (0.4%) and mixed infections P. falciparum and P. malariae in 44 TBF (0.8%).
Conclusion: The very low frequency of P. malariae could explain the fact it is usually not reported in classical point prevalence surveys. Our study confirms the presence of this species in Angola, which must be known due to its special clinical impact, quartan fever, kidney failure, chronicity, symptomless carriers, persistence for several years with long term recrudescence and reported cases of resistance to classical ACTs. The prevalence of P. malariae decreased after implementation of vector control methods.
... 1 Kidney failure in this article is used to mean End-Stage Renal Disease (ESRD). 2 Hormones: erythropoietin secreted by kidneys increases the rate of production of red blood cells in response to falling levels of oxygen; calcitriol (the active form of vitamin D) increases calcium levels in body in skeletal and tissues diseases; and renin raises blood pressure. 3 The following references are pertinent to the discussion in this paragraph: Murry et al. 2015;Jiro & Yuji 2017;Seyid, Fetimah, Shokouh & Seyid 2015;Leticia & Charlotte 2012;Jack, Corine & David 2020;Jinsoo et al. 2018;Rashad 2020;Geraldo et al. 2017;Eriksen & Ingebresten 2006;Elisabetta & Giorgina 2019; Oncohema Key, https://oncohemakey.com/end-stage-renal-disease/. Babau et al. (2015), in a study at a national referral hospital in Uganda, indicated that up to 51% of 111 patients attending the outpatient nephrology department had kidney failure. ...
... Two things mainly cause the alteration that occurs in the kidneys. First, the attachment of Plasmodium-infected erythrocytes to the endothelium, and the second one is the rosette phenomenon, which is an infected erythrocyte clotted with normal erythrocytes (Barsoum, 2000;Rowe et al., 2009). Both of these can interfere with microcirculation (Sriboonvorakul et al., 2018). ...
Malaria is a parasitic infectious disease caused by Plasmodium, which remains a world health problem with an estimated 219 million cases worldwide. In severe malaria infection, several organs of the body can be affected, including the kidneys. One of the pathophysiology associated with the worsening of this disease is oxidative stress. The use of antioxidants is expected to prevent this, and one product that has a high antioxidant content is virgin coconut oil (VCO). This study aimed to analyze the effect of VCO on the kidney in Plasmodium berghei ANKA-infected mice. This study was an in vivo laboratory experimental study with a randomized post-test only control group design using 35 BALB/c mice infected with P. berghei ANKA, weighing 20-30 grams. VCO with the Javara® brand is used with doses of 1, 5, and 10 ml/kg body weight (kgBW)/ day. The parameter assessed were levels of BUN, creatinine, and renal histopathological changes. The administration of VCO on the treated group shows minimal tubular necrosis and glomerulonephritis compared to the negative control group. The BUN and creatinine levels in the treated group were also lower than the negative control group. The results showed that VCO has a nephroprotective effect against P. berghei ANKA infection in mice.
Keywords: malaria, kidney, virgin coconut oil
... Typical histopathology features in malaria-related AKI include acute tubular necrosis (ATN) and, less commonly, interstitial nephritis and glomerulonephritis (18,19). Examination of kidney tissues from autopsies of Southeast Asian adult SM patients revealed the presence of sequestered pRBCs within glomerular and tubulo-interstitial vessels, as well as the accumulation of host monocytes within glomerular and peritubular capillaries (20). ...
Acute kidney injury (AKI) is a common feature of severe malaria, and an independent risk factor for death. Previous research has suggested that an overactivation of the host inflammatory response is at least partly involved in mediating the kidney damage observed in P. falciparum patients with AKI, however the exact pathophysiology of AKI in severe malaria remains unknown. The purpose of this mini-review is to describe how different aspects of malaria pathology, including parasite sequestration, microvascular obstruction and extensive intravascular hemolysis, may interact with each other and contribute to the development of AKI in severe malaria, by amplifying the damaging effects of the host inflammatory response. Here, we highlight the importance of considering how the systemic effects and multi-organ involvement of malaria are intertwined with the localized effects on the kidney.
... At a lesser extent, acute kidney injury had also been reported in vivax malaria (Anstey et al., 2012). The renal involvement in P. falciparum and P. vivax infection may be due to erythrocyte abnormalities, particularly, the formation of rosettes and clumps by sticky parasite-infected red blood cells, which causes impaired microcirculation of internal organs (Barsoum, 2000). Events such as endothelial cytoadherence, sequestration, increased whole blood viscosity and obstruction of capillary lumen can happen when parasitized erythrocytes aggregates together and hence, causing AKI. ...
In recent years, increasing cases of Plasmodium vivax complications had been reported all over the world. This former benign Plasmodium species is now recognized to be one of the human malaria parasites that can produce severe disease. In this article, we report two cases of sub-microscopic P. vivax malaria confirmed by PCR. Both patients were asymptomatic before treatment. They showed unusual presentations few days after initiation of antimalarial treatment. Both patients had subsequently completed antimalarial treatment and recovered completely.
... Kidney injury, acute or chronic, is one of the common differential diagnosis of malaria manifesting as syndrome. The diverse presentations and aetiological mechanisms of AKI orbit around the properties of pRBC's on microcirculation, hypovolaemia, metabolic derangements or host immunologic responses to infection [175][176][177]. These major pathogenic features are originated by the Plasmodium infection but may not be limited by the annihilation of the infection. ...
... It has been previously reported that kidney involvement is not uncommon in falciparum and malariae malaria [28]. Haemodynamic dysfunction and immune response are the main mechanism of malaria associated kidney pathology [29]. Furthermore, malaria has been reported as the first parasitic infection to be clearly associated with glomerular diseases in tropical areas [30] with subsequent detection of Plasmodium antigens in the glomeruli [28]. ...
Objective:
Microscopy remains the gold standard for identification of malaria parasites. However, the sensitivity of malaria microscopy is low. This study evaluated the impact of repeated sampling up to 12 h in 177 children < 6 years with suspected malaria.
Results:
The median age was 3 years (interquartile range, 2.0-4.0 years). Eighty-nine percent (158/177) presented with hyperthermia together with one or more of the following symptoms: chills, headache, sweating, fatigue, nausea, abdominal pain, vomiting, diarrhea and cough. Baseline microscopy confirmed malaria in 29.9% (53/177) of the suspects. Repeated testing at 6 and 12 h increased the positive detection rates to 35.0% (62/177) and 41.8% (74/177), respectively. Microscopy underestimated malaria diagnosis by 11.9% on single testing. Children showing classical signs of malaria but with initial negative parasitological reports should be retested between 6 to 12 h to confirm or rule out a diagnosis of malaria.
... Acute kidney injury (AKI), which is one of the most hypercritical complications experienced by patients with severe malaria, affects 40% of adult patients and is associated with a high mortality rate [3]. At present, the pathogenesis and precise mechanism of P. falciparum-induced AKI remain unclear although previous studies have hypothesized involving an excessive immune response, mechanical obstruction by infected red blood cells, fluid loss due to multiple mechanisms, and alterations in the renal microcirculation [4][5][6]. e pathophysiology of malaria involves oxidative stress arising from many possible sources, such as red blood cells infected with P. falciparum [7], human phagocytic cells activated by P. falciparum [8], elevation of the oxidative host enzyme levels [9], and the occurrence of ischemia and reperfusion syndrome during malarial paroxysm and cytoadherence [10]. Additional possible sources could be reactive oxygen species (ROS) production by parasites and the action of prooxidants and antimalarial drugs [10]. ...
Acute kidney injury (AKI) is one of the most serious complications of severe Plasmodium falciparum malaria, but the exact pathogenic mechanisms of AKI in P. falciparum infection have not been clearly elucidated. We hypothesized that oxidative stress is a potential mediator of acute tubular necrosis in P. falciparum-infected kidneys. Therefore, this study aimed to investigate the histopathological changes and markers of oxidative stress in kidney tissues from mice with experimental malaria. DBA/2 mice were divided into two groups: the mice in the malaria-infected group (n = 10) were intraperitoneally injected with 1 × 106P. berghei ANKA-infected red blood cells, and the mice in the control group (n = 10) were intraperitoneally injected with a single dose of 0.85% normal saline. Kidney sections were collected and used for histopathological examination and the investigation of 4-hydroxynonenal (4-HNE) and heme oxygenase-1 (HO-1) expression through immunohistochemistry staining. The histopathology study revealed that the P. berghei-infected kidneys exhibited a greater area of tubular necrosis than those of the control group (p < 0.05). The positive staining scores for 4-HNE and HO-1 expression in tubular epithelial cells of the P. berghei-infected group were significantly higher than those found for the control group (p < 0.05). In addition, significant positive correlations were found between the tubular necrosis score and the positive staining scores for 4-HNE and HO-1 in the kidneys from the P. berghei-infected group. In conclusion, this finding demonstrates that increased expression of 4-HNE and HO-1 might be involved in the pathogenesis of acute tubular damage in the kidneys during malaria infection. Our results provide new insights into the pathogenesis of malaria-associated AKI and might provide guidelines for the future development of a therapeutic intervention for malaria.
Acute kidney injury (AKI) secondary to severe falciparum malaria possesses a high mortality rate; however, a prognostic marker of renal dysfunction has not yet been identified. Thus, we reported a case of a patient with AKI secondary to falciparum malaria who underwent hemodialysis and a renal biopsy due to prolonged renal dysfunction. The male patient, in his 50 s, presented to our hospital with vomiting, diarrhea, fever, and decreased level of consciousness. The Giemsa-stained peripheral blood film revealed approximately 5% parasitemia, and a rapid diagnostic test was positive for Plasmodium falciparum. He was diagnosed with severe falciparum malaria and was started on quinine hydrochloride. Hemodialysis was initiated due to the decreased urine output and fluid retention. Subsequently, he was weaned off hemodialysis. The histopathological analysis of a renal biopsy revealed interstitial fibrosis, tubular atrophy, and chronic inflammatory cell infiltration; thus, malarial nephropathy was diagnosed. Thereafter, his renal function stabilized, and he was discharged from the hospital. The urinary liver-type fatty acid-binding protein (L-FABP) level decreased before renal function improved. Our report highlighted that long-term follow-up is essential for severe AKI secondary to malaria. The urinary L-FABP level may be a useful prognostic indicator of AKI secondary to severe falciparum malaria.
As Odisha is an endemic region for malaria with many acute kidney injury (AKI) cases, this study evaluated the clinical profile and treatment outcomes of patients with malaria complicated by AKI. This prospective observational study was conducted between December 2015 and September 2017. Detailed histories and clinical examinations were recorded. On admission, tests for routine hematology, plasma glucose, liver function, renal function, serum electrolytes, thick smears, thin smears, and malarial parasites were performed. Of the 958 AKI malarial patients admitted, 202 (82.6 % males) were included in the study, with a mean age of 38.37 years. In total, 86.14%, 3.46%, and 10.39% of patients had Plasmodium falciparum, Plasmodium vivax, and mixed malaria, respectively. Headache and decreased urination (83.66% each) were the most common symptoms after fever (100%). Anuria and oliguria were reported in 5.95% and 67.82% of patients, respectively, whereas 26.23% reported a urine output of >400 mL/24 h. All patients had raised serum creatinine and urea levels, and >60% had anemia, proteinuria, and/or hyponatremia. Multiple organ dysfunction syndrome was observed in 62.87% of patients. Acute tubular necrosis was seen in 60% of renal biopsy specimens ( n = 15). Of the 75.75% of patients requiring dialysis, 82.12% and 17.88% of patients required hemodialysis and peritoneal dialysis, respectively, during which 11 patients died. AKI, a serious complication of P. falciparum or P. vivax malaria, is a life-threatening condition. Fever, anemia, oligo/anuria, hepatic involvement, cerebral malaria, high serum creatinine and urea, and disseminated intravascular coagulation were the main predictors of mortality in our study.
Plasmodium falciparum-induced malaria remains a fatal disease affecting millions of people worldwide. Mainly, the blood stage of malaria is highly pathogenic and symptomatic, rapidly damaging the host organs and occasionally leading to death. Currently, no vaccines are approved for use against the blood stage of malaria. Canonical vaccines in the past have selected the most immunodominant or essential protein to block the growth of the parasite. This strategy works efficiently for low-complexity organisms such as viruses and a few bacteria but has not shown promising results for a malaria vaccine. Plasmodium has a complex life cycle and vaccine candidates especially during blood stage are ineffective due to multiple gene families showing redundancy, immune evasion, and insufficient antibody titer. Herein, we demonstrate a novel strategy of combining multiple antigens from the blood stage of Plasmodium falciparum using only the most immunodominant peptide sequences as a way of tackling polymorphism and redundancy. We created three chimeric antigens targeting eight PfEMP1 proteins (chimeric varB) and eight merozoite surface proteins (chimeric MSP and InvP) by selecting and stitching B-cell epitopes. Our chimeric constructs show naturally circulating antibodies against individual peptides using epitope-mapping microarray as well as entire proteins in malaria-infected patients. We demonstrate that anti-varB antibodies are neutralizing in nature and significantly reduce the cytoadhesion on an organ-on-chip system with a microfluidic device mimicking physiological conditions. We have applied a Deep Learning based method to quantify the number of adhered RBCs under fluidic conditions that is used to study cytoadhesion. Furthermore, the anti-MSP and InvP antibodies show complete growth inhibition in a single cycle at a combined concentration of 0.13 mg/ml. Overall, our results show that a combination of antigenic peptides from multiple antigens can function as a next-generation vaccine and effectively block the blood stage by reducing cytoadhesion and inhibiting the parasite growth.
Background:
The concern about the global spread of resistant malaria has made the researchers not focus only on the treatment of established infections but relatively more on the prevention of the disease.
Objective:
This study evaluates the chemopreventive activity of ketoconazole in a murine malarial model.
Method:
Five out of seven groups of mice were pretreated for five days with proguanil (PRG), sulfadoxine/ pyrimethamine (SP), 10, 20, and 40 mg/kg body weight (b.w) of ketoconazole (KET10, KET20, and KET40), before being infected (on the sixth day) with Plasmodium berghei. Two other groups were infected-not-treated (INT) and not-infected-nor-treated (NINT). At 72 hours postinfection, five out of ten mice in each group were sacrificed to assess parasitemia, chemoprevention, hematologic, hepatic, and renal parameters. The remaining mice were observed for 28 days to determine their mean survival day post-infection (SDPI).
Results:
All ketoconazole groups, except KET10, demonstrated 100% chemoprevention and significantly higher mean SDPI (p<0.001) in relation to INT (negative control). There was no significant difference in the mean SDPI observed in KET20 in relation to PRG or NINT (healthy control). A dose-related increase (p<0.01) in the mean plasma urea was observed when ketoconazole groups were compared to one another: KET10 versus KET20 (p<0.01) and KET20 versus KET40 (p<0.01). Sulfadoxine/pyrimethamine demonstrated significantly reduced mean plasma urea (p<0.001) and creatinine (p<0.05) in relation to INT and NINT, respectively. While PRG demonstrated significantly higher mean red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) in relation to INT.
Conclusion:
Ketoconazole possesses prophylactic antimalarial activity with associated dose-related renal impairment. Sulfadoxine/pyrimethamine demonstrated renoprotective potentials, while PRG prevented malaria-associated anemia.
Infections of the kidney and urinary tract are a common cause of morbidity, and sometimes mortality, especially in young women. The responsible pathogens include bacteria, viruses, protozoa, parasites, and fungi. The clinical nature of the infection can be different in the immunosuppressed, in the setting of kidney transplantation, and in other conditions, including vasculitis, glomerulopathy and cancer. Some infections can lead to systemic immune activation, which can in turn lead to kidney disease.KeywordsHaematuriaProteinuriaUrinary tract infectionUTIBacterial infectionViral infectionFungal infectionPyelonephritisAcute kidney injuryAKI
Background
Simultaneous increase in transaminases and bilirubin is an indicator of hepatic dysfunction in malaria. Malaria-induced hyperbilirubinemia has been associated with acute kidney injury and pathogenesis of cerebral malaria which are significantly associated with mortality in malaria infection. This retrospective study was designed to assess the lipid profile, and hematological, renal and hepatic function data of malaria patients in Sir Yahaya Memorial hospital Birnin Kebbi from 2016 to 2020 who are 18 years and above.
Methods
The data of all patients between 2016 and 2020 who are 18 years and above were collected. Complete data of 370 subjects who met the inclusion criteria which consist of 250 malaria subjects and 120 control subjects were analyzed.
Results
The results showed that females constitute 65.2% of malaria patients with complete records while the remaining 34.8% were males. Age distribution of the patients showed that the infection was more prevalent among 26–45 years and least among 65 years and above. Anemia and thrombocytopenia were prevalent among the female malaria patients compared to the male patients. Liver and kidney function parameters analyzed correlate positively with the gender. The infected male showed higher dysfunction in liver parameters while infected female patients showed significant dysfunction in kidney function parameters and lipid profile.
Conclusions
In conclusion, to prevent the potential widespread of acute renal and hepatic failure with the attendant morbidity and mortality among malaria patients, it is recommended that liver and kidney function tests be mandated for patients with recurring malaria and those with a history of treatment failure in the endemic area to ensure early diagnosis of malarial induced kidney and liver injury among malaria patients.
The pathogenesis of infection-related renal complications in children is multifactorial and includes direct invasion of renal parenchyma, stimulation of an immune reaction, injury to the capillary endothelium, induction of a humoral response, or nephrotoxicity associated with the therapy of choice. This chapter presents non-streptococcal bacterial, fungal, and parasitic infections, some of which occur predominantly in tropical and subtropical regions, but which have been increasingly diagnosed in other regions of the globe on account of travel mobility.
Malaria-related renal failure is usually ascribed to acute tubular necrosis (ATN) and interstitial nephritis, and rarely to cortical necrosis. Clinical features of hemolytic uremic syndrome (HUS) and thrombotic microangiopathy (TMA) on renal histology have not been described conclusively in relation to malaria. Renal biopsy performed in all the patients showed characteristic features of TMA like mucointimal proliferation, subintimal fibrin deposits with luminal thrombi along with ATN, and cortical necrosis
Many red cell haematological disorders have significant renal sequelae. These are primarily related to conditions associated with acute or chronic intravascular haemolysis, which are either innate (e.g. sickle cell disease and glucose-6-phospahte dehydrogenase (G6PD) deficiency) or acquired (e.g. paroxysmal nocturnal haemoglobinuria (PNH) and malaria). Prevention of renal complications is largely focused on treatment of the underlying condition, but once established, acute kidney injury and chronic kidney disease are managed with renal replacement therapy including renal transplantation when indicated. Integrated care between haematologists and nephrologists is key to providing optimal patient care.KeywordsHaemolysisHemeHyperfiltrationTransfusionProteinuriaSickle cellSickle nephropathyParoxysmal nocturnal haemoglobinuriaMalariaThalassemiaIron overloadExchange transfusion
Plasmodium falciparum remains one of the world’s deadliest diseases and with ongoing concerns of evolving drug resistance, there is a need for continued refinement of the Plasmodium coatneyi infection model in macaques to study severe malaria. As such, the systemic ultrastructural lesions associated with P. coatneyi infection in splenectomized rhesus macaques was evaluated in 6 animals. Autopsy samples from multiple areas of the central nervous system (CNS), kidneys, heart, liver, and lungs of all 6 animals were processed for electron microscopy. A systematic analysis of the ultrastructural changes associated with the plasmodium was undertaken by multiple pathologists to ensure consensus. All tissues exhibited marked sequestration of infected red blood cells comprised either of cytoadherence to endothelium or rosette formation, associated with variable degrees of host cell damage in a range of tissues that in severe cases resulted in necrosis. This is the first complete systemic evaluation of ultrastructural tissue lesions in P. coatneyi–infected rhesus macaques, and the findings have important implications evaluating of the use of this model for the study of severe malaria caused by P. falciparum in humans.
Infection-induced kidney diseases need to be promptly detected to offer timely treatment of infections. The mechanisms by which infections lead to chronic kidney disease (CKD) includes direct invasion or indirectly by immune-mediated pathways known as infection-related glomerulonephritis. Clinical manifestations vary depending on the microorganisms and their mechanism of infection. All microorganisms like virus, bacteria, mycobacteria, fungus, and protozoa have been implicated in infection-related CKD. Worldwide, infection control practices are limited by socioeconomic status, inadequate access to safe drinking water, and disorganized health care systems. Despite the success of vaccination and antimicrobials in controlling many infectious diseases, clinicians still face either chronic persistent infection or reemergence of multi-drug resistant organisms leading to prevalent infection-related kidney disease.
This chapter aims to describe nephrology care in Pakistan. It covers general information about the country, including location, its population, literacy rate, gross domestic product, health budget, and status of heathcare facilities in general. Then, it introduces the birth of nephrology in the country, its timeline with different nephrology facilities developing at different times, and number of trained nephrologists. This chapter also covers acute kidney injury causes common in Pakistan. It describes common causes of renal diseases and chronic kidney diseases and types and benefits of the available renal replacement therapies, with particular focus on renal transplantation and its related issues. This chapter also addresses the pediatric nephrology status in the country and concludes indicating future directions for nephrology in Pakistan.
Asia is the largest and most populous continent and has huge differences in socioeconomic status, development, and health care between the different countries and regions within each country. This manifests in the varied causes of acute kidney injury (AKI), particularly higher rates of community-acquired AKI and in the differential access to health care for the population. Because of resource limitations, prevention and treatment of AKI is a difficult challenge. This review highlights the differences in AKI in Asia compared with the developed world and discusses prevention and treatment of AKI within the context of resource limitations.
Respiration, oxidative phosphorylation, calcium uptake, and the mitochondrial membrane potential of trophozoites of the malaria parasite Plasmodium berghei were assayed in situ after permeabilization with digitonin. ADP promoted an oligomycin-sensitive transition from resting to phosphorylating respiration. Respiration was sensitive to antimycin A and cyanide. The capacity of trophozoites to sustain oxidative phosphorylation was additionally supported by the detection of an oligomycin-sensitive decrease in mitochondrial membrane potential induced by ADP. Phosphorylation of ADP could be obtained in permeabilized trophozoites in the presence of succinate, citrate, α-ketoglutarate, glutamate, malate, dihydroorotate, α-glycerophosphate, andN,N,N′,N′-tetramethyl-p-phenylenediamine. Ca²⁺ uptake caused membrane depolarization compatible with the existence of an electrogenically mediated Ca²⁺transport system in these mitochondria. An uncoupling effect of fatty acids was partly reversed by bovine serum albumin, ATP, or GTP and not affected by atractyloside, ADP, glutamate, or malonate. Evidence for the presence of a mitochondrial uncoupling protein in P. berghei was also obtained by using antibodies raised against plant uncoupling mitochondrial protein. Together these results provide the first direct biochemical evidence of mitochondrial function in ATP synthesis and Ca²⁺ transport in a malaria parasite and suggest the presence of an H⁺ conductance in trophozoites similar to that produced by a mitochondrial uncoupling protein.
The surface of erythrocytes infected with late developmental stages of Plasmodium falciparum is profoundly altered and new antigenic determinants can be detected by surface immunofluorescence using immune squirrel monkey serum. The expression of these parasite-specific antigenic determinants on the surface of the host erythrocyte can be modulated by the presence or absence of the spleen and by immune pressure. An antigenic switch occurred when a cloned population of the Ugandan Palo Alto strain of P. falciparum was transferred from a splenectomized into an intact monkey and this switch was reversible. In another strain (Indochina-1), we showed that the parasites isolated during secondary and recrudescent peaks expressed erythrocyte-associated surface antigens different from the parasites isolated during the primary infection; six variant antigenic types distinct from the original population were isolated in this way. The passive transfer of immune serum can induce antigenic variation and this can occur in a cloned parasite. The various mechanisms of antigenic variation in P. falciparum are discussed in the context of strain-specific diversity and the role of antigenic diversity in acquired immunity.
The sequestration of parasitized erythrocytes in the microvasculature of vital organs is central to the pathogenesis of severe Plasmodium falciparum malaria. This process is mediated by specific interactions between parasite adherence ligands and host receptors on vascular endothelium such as intercellular adhesion molecule-1 (ICAM-1) and CD36. Using immunohistochemistry we have examined the distribution of putative sequestration receptors in different organs from fatal cases of P. falciparum malaria and noninfected controls. Receptor expression and parasite sequestration in the brain were quantified and correlated. Fatal malaria was associated with widespread induction of endothelial activation markers, with significantly higher levels of ICAM-1 and E-selectin expression on vessels in the brain. In contrast, cerebral endothelial CD36 and thrombospondin staining were sparse, with no evidence for increased expression in malaria. There was highly significant co-localization of sequestration with the expression of ICAM-1, CD36, and E-selectin in cerebral vessels but no cellular inflammatory response. These results suggest that these receptors have a role in sequestration in vivo and indicate that systemic endothelial activation is a feature of fatal malaria.
Plasmodium falciparum expresses on the host erythrocyte surface clonally variant antigens and ligands that mediate adherence to endothelial receptors. Both are central to pathogenesis, since they allow chronicity of infection and lead to concentration of infected erythrocytes in cerebral vessels. Here we show that expression of variant antigenic determinants is correlated with expression of individual members of a large, multigene family named var. Each var gene contains copies of a motif that has been previously shown to bind diverse host receptors; expression of a specific var gene correlated with binding to ICAM-1. Thus, our findings are consistent with the involvement of var genes in antigenic variation and binding to endothelium.
Spontaneous binding of uninfected erythrocytes to Plasmodium falciparum-infected erythrocytes (rosetting) has been suggested to have a critical role in the induction of cerebral malaria. We report here that rosetting can be mediated by several molecular mechanisms involving parasite polypeptides with M(r)s of 22,000 or 28,000, termed rosettins. Antibodies to either polypeptide disrupt rosettes in a strain-specific fashion. Rosettes of five of the seven isolates examined thus far are more easily disrpted by anti-22,000-M(r) rosettin antibodies than by anti-28,000-M(r) rosettin antibodies. Polyclonal anti-22,000-M(r) rosettin antibodies raised in mice or rabbits strongly and strain specifically stain the surface of nonfixed erythrocytes infected with late asexual stages of rosetting P. falciparum. Simultaneous antibody staining and rosetting are seen when the anti-22,000-M(r) rosettin antiserum is diluted so that only partial disruption of rosettes is obtained, confirming that the fluorescence-labelled infected erythrocytes are involved in rosetting. The 22,000-M(r) rosettin is accessible for surface iodination on erythrocytes infected with strains of rosetting parasites sensitive to anti-22,000-M(r) rosettin antibodies, whereas no labelling occurred on either normal erythrocytes or nonrosetting-P. falciparum-infected erythrocytes. Purified anti-22,000-M(r) rosettin serum immunoglobulin G immunoprecipitated three parasite-derived polypeptides with M(r)s of 22,000, 45,000 (doublet), and 50,000 from lysates of [35S]methionine-labelled, parasite-infected erythrocytes. Our results suggest that rosetting is mediated by strain-specific, antigenically distinct, P. falciparum-derived polypeptides.
Most children and adults living in areas where the endemicity of Plasmodium falciparum malaria is high have significantly elevated levels of both total immunoglobulin E (IgE) and IgE antimalarial antibodies in blood. This elevation is highest in patients with cerebral malaria, suggesting a pathogenic role for this immunoglobulin isotype. In this study, we show that IgE elevation may also be seen in severe malaria without cerebral involvement and parallels an elevation of tumor necrosis factor alpha (TNF). IgE-containing serum from malaria immune donors was added to tissue culture plates coated with rabbit anti-human IgE antibodies or with P. falciparum antigen. IgE-anti-IgE complexes as well as antigen-binding IgE antibodies induced TNF release from peripheral blood mononuclear cells (PBMC). Nonmalaria control sera with no IgE elevation induced significantly less of this cytokine, and the TNF-inducing capacity of malaria sera was also strongly reduced by passing them over anti-IgE Sepharose columns. The cells giving rise to TNF were adherent PBMC. The release of this cytokine probably reflects cross-linking of their low-affinity receptors for IgE (CD23) by IgE-containing immune complexes known to give rise to monocyte activation via the NO transduction pathway. In line with this, adherent monocytic cells exposed to IgE complexes displayed increased expression of CD23. As the malaria sera contained IgG anti-IgE antibodies, such complexes probably also play a role in the induction of TNF in vivo. Overproduction of TNF is considered a major pathogenic mechanism responsible for fever and tissue lesions in P. falciparum malaria. This overproduction is generally assumed to reflect a direct stimulation of effector cells by certain parasite-derived toxins. Our results suggest that IgE elevation constitutes yet another important mechanism involved in excessive TNF induction in this disease.
To assess the eosinophil response to Plasmodium falciparum infection a cohort of initially parasite-free Ghanaian children was followed for 3 months. Seven of nine children who acquired an asymptomatic P. falciparum infection showed increase in eosinophil counts, while a decrease was found in seven of nine children with symptomatic malaria, and no change was observed in 14 children who remained parasite-free. In a hospital-based study, paediatric patients with cerebral malaria (CM), severe anaemia (SA), or uncomplicated malaria (UM) had uniformly low eosinophil counts during the acute illness followed by eosinophilia 30 days after cure. Plasma levels of eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured as indicators of eosinophil activation. In spite of the low eosinophil counts, ECP levels were increased on day 0 and significantly higher in patients with CM (geometric mean (95% confidence interval) 8.5 ng/ml (6.8-10.7 ng/ml)) than in SA (4.7 ng/ml (3.0-7.5 ng/ml)) and UM patients (4.3 ng/ml (3.6-5.3 ng/ml), P < 0.001). A similar pattern was found for EPX. It thus appears that the low eosinophil counts may be due to tissue sequestration and destruction rather than decreased production. The plasma levels of the granule proteins correlated with levels of tumour necrosis factor and soluble IL-2 receptor, implicating inflammatory responses and T cell activation as causes of the eosinophil activation. By contrast, the eosinophil induction did not appear to be part of a Th2-like response. Eosinophil granule proteins may be important in both control of malaria infection and the pathogenesis of severe malaria.
Many pathogens evade the host immune response or adapt to their environment by expressing surface proteins that undergo rapid switching. In the case of Plasmodium falciparum, products of a multigene family known as var are expressed on the surface of infected red cells, where they undergo clonal antigenic variation and contribute to malaria pathogenesis by mediating adhesion to a variety of host endothelial receptors and to uninfected red blood cells by forming rosettes. Herein we show that a second gene family, rif, which is associated with var at subtelomeric sites in the genome, encodes clonally variant proteins (rifins) that are expressed on the infected red cell surface. Their high copy number, sequence variability, and red cell surface location indicate an important role for rifins in malaria host-parasite interaction.
The surface of erythrocytes infected with late developmental stages of Plasmodium falciparum is profoundly altered and new antigenic determinants can be detected by surface immunofluorescence using immune squirrel monkey serum. The expression of these parasite-specific antigenic determinants on the surface of the host erythrocyte can be modulated by the presence or absence of the spleen and by immune pressure. An antigenic switch occurred when a cloned population of the Ugandan Palo Alto strain of P. falciparum was transferred from a splenectomized into an intact monkey and this switch was reversible. In another strain (Indochina-1), we showed that the parasites isolated during secondary and recrudescent peaks expressed erythrocyte-associated surface antigens different from the parasites isolated during the primary infection; six variant antigenic types distinct from the original population were isolated in this way. The passive transfer of immune serum can induce antigenic variation and this can occur in a cloned parasite. The various mechanisms of antigenic variation in P. falciparum are discussed in the context of strain-specific diversity and the role of antigenic diversity in acquired immunity.
The membrane potential (Em) of normal and Plasmodium chabaudi-infected rat erythrocytes was determined from the transmembrane distributions of the lipophilic anion, thiocyanate (SCN), and cation, triphenylmethylphosphonium (TPMP). The SCN- and TPMP-measured Em of normal erythrocytes are -6.5 +/- 3 mV and -10 +/- 4 mV, respectively. The TPMP-measured Em of infected cells depended on parasite developmental stage; "late" stages (schizonts and gametocytes) were characterized by a Em = -35 mV "early stages (ring and copurifying noninfected) by a low Em (-16 mV). The SCN-determined Em of infected cells was -7 mV regardless of parasite stage. Studies with different metabolic inhibitors including antimycin A, a proton ionophore (carbonylcyanide m-chlorophenylhydrazone [CCCP] ), and a H+ -ATPase inhibitor (N,N'-dicyclohexylcarbodiimide, [DCCD] ) indicate that SCN monitors the Em across the erythrocyte membrane of infected and normal cells whereas TPMP accumulation reflects the Em across the plasma membranes of both erythrocyte and parasite. These inhibitor studies also implicated proton fluxes in Em-generation of parasitized cells. Experiments with weak acids and bases to measure intracellular pH further support this proposal. Methylamine distribution and direct pH measurement after saponin lysis of erythrocyte membranes demonstrated an acidic pH for the erythrocyte matrix of infected cells. The transmembrane distributions of weak acids (acetate and 5,5-dimethyloxazolidine-2,4-dione) indicated a DCCD-sensitive alkaline compartment. The combined results suggest that the intraerythrocyte parasite Em and delta pH are in part the consequence of an electrogenic proton pump localized to the parasite plasma membrane.
The functional properties, regarding parasite growth inhibition in vitro , the cytotoxic potential and cytokine profiles of human γδ ⁺ and αβ ⁺ T cells, T‐cell lines and clones stimulated with Plasmodium falciparum‐ antigen‐or T‐cell mitogen in vitro were investigated. Using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the γδ‐ and the αβT cells. Despite this fact, only γδT cells inhibited, both Vδ1 ⁺ and Vδ2 ⁺ , the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell‐to‐cell contact and was not observed until the second parasite replication implied that the likely γδT‐cell target was the extracellular merozoite or schizont. The failure of αβT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the γδT cells. Both the γδ‐ and αβT cells expressed mRNA for a large number of cytokines. Interferon (IFN)‐γ, interleukin (IL) IL‐5, IL‐6, IL‐8, tumour necrosis factor alpha (TNFα), tumour necrosis factor beta (TNF‐β)/lymphotoxin (LT) and T‐cell growth factor beta‐1 (TGF‐β1) were observed in all activated clones tested. No IL‐3 was detected, while IL‐1β, IL‐2, IL‐4, IL‐10 and GM‐CSF were variably expressed. In conclusion, our data show that γδT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated αβT cells do not. Thus, it is likely that the γδT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.
The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.
To compare the efficacy of exchange transfusion as the adjunct to quinine treatment (21 patients) with quinine therapy alone (29 patients).
A retrospective study of 50 patients with severe falciparum malaria was conducted at Chumphorn Hospital, Southern Thailand.
Clinical characteristics in both treatment groups were not significantly different although in the exchange transfusion group, the admission geometric mean parasitaemia (18 (5%), and the proportion of patients with more than 10% parasitaemia was higher (76%, P = 0.03) than in the group who received quinine alone (10 +/- 4%; 38%, P = 0.1). The mortality rate of patients who received exchange transfusion was 48%; that of the remainder, 69%. (P = 0.3). ARDS (P = 0.01) and oliguric renal failure (P = 0.04) were significant risk factors for death in these patients.
Exchange transfusion was safe and well tolerated. Results of our study revealed a 20% reduction in mortality when exchange transfusion was used as an adjunct to quinine treatment. It should therefore be considered in patients with severe falciparum malaria when possible.
A Thai female patient infected with P. falciparum had 80 per cent P. falciparum infected red cells at ring stage in the peripheral blood smear. The complications included anemia, thrombocytopenia, acute renal failure and pulmonary edema. A marked decrease in platelets number, low hemoglobin, low hematocrit and decreased red blood cell count were detected. More than 70 per cent of total platelets detected in the blood smear were binding to parasitized red blood cells. The number of binding platelets declined with decreasing per cent parasitized red cells. It was also noted that some platelets (10-20%) adhered to nonparasitized red cells. An increased number of large lymphocytes was shown by increased numbers of large unstained cells (LUC) by H* 1 automated analyzer. The peripheral blood smear showed abnormal binding of platelets to the infected red cells more frequently than to non infected red cells and free platelets on the day of high parasitemia. This abnormal phenomena was related to the number of platelets in the circulation. When the parasitized red cells were not detected in the blood smear, the number of platelets in the circulation had returned to normal.
Malaria has become a very uncommon disease in Italy. Recently a variety of circumstances, such as travel to tropical countries as well as immigration from Asia and Africa, have combined to increase the number of malaria cases recorded annually. In this report we describe the use of red cell exchange transfusion and plasma exchange in the treatment of a patient with hyperparasitemic malaria (51% erythrocytes or more parasitized). When first observed the patient was in shock and had signs of cerebral malaria, disseminated intravascular coagulation, and acute respiratory distress syndrome, which in the following 2 days were complicated by acute renal failure. After mefloquine therapy combined with 3 red blood cell exchanges, 2 plasma exchanges, and 10 dialysis sessions over 14 days, the patient recovered completely. This case of severe malaria with multiple complications, treated with mefloquine in conjunction with both exchange transfusion and plasmapheresis, had a successful outcome and lends further support to the possible beneficial role of exchange transfusion in complicated malaria.
Since 1988 in this referral center for severe cases of malaria for South Vietnam, a specialist team has managed malaria-associated
renal failure (MARF) with peritoneal dialysis, and the mortality rate of MARF has fallen from 75% (78 of 104) to 26% (27 of
104) (P < .0002). Sixty-four patients with MARF (of whom 12 died) were compared to 66 patients with severe malaria whose serum creatinine
levels remained <250 µmol/L (six died). MARF had the clinical and biochemical features of acute tubular necrosis and was significantly
associated with liver dysfunction (P < .05). A fatal outcome was associated significantly with anuria, a short history of illness, multisystem involvement, and
high parasitemia. Most patients died from complications related to renal failure. Recovery of renal function was unrelated
to parasitemia or hemoglobinuria; the median (range) time until urine output exceeded 20 mL/(kg · d) was 4 (0–19) days, and
the time (mean ± SD) for serum creatinine level to return to normal was 17 ± 6 days. MARF can be managed effectively by prompt
and careful peritoneal dialysis, but more effective dialysis or diafiltration might reduce the mortality rate further.
In order to ascertain the protective role of a potent calcium entry blocking agent in human acute renal failure, 10 patients were randomised to treatment with either intrarenal gallopamil plus intravenous furosemide (frusemide) 0.5 mg/kg/h for 24 hours, or furosemide alone. Gallopamil was infused into each kidney at the rate of 40 to 80 µg/min for 4 hours. During 7 days of post-treatment follow-up, the gallopamil treatment group exhibited a significantly higher urine output [257 ml/h vs 81 ml/h (p < 0.001) after 2 days, and 199 ml/h vs 120 ml/h (p < 0.005) after 7 days] and creatinine clearance [20 vs 4 ml/min (p < 0.005) after 2 days, and 38 vs 14 ml/min (p < 0.001) after 7 days] than the furosemide-only control group. Furthermore, gallopamil treatment accelerated the decline of serum creatinine after renal failure and reduced the requirement for dialysis.
Although patient numbers were small, these results indicate that the addition of intrarenal gallopamil to intravenous furosemide treatment enhances the recovery of renal function after acute renal failure.
Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) is a water-soluble protein released from parasitized erythrocytes into in vitro culture supernatants. This study sought to determine whether PfHRP-2 could be detected in the plasma of humans with P. falciparum malaria. A monoclonal antibody (1E1) is described that binds to PfHRP-2. By using monoclonal antibody 1E1, PfHRP-2 was identified by Western blot (immunoblot) analysis in the plasma of 37 of 39 (95%) patients experiencing either a first or repeat episodes of P. falciparum malaria and by dot blot analysis in the plasma of 40 of 41 patients tested. PfHRP-2 was not detected in 30 control, uninfected subjects. The current demonstration of PfHRP-2 in plasma, plus the fact that it is a structurally well-characterized molecule present in all natural isolates of P. falciparum tested, makes PfHRP-2 of interest for its potential effects on the host immune system and as an antigen for specific diagnosis of malaria.
Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
Plasmodium fragile infection of the toque monkey is a natural host-parasite association in which parasite sequestration occurs as during P. falciparum infection of humans. We have studied parasite sequestration of P. fragile and demonstrated the existence of a new property of cytoadherence of infected erythrocytes, "rosetting," which is defined as the agglutination of uninfected erythrocytes around parasitized erythrocytes. Rosetting in vitro and sequestration in vivo appear simultaneously as the parasite matures. The spleen plays a role in modulating cytoadherence; both sequestration and rosetting, which occur with cloned parasites from spleen-intact animals, are markedly reduced in splenectomized animals infected with parasites derived from the same clone. Sequestration and rosetting can be reversed by immune serum. Protease treatment of infected blood abolishes rosetting; however, if treatment is performed at an early stage of schizogony, rosetting reappears if parasites are allowed to further develop in the absence of protease. These results indicate that with P. fragile in its natural primate host, rosetting and sequestration are related to the presence on the infected erythrocyte surface of a parasite-derived antigenic component, the expression of which is modulated by the spleen.
For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.
Plasmodium falciparum-infected human erythrocytes evade host immunity by expression of a cell-surface variant antigen and receptors for adherence to endothelial cells. These properties have been ascribed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), an antigenically diverse malarial protein of 200-350 kDa on the surface of parasitized erythrocytes (PEs). We describe the cloning of two related PfEMP1 genes from the Malayan Camp (MC) parasite strain. Antibodies generated against recombinant protein fragments of the genes were specific for MC strain PfEMP1 protein. These antibodies reacted only with the surface of MC strain PEs and blocked adherence of these cells to CD36 but without effect on adherence to thrombospondin. Multiple forms of the PfEMP1 gene are apparent in MC parasites. The molecular basis for antigenic variation in malaria and adherence of infected erythrocytes to host cells can now be pursued.
The human malaria parasite Plasmodium falciparum evades host immunity by varying the antigenic and adhesive character of infected erythrocytes. We describe a large and extremely diverse family of P. falciparum genes (var) that encode 200-350 kDa proteins having the expected properties of antigenically variant adhesion molecules. Predicted amino acid sequences of var genes show a variable extracellular segment with domains having receptor-binding features, a transmembrane sequence, and a terminal segment that is a probable submembrane anchor. There are 50-150 var genes on multiple parasite chromosomes, and some are in clustered arrangements. var probes detect two classes of transcripts in steady-state RNA: 7-9 kb var transcripts, and an unusual family of 1.8-2.4 kb transcripts that may be involved in expression or rearrangements of var genes.
To demonstrate the liver profile abnormalities in jaundiced falciparum malaria patients and to determine whether jaundice was associated with other complications in falciparum malaria, 390 patients with acute falciparum malaria were studied. 124 patients were jaundiced and the others were non-jaundiced. Hyperbilirubinemia (total serum bilirubin 3 to 64 mg/dl) was found in jaundiced patients predominantly as unconjugated bilirubin. Asparatate amino-transferase and alanine minotransferase were significantly higher in jaundiced patients (p < 0.01). There was a slight decrease of serum albumin in jaundiced malaria. The complications in jaundiced patients included cerebral malaria (n = 10), acute renal failure (n = 12), pulmonary edema (n = 3), shock (n = 3), and other severe malarial complications (n = 43). Jaundice was associated with cerebral malaria (p < 0.05), acute renal failure (p < 0.01), and hyperparasitemia (p < 0.01). After successful treatment, liver profile returned to normal within a few weeks. We found that jaundiced malaria patients had transient liver profile impairment which indicated predominantly hemolysis rather than liver damage; complications were more frequent in jaundiced patients.
T-cells have a major role both as helper cells for efficient antibody production and as inducers and effector cells in antibody-independent malaria immunity. Thus, antigens to be included into a subunit vaccine must contain T-cell epitopes to become effectively immunogenic. The P. falciparum blood stage vaccine antigen Pf155/RESA has been shown to contain T-helper epitopes inducing T-dependent anti-malarial antibodies in vitro. We have also shown that synthetic peptides representing sequences from the amino-acid repeat regions of Pf155/RESA stimulate T-cells from P. falciparum primed donors to proliferate, to release IFN-gamma and/or IL-4. In individual donors there was no correlation between these different activities. Rather, they were frequently negatively associated. However, IL-4 secretion could be induced in T-cells from donors who had elevated concentrations of serum antibodies to the same peptide as used for T-cell activation. Taken together the results support the occurrence of malaria-specific CD4+ T-cell subsets (e.g. TH1 and TH2) in humans similar to what has been found in mice and suggest the involvement of TH2-type helper cells in the induction of some important P. falciparum specific antibodies. CD4+ T-cells recognize the antigen in the context of MHC class II molecules. However, in human outbred populations no consistent MHC restrictions of anti-Pf155/RESA immune responses could be demonstrated. This is not surprising in view of the extensive polymorphism of the HLA system. Neither were there any obvious MHC class II restrictions seen when antibody- and t-cell responses were measured in naturally primed monozygotic twins.(ABSTRACT TRUNCATED AT 250 WORDS)
Prolonged haemolysis may accompany infection with Plasmodium falciparum. We observed prolonged haemolysis in 4 of 10 patients with this type of malaria after parasitological cure. IgM antibodies specific for the glycolytic enzyme triosephosphate isomerase were detected in these patients' sera. Clinical recovery and a decrease in haemolysis coincided with a fall in these autoantibodies. In vitro, affinity purified autoantibodies isolated from the sera directed against triosephosphate isomerase induced lysis of erythrocytes and activation of complement as shown by the 51Cr release assay. We assume that autoantibodies against triosephosphate isomerase contribute to the development of prolonged haemolysis and anaemia in P falciparum malaria.
The severe disease and high mortality associated with Plasmodium falciparum infection have traditionally been attributed solely to parasitic virulence factors, but more recent evidence suggests that
the host's immunologic response may also contribute to the pathophysiology of the disease in humans. This response would be
expected to be proportionate—in intensity and nature—to the antigenic load created by the sequestration of parasites in the
microvasculature and to be directed against the sites of maximal parasitization; thus the immunologic response could potentially
contribute to the pathophysiology of both survival and fatal outcome in severe infection. Cytokines appear to play a pivotal
role in the activation of the immune response in human falciparum malaria, and their levels correlate with disease severity.
The putative mechanisms by which cytokines may mediate both beneficial and deleterious effects by activating phagocytic cells
in severe falciparum malaria are discussed.
The Plasmodium falciparum antigen Pf332 comprises degenerated 11-amino-acid repeats with regularly spaced pairs of glutamic acid. Epitopes formed by such repeats are recognized by polyclonal and monoclonal antibodies that interfere with the life cycle of the blood stages of the malaria parasite. In order to study the immunogenicity of one such Pf332 repeat sequence (SVTEEIAEEDK), fusion proteins containing ZZ (two IgG binding domains of staphylococcal protein A) and dimers, trimers or tetramers of the malarial sequence were injected into mice. To analyse possible major histocompatibility complex class II restrictions of the immune response, mice of different H-2 haplotypes were used. A significant antibody response was elicited by administration of all the three fusion proteins in mice expressing the I-Ak allele (B10.BR, B10.A(2R) and B10.A(4R)) whereas B10 and C57BL/6 (H-2b) mice were low responders. In comparison, B10.D2 (H-2d) mice were low responders to fusion proteins with 2 or 3 repeats but responded well to the protein containing 4 repeats. Lymph node cells from B10.BR (H-2k) mice, primed in vivo with ZZ-fusion proteins containing either 2 or 4 repeats, proliferated in vitro in response to repeat sequences fused to ZZ or to an unrelated fusion partner, as well as to a synthetic peptide containing less than two repeats. In contrast, a response of lymph node cells from B10.D2 (H-2d) mice was only obtained when a fusion protein containing 4 repeats was used both for in vivo priming and in vitro restimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous studies have shown depressed serum corrected calcium and phosphate concentrations in acute falciparum malaria. To characterize malaria-associated disturbances in mineral homoeostasis further, serum ionized calcium and intracellular phosphate were measured in 18 patients (10 with falciparum malaria, 8 with vivax malaria) and 10 healthy controls. Six patients (4 falciparum, 2 vivax) had admission serum ionized calcium concentrations below the absolute control range (< 1.15 mmol/litre) and a further six (3 falciparum, 3 vivax) developed ionized hypocalcaemia during treatment. The patients with falciparum malaria had the lowest values at presentation (median [95% confidence intervals in brackets]: 1.17 [1.12-1.23] vs. 1.20 [1.18-1.24] mmol/litre in controls, P = 0.035) in the presence of depressed simultaneous serum parathormone concentrations (1.2 [0.6-1.9] vs. 1.6 [1.1-2.6] pmol/litre; P = 0.05). Admission serum phosphate concentrations were lower in the malaria patients (P = 0.007 vs. controls), especially in those with falciparum malaria (0.85 [0.7-1.1] vs. 1.2 [1.1-1.3] mmol/litre in controls; P = 0.002); patients with falciparum malaria also had significantly lower intracellular phosphate than controls (0.74 [0.58-0.90] vs. 0.88 [0.66-1.04] mmol/litre red cells; P = 0.047). There was a weak association between serum corrected and ionized calcium in the malaria patients (rs = 0.31, n = 18, P > 0.1), but serum and intracellular phosphate correlated significantly (rs = 0.71, n = 17, P < 0.001) with a regression line slope of 0.49 and intercept of 0.27 mmol/litre of red cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Exoerythrocytic stages of Plasmodium berghei cultured in HepG2-A16 hepatoma cells and those of P. falciparum in human hepatocytes transplanted under the kidney capsule of CB-17/ICr scid/scid mice were used to evaluate expression of heat-shock-related stress proteins. Although undetectable in the sporozoites, the expression of proteins similar in sequence of a heat-shock protein of 70 kDa and a glucose-regulated protein of 78 kDa was markedly induced in the hepatic stages of malaria parasites. Expression of these proteins in the exoerythrocytic stages of the malaria parasite warrants a systematic evaluation of their potential role in eliciting cellular immune responses directed against infected hepatocytes.
Serum sCD14, tumour necrosis factor-alpha (TNF-alpha), IL-6, and endotoxin were analysed in 45 patients with complicated malaria, in 14 patients with Gram-negative septicaemia and in 24 healthy subjects by ELISA. Malaria patients with renal failure (n = 16) had higher levels than patients without renal failure (n = 29) (8116 + 1440 micrograms/l versus 9453 + 1017 micrograms/l; P < 0.05) and both had higher levels than patients with septicaemia (6155 + 1635 micrograms/l) and normal subjects (2776 + 747 micrograms/l). A significant correlation between sCD14 and IL-6 (r = 0.756) and TNF (r = 0.822) existed. However, no relation between sCD14 and serum endotoxin or indices of clinical disease severity (parasitaemia, fever, parasite or fever clearance time) was seen. Although the role of sCD14 in malaria remains to be determined, elevated levels may participate in the inflammatory response in complicated malaria.
While various infectious agents have been reported to induce hemophagocytic syndrome (HPS), protozoan malaria-associated HPS has not been documented. We describe a patient with Plasmodium falciparum malaria complicated by HPS. A 24-year old man with a history of recent travel in tropical areas was hospitalized with high fever and hepatosplenomegaly. Blood smear showed many of the erythrocytes infected with the ring form of P. falciparum. Laboratory data disclosed bicytopenia with coagulopathy, a high serum level of LDH, hyperferritinemia and hypercytokinemia. Bone marrow smear demonstrated proliferation of mature histiocytes with vivid hemophagocytosis. He was free from other active, disseminated viral, bacterial and fungal infections which have been reported to induce HPS. He recovered rapidly from HPS after resolution of the original malarial infection.
Renal and systemic hemodynamics, plasma arginine vasopressin, plasma renin activity, plasma norepinephrine, blood volume and water loading test were studied in 10 patients with falciparum malaria without renal failure. Six patients responded to water load normally, while 4 patients had a decreased response to water load. The patients with a normal water load response had normal renal and systemic hemodynamics and a normal hormonal profile. The patients with a decreased response to water load had hyponatremia, hypervolemia, high cardiac index, low systemic vascular resistance, high plasma arginine vasopressin, high plasma renin activity, high plasma norepinephrine, low creatinine and p-aminohippurate clearances, low urine sodium and high urine osmolality. They had a lower mean arterial pressure during the acute phase of the disease than during the recovery phase. The findings suggest that a decreased response to water load is due to peripheral vasodilatation which results in a decreased effective blood volume leading to the release of vasopressin and norepinephrine, increased renin activity and decreased renal hemodynamics.
People living in Plasmodium falciparum-endemic areas frequently have elevated levels of total as well as P. falciparum-specific serum IgE. This study aimed at investigating whether the elevated serum IgE levels reflect a shift in the balance between CD4+ T helper 1 (Th1) and T helper 2 (Th2) cells in individuals naturally exposed to the P. falciparum parasite. To investigate the role of Th1 and Th2 cells in the human P. falciparum system we used the ELISPOT assay to determine the ratio of IFN-gamma- and IL-4-producing cells after specific antigen or mitogen activation in vitro. The donors were individuals who had acquired immunity through natural exposure to the parasite. In response to the specific malaria antigens, very few IL-4-producing cells were seen. However, in the response of individual donors to the polyclonal T cell activator, leucoagglutinin (La), the anti-malarial IgE levels in plasma were correlated with an increased ratio of IL-4/IFN-gamma producing cells. Thus, donors with ratios of IL-4/IFN-gamma > 1 exhibited mean plasma anti-malarial IgE levels significantly greater than those with ratios < 1. In individuals not living in P. falciparum-endemic areas the ratio of IL-4/IFN-gamma was always < 1. Taken together, our data suggest a shift in the balance between Th1 and Th2 cells in naturally P. falciparum-primed individuals, associated with elevated anti-P. falciparum plasma IgE levels. The role and biological significance of IgE (Th2-type immune response) for protection against P. falciparum and/or pathogenesis of malaria require further study.
Autoantibodies of diverse specificities are detected in sera of patients with acute malaria. The clinical relevance of these autoantibodies is not clear, though there are reports associating some autoantibodies with specific disease manifestations. We have investigated the occurrence of ANCA in the sera of 93 patients during episodes of acute malaria. Sera were tested by indirect immunofluorescence (IIF) and by ELISA for antibodies to neutrophil cytoplasmic components proteinase 3 (PR3), myeloperoxidase (MPO), cathepsin G (CG), human leucocyte elastase (HLE), and lactoferrin (LF). Forty-seven sera samples (50.5%) were positive by IIF, all except one with the atypical ANCA pattern (a-ANCA). When screened by ELISA, anti-CG antibodies were detected in 52 samples (56%), while anti-PR3 and anti-MPO antibodies were detected in three and one samples, respectively. Antibody binding to HLE and LF was not significant. Anti-CG antibodies were detected in 93% of the IIF-positive sera. A combination of anti-CG and anti-PR3 antibodies was noted in three samples. Our study demonstrates the presence of ANCA in sera from patients with acute malaria, almost all with the a-ANCA pattern on IIF. The antibody specificity, noted for the first time in our study, appears to be predominantly directed against CG. The significance of CG and CG-ANCA in the pathogenesis and clinical manifestations of malaria has yet to be elucidated.
Thiamine deficiency (beriberi) is common in some parts of southeast Asia. Acute thiamine deficiency can mimic many complications of malaria, such as encephalopathy and lactic acidosis. We examined the incidence of thiamine deficiency in adults admitted to hospital with malaria in Thailand.
For this prospective study, we recruited consecutive patients with malaria or other febrile illness who presented to Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, between May and July, 1992. We used the activation coefficient (alpha) for transketolase activity in erythrocytes to measure thiamine deficiency (defined as alpha>1.31) in patients with severe and uncomplicated malaria and in controls (patients' relatives and healthy volunteers). To exclude the possibility of interference in the assays, transketolase activity was also measured in erythrocytes used to culture parasites.
12 (52%) of 23 patients with severe malaria and ten (19%) of 54 patients with uncomplicated malaria had alpha values above the normal range (p<0.0001 and p=0.0014, respectively, compared with controls), which indicated severe thiamine deficiency. Thiamine deficiency was more severe in patients with cerebral malaria than in those with uncomplicated malaria and the controls (p=0.008).
In adults admitted to hospital in Thailand, thiamine deficiency commonly complicates acute falciparum malaria, particularly in severe infections, and could contribute to dysfunction of the central nervous system.
In the past year, the major advances in malaria antigenic variation have been concerned with the transcription and switching of variant antigen genes, and the functional expression of regions of the major variant antigen. Also, new variant gene families have been discovered as a result of the Malaria Genome Project.
Long chain polyunsaturated fatty acids derived from essential fatty acids have been shown to be toxic to Plasmodium falciparum both in vitro and in vivo. Here, we present evidence to suggest that in patients with Plasmodium falciparum malaria the levels of lipid peroxides (a marker of free radical generation) nitric oxide (a potent free radical with immunomodulatory actions), and concentrations of linoleic acid (LA) and alpha-linolenic acid (ALA) are low, whereas those of eicosapentaenoic acid (EPA) are high. The ability of the fatty acids to kill P. falciparum is dependent on their capacity to stimulate free radical generation in neutrophils and macrophages. EPA is more potent than LA in killing the parasite. In view of this, the results of the present study suggest that in patients with P. falciparum malaria the decreased levels of lipid peroxides and nitric oxide may contribute to the persistence of the infection, whereas elevated levels of EPA may be a feeble attempt to overcome this defect.
Respiration, oxidative phosphorylation, calcium uptake, and the mitochondrial membrane potential of trophozoites of the malaria parasite Plasmodium berghei were assayed in situ after permeabilization with digitonin. ADP promoted an oligomycin-sensitive transition from resting to phosphorylating respiration. Respiration was sensitive to antimycin A and cyanide. The capacity of trophozoites to sustain oxidative phosphorylation was additionally supported by the detection of an oligomycin-sensitive decrease in mitochondrial membrane potential induced by ADP. Phosphorylation of ADP could be obtained in permeabilized trophozoites in the presence of succinate, citrate, alpha-ketoglutarate, glutamate, malate, dihydroorotate, alpha-glycerophosphate, and N,N,N',N'-tetramethyl-p-phenylenediamine. Ca(2+) uptake caused membrane depolarization compatible with the existence of an electrogenically mediated Ca(2+) transport system in these mitochondria. An uncoupling effect of fatty acids was partly reversed by bovine serum albumin, ATP, or GTP and not affected by atractyloside, ADP, glutamate, or malonate. Evidence for the presence of a mitochondrial uncoupling protein in P. berghei was also obtained by using antibodies raised against plant uncoupling mitochondrial protein. Together these results provide the first direct biochemical evidence of mitochondrial function in ATP synthesis and Ca(2+) transport in a malaria parasite and suggest the presence of an H(+) conductance in trophozoites similar to that produced by a mitochondrial uncoupling protein.
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