Acute kidney injury in malaria: An update

Acute kidney injury in malaria: An update

G Model CQN-84; No. of Pages 7 Clinical Queries: Nephrology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Clinical Queries: Nephrolo...

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G Model

CQN-84; No. of Pages 7 Clinical Queries: Nephrology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Clinical Queries: Nephrology journal homepage:


Acute kidney injury in malaria: An update Anand Chellappan, D.S. Bhadauria * Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India



Article history: Received 14 April 2016 Accepted 19 April 2016 Available online xxx

Malaria is a mosquito-borne infectious disease with active transmission in the tropics. Malaria is becoming a global threat with the increasing number of cases of ‘imported malaria’. According to the World Health Organization, half of the world’s population is at the risk of malaria. Severe malaria is associated with high mortality. There has been a change in the spectrum of manifestations of severe malaria over the past two decades. Acute kidney injury (AKI) in malaria is being frequently reported. AKI is commonly caused by Plasmodium falciparum. However, Plasmodium vivax and Plasmodium knowlesi are also shown to cause AKI. A combination of hemorheological, inflammatory and humoral responses has been implicated in the pathogenesis. AKI in malaria is frequently oliguric and hyper-catabolic. Cerebral malaria and jaundice are often associated with acute kidney injury and portend a poor prognosis. The KDIGO criteria enable earlier detection of acute kidney injury in malaria. Acute tubular necrosis is the most consistent histological feature. A lot of uncertainty surrounds fluid management in severe malaria. A conservative approach to fluid replacement is recommended. Artesunate is the recommended first choice antimalarial for the treatment of severe malaria. Prompt recognition and early institution of renal replacement therapy reduces the mortality. ß 2016 Published by Elsevier, a division of Reed Elsevier India, Pvt. Ltd.

Keywords: Malaria Acute kidney injury Plasmodium falciparum Plasmodium vivax Hemodialysis Peritoneal dialysis

1. Introduction Malaria is a mosquito-borne infectious disease transmitted by the bite of an infected female anopheles mosquito. Five species of the genus Plasmodium are known to cause human disease namely Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi. Globally a significant progress has been achieved in malaria control with a reduction in the incidence of malaria of 37% between 2000 and 2015. Severe malaria is associated with high mortality. There has been a recent change in the spectrum of manifestations of severe malaria. The incidence of acute kidney injury in malaria is on the rise. P. malariae causes nephrotic syndrome due to immune-complex mediated glomerular disease and is referred to as ‘quartan malarial nephropathy’. Most cases of malarial acute kidney injury are attributable to P. falciparum infection. However, vivax malaria which was historically hailed to be a benign form of malaria is now recognized to give rise to a whole spectrum of pathological changes resulting in high morbidity and mortality.1 Early recognition of

* Corresponding author at: Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India. Tel.: +91 8004904367. E-mail address: [email protected] (D.S. Bhadauria).

renal impairment in malaria is of profound importance. Prompt institution of antimalarial therapy and renal replacement therapy has been shown to improve the prognosis.2 This review gives an overview of the epidemiology and pathogenesis of acute kidney injury in malaria and highlights the recent developments in diagnosis and management. 2. Epidemiology 2.1. Geographical distribution Malaria occurs predominantly in the tropics. This tropical distribution is attributable to the favorable conditions for parasite survival in the vector. However, malaria is becoming a global threat with the advent of cases of ‘imported malaria’.3–5 The various species of genus Plasmodium have varying geographical distribution with P. falciparum predominating in Africa whereas P. vivax infection occurs in high frequency in the South East Asian Region (SEAR). More than 50% of the malaria cases outside Africa are caused by P. vivax and it constitutes more than 80% of the cases occurring in Ethiopia, Pakistan, and India.6 P. malariae and P. ovale are largely restricted to the African continent. The fifth malarial parasite which has assumed recent importance is P. knowlesi. The first large focus of P. knowlesi infection was described in the Island of Borneo, Malaysia.7 Since then P. knowlesi infections have been 2211-9477/ß 2016 Published by Elsevier, a division of Reed Elsevier India, Pvt. Ltd.

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reported inThailand,8,9 Philippines,10 Myanmar,11 Singapore,12 Vietnam,13 Indonesia,14 and Cambodia.15 The long-tailed and pig-tailed macaques act as reservoir hosts for P. knowlesi. The discovery of P. knowlesi infection in humans has led to a paradigm shift in the generally held view that zoonotic malaria was an extremely rare event.16 2.2. Global trends In the year 2015, it was estimated that nearly half of the world’s population was at risk of malaria. There were 214 million cases and 438,000 deaths globally.6 The year 2015 marked the final year for achieving the targets set by the world health assembly and the roll back malaria program to reduce malaria incidence and mortality.17 It also marked the end of Millennium Development Goals and the beginning of sustainable development goals. Significant progress has been made over the past 15 years in malaria control. Globally, the number of cases of malaria has decreased by 18% between 2000 and 2015 with the majority of the reduction happening in Africa (88%).6 The incidence of malaria has dropped by 37%. The malarial mortality rate has fallen by 60%.6 The Millennium Development Goal 6C to have halted and reversed the incidence of malaria was achieved. Out of the 106 countries which had active malaria transmission, 57 countries had recorded more than 75% reduction in the incidence of malaria and a further 18 reduced by 50–75%.6 2.3. Epidemiology of malarial acute kidney injury Acute kidney injury (AKI) in malaria is often caused by P. falciparum. However, among the other species, P. vivax and P. knowlesi are notable for causing acute kidney injury. The incidence of malarial acute kidney injury varies from 15 to 48% in different studies.18–22 The varying incidence in different populations is attributed to its dependence on age and the presence of antimalarial immunity. Naturally acquired immunity (NAI) to falciparum malaria occurs among people living in the hyper and holoendemic regions of malaria transmission. This immunity confers protection against the severe manifestations of malaria and death.23 Nonimmune adults from areas of low transmission and older children are susceptible to develop acute kidney injury. Renal failure was as common as cerebral malaria in non-immune Europeans with falciparum malaria.24 AKI has been reported from Austria and Netherlands and most of these cases were imported.4 The incidence of malarial AKI in Africa seems to be low due to the hyperendemicity of the region which confers naturally acquired immunity. Waller et al. found that none of the 180 Gambian children with severe malaria had acute renal failure.25 However due to the difference in the transmission rates, certain regions of Africa seem to have a high incidence of AKI. In a study done in Addis Ababa, it was found that malarial AKI contributed to 21% of the 136 consecutive treated adult AKI patients. The case fatality rate was as high as 37.9%.26 AKI is a common manifestation of severe malaria in the South East Asian Region. Malarial AKI is being reported in increasing numbers from Kampuchea, Vietnam, Thailand, and Singapore. The overall incidence of malarial acute kidney injury in India varies between 4 and 17.2%.27 In the pediatric population, the incidence of malarial AKI was found to be 7.7% in the under-5 year age group and 18.4% in the 5–14 year age group.28 A recent upsurge in the number of cases of P. vivax associated AKI from India is also notable.29 3. Life cycle of the malarial parasite Malaria is transmitted by the bite of an infected female anopheles mosquito. Four hundred different species of Anopheles

mosquito have been identified of which 30 are of major importance.* The mosquito inoculates the sporozoites which then traverse through 2 phases in the humans. In the pre-erythrocytic or intrahepatic phase, the inoculated sporozoites reach the liver and invade the hepatocytes. After the invasion, they may either remain dormant (as in the case with P. vivax and P. ovale infections) or undergo asexual reproduction to produce the merozoites. An increasing number of merozoites causes the hepatocyte to burst and release the merozoites into the circulation. In the circulation, merozoites invade the red blood cells (RBC’s). In the case of P. falciparum, reticulocyte binding protein homologue 5 (PfRh5) and the corresponding erythrocyte receptor Basigin (CD147) are involved.30 P. vivax invades the erythrocytes via the Duffy antigen Fya and Fyb and the absence of this antigen in the West African population renders them resistant to the infection with P. vivax.31 The merozoites feed on the RBC’s hemoglobin and develop into the schizont. The RBC ruptures to release the merozoites which then invade another RBC to repeat the cycle. Some of the merozoites transform into the sexual forms, gametocytes. The circulating male and female gametocytes are taken up by the vector during a blood meal. The gametocytes then form the zygote in the insect’s midgut which then transforms into the ookinete. The ookinete ruptures to release the sporozoites which reach the insect’s salivary gland ready to be inoculated into another host. 4. Pathogenesis P. falciparum is responsible for the majority of the mortality associated with malaria. However, P. vivax and P. knowlesi can also cause severe illness. The pathogenesis of malaria associated acute kidney injury is not clearly understood. A combination of hemorheological, inflammatory and humoral responses has been implicated in the pathogenesis. Recent studies have thrown insights into the pathogenesis of the clinical manifestations of malaria caused by these 3 species of Plasmodium. 4.1. Falciparum malaria Three processes are central to the pathogenesis of Falciparum malaria: cytoadherence, rosetting, and agglutination.32 These processes culminate in microvascular clogging and tissue hypoxia. 4.1.1. Cytoadherence P. falciparum infected erythrocytes can bind to a diverse array of receptors on different cell types including endothelial cells, uninfected RBC’s, platelets, dendritic cells, B cell, monocytes, and macrophages. Parasitized RBC’s develop protrusion on their surfaces called as ‘knobs’.33 These knobs express parasite-derived proteins termed PfEMP1 (P. falciparum derived epithelial membrane protein 1). These proteins are encoded by the var gene.34 Each parasite encodes 60 different var genes and switching between them permits the parasite to evade host defense mechanisms. PfEMP1 mediates attachment of the RBC’s to the receptors on the capillary and venular endothelium. The parasitized RBC’s thus become sticky and adheres to the microvasculature eventually blocking them. Various receptors for PfEMP1 binding have been identified of which Intracellular adhesion molecule-1 (ICAM-1) is more important in the brain, chondroitin sulfate B in the placenta and CD 36 in most other organs. CD36 binding also plays a role in the non-opsonic phagocytosis of the infected RBC’s. Another novel receptor described recently by Turner et al. is the endothelial protein C receptor (EPCR), which is expressed on the endothelial cells and leucocytes.35 The protein C-EPCR pathway has anti-inflammatory activity in leucocytes and protects the endothelial cells. EPCR binding of parasitized RBC’s is associated with severe malaria.

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4.1.2. Rosetting Rosetting is an adhesion phenotype, by which the infected erythrocytes bind to uninfected RBC’s. Rosetting occurs by the binding of PfEMP1 to receptors on the uninfected erythrocytes some of which include the compliment receptor 1 (CR1) and the A and B blood group trisaccharides.36 Rosetting compliments the cytoadherence property of infected erythrocytes in clogging the microcirculation. The contribution of cytoadherence and sequestration to the pathogenesis of malarial acute kidney injury, however, is marginal.37 Post-mortem studies on adults dying from severe malaria showed a significantly higher number of infected erythrocytes in the renal vasculature in patients with AKI than in patients without AKI. However, the ultrastructural examination revealed much less sequestration in the renal tissue than the brain tissue.38 4.2. Vivax malaria P. vivax contributes to more than half of the malaria cases out of Africa.6 It is being recognized that vivax malaria is not benign as previously conceived.39 Anemia and ARDS are common manifestations of severe vivax malaria. However, cases of acute kidney injury accompanying vivax malaria are being increasingly reported.29 The immunopathogenesis of vivax malaria is largely unknown. Elevated levels of TNF-a, IFN-g, superoxide dismutase-1 (SOD-1) and soluble CD163 have been observed in patients with respiratory failure.40 P. vivax contains a major subtelomeric multigene superfamily termed vir which could aid in immune evasion.41 Also, the widely accepted hypothesis that P. vivax invasion requires Duffy antigen has been recently questioned as reports of vivax malaria have been reported in Duffy-negative people.42 4.3. Knowlesi malaria P. knowlesi causes zoonotic malaria. The P. knowlesi surface proteins are termed schizont-infected cell agglutinin antigens (SICA), which are encoded by the SICA var gene family.43 These proteins share binding motifs with the PfEMP1 proteins. The infected erythrocytes bind in a specific and variable manner to the endothelial cell receptors ICAM-1 and VCAM but not CD36. The pathological implication of these interactions remains to be defined. 4.4. Host response The host immune response acts as a double-edged sword in malaria conferring host protection as well as contributing to the pathogenesis of the disease. The levels of inflammatory cytokines such as TNF-a, IFN-g, IL-1a, 6 and 8 are found to be elevated. Increased production of reactive oxygen species and nitric oxide has also been observed.44 The activation of Th1 and Th2 type helper T cell response and alternate complement pathway could be responsible for some of the immune-mediated phenomena.45 Reduced renal perfusion is a major contributor to the development of acute kidney injury in malaria. This could result from decreased intake of fluids, loss of fluids because of vomiting and fever and from the state of generalized vasodilatation mediated by nitric oxide. There is also hypo-responsiveness to pressor hormones due to a higher hydrogen ion and lactic acid concentrations.46 5. Histology The spectrum of morphological changes seen in malarial acute kidney injury includes acute tubular necrosis, interstitial nephritis, and glomerulonephritis.47 These changes are seen in P. falciparum


infections. However, similar changes may be found in vivax infections as well. Acute tubular necrosis is the most consistent histological feature.48 ATN results from the relative hypovolemia and hypoperfusion of the kidneys. Tubular changes include cloudy swelling, hemosiderin granular deposits and variable degrees of cell necrosis. Acute cortical necrosis has also been reported in malaria and should be suspected in cases of prolonged oligoanuria.49 Acute interstitial inflammation accompanies ATN and acute glomerulonephritis. Isolated acute interstitial nephritis is rare. Interstitial inflammation results from the influx of Th1 lymphocytes. Glomerular lesions seen in patients dying of falciparum malaria include mesangial proliferation with moderate matrix expansion and occasional basement membrane thickening. Deposition of an eosinophilic material has been noticed along the capillary walls, within the mesangium, and in the Bowman’s capsule. The capillaries are often empty, but may contain occasional infected RBC’s. Immunofluorescence may reveal positivity for IgM and C3 along the capillary walls and the mesangium. There are also rare case reports describing an association of IgA nephropathy with malaria.50,51 Electron microscopy may show subendothelial and mesangial electron-dense deposits with thegranular, fibrillar and amorphous material. Immune complexes containing the P. falciparum antigen have been observed in the glomerular basement membrane and the mesangium. Recently, Sinha et al. reported thrombotic microangiopathy associated with vivax infection in nine patients.52 Hemolytic uremic syndrome has been reported in association with malaria.53–55 Endothelial damage is thought to underlie the pathogenesis of this disorder. 6. Clinical features According to the World health organization definition of severe malaria [2014], a serum creatinine of greater than 3 mg/dL (265 mmol/L) is essential to categorize a patient as having acute kidney injury. Different classification systems have been used by investigators such as the RIFLE and KDIGO.2,22 The latest KDIGO criteria include three stages of progressive renal dysfunction. It merges the AKIN and the RIFLE criteria. It defines acute kidney injury (stage 1) as a. An increase in serum creatinine to 1.5–1.9 times the baseline value OR more than 0.3 mg/dL (26 mmol/L) increase in serum creatinine b. Urine output less than 0.5 ml/kg/h for 6–12 h It has also been shown that the severity of AKI has prognostic value in morbidity and mortality in severe malaria.56 A large majority of patients with mild renal dysfunction could be missed by using the WHO criterion for acute kidney injury. The use of the KDIGO criteria allows early recognition of a decline in renal function and helps to guide treatment.4 AKI in malaria can occur as a part of multi-organ dysfunction or as an isolated renal involvement. Malarial AKI associated with multi-organ dysfunction carries a poor prognosis. AKI is usually present at the time of diagnosis. These patients have a high incidence of associated complications such as anemia, acidosis, jaundice, hypoglycemia and prolonged coma. In the other group of patients who have isolated renal involvement, the prognosis is better. These patients present with oliguria, encephalopathy, hyperkalemia and metabolic acidosis. Oliguria is observed in 70– 76% of the patients and may persist for 3–10 days. However, patients may also be non-oliguric. They tend to present when the other complications of malaria have subsided and when the parasite is no longer detectable in the peripheral blood.37 Hence, a high index of suspicion should be held and regular frequent monitoring of renal function is essential.

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The spectrum of renal abnormalities observed in malaria includes the following. 6.1. Proteinuria Glomerular or tubular proteinuria may be observed transiently during active disease. The proteinuria is usually less than 1 g/day and occurs in 60% of the cases.48 However, persistent proteinuria would point toward the presence of significant glomerular or tubular involvement. Hemoglobinuria and myoglobinuria may be observed with intravascular hemolysis. 6.2. Oliguria Variable incidence from published reports. Though oliguric acute renal failure is the common presentation in malaria, there are an increasing number of reports of nonoliguric acute renal failure. Gupta et al. did a comparative study of oliguric and nonoliguric acute renal failure in malaria. Renal failure was nonoliguric in 75.68% of the patients.57 Another study by Mehta et al. noted no-oliguric renal failure in 58% of the patients.19 6.3. Electrolyte abnormalities Table 1 summarizes the electrolyte abnormalities observed in severe malaria, their pathogenesis, and the clinical significance. 6.4. Associations 6.4.1. Cerebral malaria AKI occurs often with cerebral malaria. The concurrence of these two complications has been shown to compound the mortality risk. In the study done by Mishra et al. the mortality was 39.5%, when cerebral malaria was associated with AKI and was 13.9%, when there was no AKI.58 Shukla et al. also showed that cerebral malaria is an important determinant of mortality in AKI patients.2 6.4.2. Hematological abnormalities Anemia occurs in 70% of the patients and is typically hemolytic. However, anemia due to blood loss can also occur. Severe anemia has been reported in 10–20% of the cases.37 Neutrophilic leukocytosis can be observed even in the absence of bacterial infection. Leucopenia and monocytosis may be seen. Thrombocytopenia is a common feature in vivax and falciparum malaria. It

may occur due to excess peripheral destruction, splenic sequestration or as a part of the disseminated intravascular coagulation initiated by the parasite.59–61 Platelet clumping along with the parasite may also result in pseudo thrombocytopenia. Profound thrombocytopenia is encountered with falciparum infections. Malarial infestation can also cause hemophagocytic syndrome and present with pancytopenia.62 Hemophagocytic syndrome in malaria should be suspected, when the anemia does not improve with antimalarial therapy.63 Thrombocytopenia and leucopenia are the two most reliable hematological parameters for predicting malaria in people from endemic areas.64 6.4.3. Jaundice The incidence of jaundice in falciparum malaria varies between 2 and 57%. Acute kidney injury is associated with jaundice in more than 75% of the patients and is frequently of the unconjugated type resulting from intravascular hemolysis.65 However, derangement of liver functions could also occur occasionally as a result of true malarial hepatitis.48 7. Prognosis Acute kidney injury is a serious complication of malaria with mortality ranging between 15 and 45%.23 Several factors have been shown to increase the mortality in malarial AKI (Table 2). Sitprija showed that heavy parasitemia, hypovolemia, hyperviscosity, and jaundice are critical predisposing factors.66 Central nervous system involvement is a strong factor associated with mortality.67 Mishra et al. analyzed 110 adult patients to study the effect of acute renal failure on survival in patients with cerebral malaria. Patients with cerebral malaria had an increased risk of death (39.5% versus 13.9%) when also suffering from acute kidney injury. For each one log unit increase of creatinine at admission, the odds of death increased by a factor of 10.8.58 Mortality increases with multiorgan involvement in malaria. Mortality is 6.4% when one or fewer organs fail and increases to 48.8% with multiorganinvolvement.21 Although most studies have analyzed the outcomes in severe AKI in the setting of malaria, the impact of milder forms of AKI on morbidity and mortality was largely unknown. Saravu et al. attempted to stratify in-hospital outcomes by the severity of AKI. They found that even mild AKI was associated with significant morbidity compared to no AKI.56 The mortality in malarial AKI can be reduced by early diagnosis, appropriate therapy and timely institution of renal replacement therapy.2 Mishra et al. devised a simple scoring system for predicting outcomes in severe malaria in adults (MSA). Factors such as the presence of severe anemia, acute renal failure,

Table 1 Electrolyte abnormalities observed in severe malaria. Electrolyte abnormality


Clinical significance


Trapping of sodium inside the cells due to decreased functioning of the Na-K-ATPase pump (internal dilution) Increased antidiuretic hormone (ADH) secretion (not an important mechanism) Resetting of the osmoreceptor Occurs in cerebral malaria Blunted thirst mechanism and decreased access to water Hyperventilation and respiratory alkalosis Decreased intake and increased losses Occurs with acute kidney injury and hemolysis

Hyponatremia is the most common electrolyte abnormality occurring in 25–60%48 Fluid administration should be done with caution in the setting of increased ADH secretion to avoid volume overload and pulmonary edema Rarely observed

Hypernatremia Hypokalemia Hyperkalemia Hypocalcemia Hypophosphatemia Lactic acidosis

Intracellular calcium shift Low serum albumin level Shift of phosphate into the cells due to respiratory alkalosis Hypoparathyroidism Tissue hypoxia and anaerobic glycolysis

Serious electrolyte abnormality Indication for RRT

Severe metabolic acidosis is a poor prognostic factor

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CQN-84; No. of Pages 7 A. Chellappan, D.S. Bhadauria / Clinical Queries: Nephrology xxx (2016) xxx–xxx Table 2 Risk factors associated with acute kidney injury in malaria. Risk factors associated with the development of AKI in malaria28 Older adults and children Late referral Short acute illness High parasitemia Oliguria Hypotension Severe anemia Significant jaundice Severe diarrhea Multisystem involvement, cerebral malaria Hepatitis Acute respiratory distress Opportunistic pulmonary viral or bacterial infections

respiratory distress and cerebral malaria were incorporated into the score. The MSA had a sensitivity of 89.9%, specificity 70.6%, and positive predictive value of 94.1%.68 8. Management The key aspects of management of acute kidney injury in malaria include the following:


8.2. Antimalarial therapy Two classes of antimalarial drugs can be used for the treatment of severe malaria – the artemisinin derivatives (artesunate and artemether) and cinchona alkaloids (quinine and quinidine). Quinine has been the standard treatment of severe malaria for centuries. However, inferior outcomes and toxicity have limited its use in the management of severe malaria. The artemisinin derivatives have emerged as the first line antimalarial for the treatment of severe malaria. Several trials have proved the superiority of artemisinin derivatives over parenteral quinine. The SEAQUAMAT and the AQUAMAT trials formed the basis for the paradigm shift in the treatment recommendations, toward the use of parenteral artesunate instead of parenteral quinine.70 The recent guidelines from the World Health Organization recommend the use of intravenous or intramuscular artesunate for the treatment of severe malaria in adults and children for the initial 24 h and until oral medication is tolerated.71 Once the patients can tolerate oral medication, the treatment should be completed with 3 days of artemisinin-based combination therapy. If parenteral artesunate is not available, then artemether should be used in preference to quinine. Dosing and adverse effects of the two classes of drugs are detailed in Table 3. 8.3. Fluid resuscitation

1. 2. 3. 4. 5. 6.

Diagnosis Antimalarial therapy Fluid resuscitation Renal replacement therapy Management of associated complications Treatment of coexisting infections

8.1. Diagnosis The diagnosis of malaria relies on the demonstration of the asexual forms of the parasite in the peripheral blood or in the tissues. Peripheral blood smear examination is the reference standard. Limitations of blood smear examination include the time consumption and the need for considerable expertise in interpreting the smears. Rapid diagnostic tests (RDT’s) for P. falciparum address the shortcomings of the blood smear examination and are recommended by the WHO. Some of the RDT’s allow the diagnosis of one or more of the other species of the malarial parasite. They are based on the detection of either the histidine-rich protein 2 (HRP2) antigen or plasmodium-falciparum-specific lactate dehydrogenase (PfLDH). The diagnosis of acute kidney injury in malaria is best arrived by utilizing the KDIGO criteria. The measurement of serum creatinine at admission is safe, inexpensive and can predict the requirement of RRT.69 Several biomarkers are being evaluated for the prediction of AKI, the most promising of it being neutrophil gelatin associated lipocalin (NGAL).

A lot of uncertainty surrounds the fluid management strategies in severe malaria. The 2010 WHO guidelines for the treatment of malaria observed that ‘In adults there is a very thin dividing line between over-hydration which may produce pulmonary edema, and under-hydration contributing to shock, worsening acidosis and renal impairment’. The following queries face a clinician while addressing the fluid requirements of a patient with severe malaria. 8.3.1. Volume status assessment Volume status assessment by physical examination has several limitations. Recognizing these limitations the 2010 WHO guidelines recommended the use of a central venous catheter and targeting a CVP of 0 to 5 cm H2O in critically ill patients. However, in the PiCCO-guided resuscitation in severe malaria (PRISM)72 and the Vietnamese hemodynamic study (VHS),73 no relationship was found between CVP and cardiac output before and after fluid resuscitation. The recent WHO guidelines (2015) recommend careful, frequent evaluation of jugular venous pressure, peripheral perfusion, venous filling, skin turgor and urine output. 8.3.2. Liberal versus conservative fluid replacement Renal failure and metabolic acidosis are strong mortality predictors in severe malaria. Volume deficit in these patients can contribute to the progression of each of these complications

Table 3 Dosing and adverse effects of artesunate and quinine. Drug




Larger children and adults: 2.4 mg/kg at 0, 12, and 24 h and then once daily Children weighing less than 20 kg: 3 mg/kg/dose Artemether/lumefantrine should be given twice a day for a total of 6 doses. The first 2 doses should be spaced 8 h apart Well tolerated Post-artemisinin delayed hemolysis

20 mg/kg loading dose followed by 10 mg/kg 8th hourly

Follow on therapy Adverse effects

Renal dose modification

Not required

10 mg/kg thrice daily orally Hypotension Hypoglycemia QTc prolongation and cardiac arrhythmias Cinchonism – tinnitus, disturbed vision, and nausea If no improvement occurs by 48 h then the dose should be reduced to 10 mg/kg given 12th hourly; dose adjustment is not necessary if the patient is receiving hemodialysis or hemofiltration

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and hence it would seem logical to administer fluids. However, neither renal failure nor metabolic acidosis showed correlation with the volume status in recent studies. Instead, the changes in malaria occur at a microvascular level. The sequestration of parasites in the microvasculature contributes to the pathophysiology of acidosis and renal failure. Fluid loading does not influence the microvascular defect in severe malaria. Adults with severe malaria tend to have an acceptable cardiac output and an extra administered is likely to contribute to the development of acute pulmonary edema due to the accumulation of fluid in the interstitial space. Hence, there may only be little advantage in infusing fluid beyond a maintenance rate of 1–2 ml/kg/h.74 8.3.3. Fluid bolus therapy versus maintenance fluid therapy The landmark fluid expansion as supportive therapy (FEAST) trial was a study that delivered unexpected results.75 It found an increased mortality among children who received saline or albumin bolus for resuscitation compared to the children who received no boluses. The increased mortality observed resulted from cardiovascular collapse.76 Accordingly the recent WHO guidelines for the management of severe malaria crystalloid or colloid boluses are contraindicated. 8.3.4. Optimal type of intravenous fluid The choice of optimal fluid for resuscitation in malaria remains elusive. Albumin cannot be recommended considering the high mortality observed with albumin-bolus resuscitation in the FEAST trial. Balanced salt solutions have shown benefit in some studies.77 The WHO guidelines in 2012 recommended 0.9% normal saline for resuscitation. Recently concerns have been raised regarding the association of chloride-rich fluids with acidosis and AKI. However, the best trial to date, the SPLIT trial found that among the patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI.78 The threshold for blood transfusion is a Hb < 7 g/dL in lowtransmission settings and a Hb < 5 g/dL in high-transmission settings. 8.4. Renal replacement therapy Prompt initiation of renal replacement therapy reduces mortality.2 The various indications for initiating renal replacement therapy include uremic symptoms, symptomatic volume overload, severe metabolic acidosis and severe hyperkalemia. Renal replacement therapy can be in the form of peritoneal dialysis, intermittent hemodialysis, continuous venovenous hemofiltration or continuous arterovenous hemofiltration. There is no consensus on the best modality of renal replacement in malaria. Each modality has its own set of advantages and disadvantages in the setting of malaria. There have been concerns over the inadequacy of PD on the one hand, and the possibility of hemodynamic worsening with intermittent HD on the other hand. Continuous forms of renal replacement therapy are being increasingly used for critically ill patients with acute kidney injury. A study done in Vietnam compared peritoneal dialysis and hemofiltration in patients with infection-associated acute kidney injury.79 They found that the mortality rate was 47% in the group assigned to peritoneal dialysis, as compared with 15% in the hemofiltration group. The rates of resolution of acidosis and decline in serum creatinine were also two times higher in the hemofiltration group. Hemofiltration was also found to be more economical than peritoneal dialysis. However, the authors of the study did not employ an optimal PD technique. A rigid catheter was used which could have increased the risk of pericatheter leaks and infection. Also, a large volume of dialysate was used which would have left very little dwell time during the exchanges. The same authors had previously

reported improved outcomes with peritoneal dialysis.80 In a recent retrospective analysis on the modality of RRT in malarial acute kidney injury done by Mishra et al. it was found that peritoneal dialysis improved survival in these patients to 36% from 20%.81 Hence, with optimally performed peritoneal dialysis outcomes similar to those achieved by hemodialysis can be achieved. In a country like India, where the majority of the population do not have access to hemodialysis centers, acute PD could prove to be the first choice modality of RRT. Intermittent hemodialysis performed daily offers better prognosis. Acute PD is given for 24–48 h but may be extended for upto 72 h. Acute kidney injury in malaria is hypercatabolic and dialysis is considered to be adequate when there is a post dialysis reduction in urea and creatinine of 50% or more. Dialysis should be continued until the urine output increases to more than 400 ml/day. Quinine and artesunate do not require dose modifications in patients on dialysis. The diuretic phase of acute kidney injury should be managed with careful attention to the fluid and electrolyte requirements. Conflicts of interest The authors have none to declare. References 1. Naqvi R. Plasmodium vivax causing acute kidney injury: a foe less addressed. Pak J Med Sci. 2015;31(6):1472–1475. 2. Kute VB, Shah PR, Munjappa BC, et al. Outcome and prognostic factors of malariaassociated acute kidney injury requiring hemodialysis: a single center experience. Indian J Nephrol. 2012;22(1):33–38. 3. Marks M, Armstrong M, Walker D, Doherty T. Imported falciparum malaria among adults requiring intensive care: analysis of the literature. Malar J. 2014; 13(March):79. 4. Koopmans LC, van Wolfswinkel ME, Hesselink DA, et al. Acute kidney injury in imported Plasmodium falciparum malaria. Malar J. 2015;14(December) [Internet]. Available from: 5. Marks ME, Armstrong M, Suvari MM, et al. Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London. BMC Infect Dis. 2013;13(March):118. 6. WHO. World Malaria Report. WHO; 2015 [Internet]. Available from: http://www. [cited 28.03.16]. 7. Singh B, Sung LK, Matusop A, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet. 2004;363(March (9414)):1017–1024. 8. Jongwutiwes S, Putaporntip C, Iwasaki T, Sata T, Kanbara H. Naturally acquired Plasmodium knowlesi malaria in human, Thailand. Emerg Infect Dis. 2004;10(December (12)):2211–2213. 9. Putaporntip C, Hongsrimuang T, Seethamchai S, et al. Differential prevalence of Plasmodium infections and cryptic Plasmodium knowlesi malaria in humans in Thailand. J Infect Dis. 2009 [Internet]. Available from: http://jid.oxfordjournals. org/content/199/8/1143.long. [cited 28.03.16]. 10. Luchavez J, Espino F, Curameng P, et al. Human infections with Plasmodium knowlesi, the Philippines. Emerg Infect Dis. 2008;14(May (5)) [Internet]. Available from: [cited 28.03.16]. 11. Jiang N, Chang Q, Sun X, et al. Co-infections with Plasmodium knowlesi and other malaria parasites, Myanmar. Emerg Infect Dis. 2010;16(September (9)):1476–1478. 12. Ng OT, Ooi EE, Lee CC, et al. Naturally acquired human Plasmodium knowlesi infection, Singapore. Emerg Infect Dis. 2008;14(May (5)):814–816. 13. Marchand RP, Culleton R, Maeno Y, Quang NT, Nakazawa S. Co-infections of Plasmodium knowlesi, P. falciparum, and P. vivax among humans and Anopheles dirus mosquitoes, southern Vietnam. Emerg Infect Dis. 2011;17(July (7)):1232– 1239. 14. Figtree M, Lee R, Bain L, et al. Plasmodium knowlesi in human, Indonesian Borneo. Emerg Infect Dis. 2010;16(April (4)):672–674. 15. Khim N, Siv S, Kim S, et al. Plasmodium knowlesi infection in humans, Cambodia, 2007–2010. Emerg Infect Dis. 2011;17(October (10)) [Internet] Available from: [cited 05.04.16]. 16. Singh B, Daneshvar C. Human infections and detection of Plasmodium knowlesi. Clin Microbiol Rev. 2013;26(April (2)):165–184. 17. Nabarro D. Roll back malaria. Parassitologia. 1999;41(September (1–3)):501–504. 18. Day NP, Phu NH, Mai NT, et al. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med. 2000 [Internet]. Available from: The_pathophysiologic_and_prognostic_significance.25.aspx. [cited 28.03.16]. 19. Mehta KS, Halankar AR, Makwana PD, Torane PP, Satija PS, Shah VB. Severe acute renal failure in malaria. J Postgrad Med. 2001;47(January (1)):24. 20. Prakash J, Gupta A, Kumar O, Rout SB, Malhotra V, Srivastava PK. Acute renal failure in falciparum malaria—increasing prevalence in some areas of India—a need for awareness. Nephrol Dial Transplant. 1996;11(December (12)):2414–2416.

Please cite this article in press as: Chellappan A, Bhadauria DS. Acute kidney injury in malaria: An update, Clin Query Nephrol. (2016),

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CQN-84; No. of Pages 7 A. Chellappan, D.S. Bhadauria / Clinical Queries: Nephrology xxx (2016) xxx–xxx 21. Krishnan A, Karnad DR. Severe falciparum malaria: an important cause of multiple organ failure in Indian intensive care unit patients. Crit Care Med. 2003;31(September (9)):2278–2284. 22. Kochar DK, Kochar SK, Agrawal RP, et al. The changing spectrum of severe falciparum malaria: a clinical study from Bikaner (northwest India). J Vector Borne Dis. 2006;43(September (3)):104–108. 23. Doolan DL, Doban˜o C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev. 2009;22(January (1)):13–36. 24. Weber MW, Bo¨ker K, Horstmann RD, Ehrich JH. Renal failure is a common complication in non-immune Europeans with Plasmodium falciparum malaria. Trop Med Parasitol. 1991;42(June (2)):115–118. 25. Waller D, Krishna S, Crawley J, et al. Clinical features and outcome of severe malaria in Gambian children. Clin Infect Dis. 1995;21(3):577–587. 26. Zewdu W. Acute renal failure in Addis Abeba, Ethiopia: a prospective study of 136 patients. Ethiop Med J. 1994;32(April (2)):79–87. 27. Panda SK, Das MC, Meher LK, Rathod PK. Risk factors for acute renal failure in severe falciparum malaria. Indian J Nephrol. 2003;13(April (2)):55. 28. Satpathy DSK, Mohanty N, Nanda P, Samal G. Severe falciparum malaria. Indian J Pediatr. 2004;71(February (2)):133–135. 29. Kute VB, Trivedi HL, Vanikar AV, et al. Plasmodium vivax malaria-associated acute kidney injury, India, 2010–2011. Emerg Infect Dis. 2012;18(May (5)):842–845. 30. Crosnier C, Bustamante LY, Bartholdson SJ, et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature. 2011;480(December (7378)):534–537. 31. Langhi DM, Bordin JO. Duffy blood group and malaria. Hematology. 2006;11(October (5–6)):389–398. 32. Hasler T, Handunnetti SM, Aguiar JC, et al. In vitro rosetting, cytoadherence, and microagglutination properties of Plasmodium falciparum-infected erythrocytes from Gambian and Tanzanian patients. Blood. 1990;76(November (9)):1845–1852. 33. Sharma YD. Knobs, knob proteins and cytoadherence in falciparum malaria. Int J Biochem. 1991;23(9):775–789. 34. Flick K, Chen Q. var genes, PfEMP1 and the human host. Mol Biochem Parasitol. 2004;134(March (1)):3–9. 35. Turner L, Lavstsen T, Berger SS, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013 [Internet]. Available from: html. [cited 05.04.16]. 36. Rowe JA, Moulds JM, Newbold CI, Miller LH. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature. 1997;388(July (6639)):292–295. 37. Mishra SK, Das BS. Malaria and acute kidney injury. Semin Nephrol. 2008;28(July (4)):395–408. 38. Nguansangiam S, Day NPJ, Hien TT, et al. A quantitative ultrastructural study of renal pathology in fatal Plasmodium falciparum malaria. Trop Med Int Health. 2007;12(September (9)):1037–1050. 39. Price RN, Tjitra E, Guerra CA, et al. Neglected and not benign. Am J Trop Med Hyg. 2007;77(December (6 suppl)):79–87. 40. Andrade BB, Reis-Filho A, Souza-Neto SM, et al. Plasma superoxide dismutase-1 as a surrogate marker of vivax malaria severity. PLoS Negl Trop Dis. 2010;4(April (4)) [Internet]. Available from: PMC2850307/. [cited 05.04.16]. 41. Gupta P, Pande V, Das A, Singh V. Genetic polymorphisms in VIR genes among Indian Plasmodium vivax populations. Korean J Parasitol. 2014;52(October (5)):557–564. 42. Woldearegai TG, Kremsner PG, Kun JFJ, Mordmu¨ller B. Plasmodium vivax malaria in Duffy-negative individuals from Ethiopia. Trans R Soc Trop Med Hyg. 2013;107(May (5)):328–331. 43. Korir CC, Galinski MR. Proteomic studies of Plasmodium knowlesi SICA variant antigens demonstrate their relationship with P. falciparum EMP1. Infect Genet Evol. 2006;6(January (1)):75–79. 44. Nahrevanian H, Dascombe MJ. Nitric oxide and reactive nitrogen intermediates during lethal and nonlethal strains of murine malaria. Parasite Immunol. 2001;23(September (9)):491–501. 45. Perez-Mazliah D, Langhorne J. CD4 T-cell subsets in malaria: TH1/TH2 revisited. Front Immunol. 2015;5(January) [Internet]. Available from: http://www.ncbi.nlm. [cited 05.04.16]. 46. Thiemermann C, Szabo´ C, Mitchell JA, Vane JR. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci U S A. 1993;90(January (1)):267–271. 47. Barsoum RS. Malarial nephropathies. Nephrol Dial Transplant. 1998;13(June (6)): 1588–1597. 48. Barsoum RS. Malarial acute renal failure. J Am Soc Nephrol. 2000;11(November (11)):2147–2154. 49. Baliga KV, Narula AS, Khanduja R, Manrai M, Sharma P, Mani NS. Acute cortical necrosis in falciparum malaria: an unusual manifestation. Ren Fail. 2008; 30(4):461–463. 50. Rafieian-Kopaei M, Nasri H, Alizadeh F, Ataei B, Baradaran A. Immunoglobulin A nephropathy and malaria falciparum infection; a rare association. Iran J Public Health. 2013;42(May (5)):529–533. 51. Yoo DE, Kim JH, Kie JH, et al. Immunoglobulin A nephropathy associated with Plasmodium falciparum malaria. J Korean Med Sci. 2012;27(April (4)):446–449. 52. Sinha A, Singh G, Bhat AS, et al. Thrombotic microangiopathy and acute kidney injury following vivax malaria. Clin Exp Nephrol. 2012;17(July (1)):66–72.


53. Keskar VS, Jamale TE, Hase NK. Hemolytic uremic syndrome associated with Plasmodium vivax malaria successfully treated with plasma exchange. Indian J Nephrol. 2014;24(1):35–37. 54. Al-Mendalawi MD. Hemolytic uremic syndrome associated with Plasmodium vivax malaria successfully treated with plasma exchange. Indian J Nephrol. 2014; 24(5):331. 55. Jhorawat R, Beniwal P, Malhotra V. Plasmodium vivax induced hemolytic uremic syndrome: an uncommon manifestation that leads to a grave complication and treated successfully with renal transplantation. Trop Parasitol. 2015;5(2):127–129. 56. Saravu K, Rishikesh K, Parikh CR. Risk factors and outcomes stratified by severity of acute kidney injury in malaria. PLOS ONE. 2014 [Internet]. Available from: [cited 28.03.16]. 57. Gupta BK, Nayak KC, Kumar S, Kumar S, Gupta A, Prakash P. Oliguric and nonoliguric acute renal failure in malaria in west zone of Rajasthan, India – a comparative study. J Acute Dis. 2012;1(2):100–106. 58. Mishra SK, Dietz K, Mohanty S, Pati SS. Influence of acute renal failure in patients with cerebral malaria – a hospital-based study from India. Trop Doct. 2007;37(April (2)):103–104. 59. Essien EM. The circulating platelet in acute malaria infection. Br J Haematol. 1989;72(August (4)):589–590. 60. Beale PJ, Cormack JD, Oldrey TBN. Thrombocytopenia in malaria with immunoglobulin (IgM) changes. Br Med J. 1972;1(February (5796)):345–349. 61. Skudowitz RB, Katz J, Lurie A, Levin J, Metz J. Mechanisms of thrombocytopenia in malignant tertian malaria. Br Med J. 1973;2(June (5865)):515–518. 62. Vinoth PN, Thomas KA, Selvan SM, Suman DF, Scott JX. Hemophagocytic syndrome associated with Plasmodium falciparum infection. Indian J Pathol Microbiol. 2011;54(3):594. 63. Tanwar GS, Lahoti A, Tanwar P, Agrawal R, Khatri PC, Kochar DK. Hemophagocytic syndrome associated with severe Plasmodium vivax malaria in a child in Bikaner (northwestern India). J Vector Borne Dis. 2013;50(December (4)):318–320. 64. Kotepui M, Phunphuech B, Phiwklam N, Chupeerach C, Duangmano S. Effect of malarial infection on haematological parameters in population near ThailandMyanmar border. Malar J. 2014;13:218. 65. Wilairatana P, Looareesuwan S, Charoenlarp P. Liver profile changes and complications in jaundiced patients with falciparum malaria. Trop Med Parasitol. 1994;45(December (4)):298–302. 66. Sitprija V. Nephropathy in falciparum malaria. Kidney Int. 1988 [Internet]. Available from: 5344355. [cited 29.03.16]. 67. Naqvi R, Ahmad E, Akhtar F, Naqvi A, Rizvi A. Outcome in severe acute renal failure associated with malaria. Nephrol Dial Transplant. 2003;18(September (9)):1820– 1823. 68. Mishra SK, Panigrahi P, Mishra R, Mohanty S. Prediction of outcome in adults with severe falciparum malaria: a new scoring system. Malar J. 2007;6:24. 69. Hanson J, Hasan MMU, Royakkers AA, et al. Laboratory prediction of the requirement for renal replacement in acute falciparum malaria. Malar J. 2011; 10(August):217. 70. Dondorp A, Nosten F, Stepniewska K, Day N, White N. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group.Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005; 366(September (9487)):717–725. 71. National Center for Biotechnology Information, U.S. National Library of Medicine. Treatment of Severe Malaria. 2015 Available from: books/NBK294445/. [cited 06.04.16]. 72. Hanson JP, Lam SWK, Mohanty S, et al. Fluid resuscitation of adults with severe falciparum malaria: effects on acid-base status, renal function, and extravascular lung water*. Crit Care Med. 2013;41(April (4)):972–981. 73. Phu NH, Hanson J, Bethell D, et al. A retrospective analysis of the haemodynamic and metabolic effects of fluid resuscitation in vietnamese adults with severe falciparum malaria. PLoS ONE. 2011;6(October (10)):e25523. 74. Hanson J, Anstey NM, Bihari D, White NJ, Day NP, Dondorp AM. The fluid management of adults with severe malaria. Crit Care. 2014;18:642. 75. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 [Internet]. Available from: http://www. [cited 06.04.16]. 76. Myburgh J, Finfer S. Causes of death after fluid bolus resuscitation: new insights from FEAST. BMC Med. 2013;11(March):67. 77. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med. 2014;42(July (7)):1585–1591. 78. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the split randomized clinical trial. JAMA. 2015;314(October (16)):1701–1710. 79. Phu NH, Hien TT, Mai NTH, et al. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med. 2002;347(September (12)):895–902. 80. Trang TT, Phu NH, Vinh H, et al. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis. 1992;15(November (5)):874–880. 81. Mishra SK, Mahanta KC. Peritoneal dialysis in patients with malaria and acute kidney injury. Perit Dial Int. 2012;32(6):656–659.

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