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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 2  |  Page : 296-300
Acute renal failure in falciparum malaria: Clinical characteristics, demonstration of oxidative stress, and prognostication


1 Department of Nephrology, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati, Andhra Pradesh, India
2 Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati, Andhra Pradesh, India

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Date of Web Publication28-Feb-2012
 

   Abstract 

In this prospective study, we aimed to assess the clinical characteristics of acute renal failure (ARF), determine oxidative stress, as well as to predict the outcome in patients with severe falciparum malaria (FM). The study included a total of 75 subjects; there were 25 adult patients with acute severe FM and ARF, 25 adult patients with uncomplicated FM without ARF, and 25 age- and sex-matched healthy subjects who served as controls. In patients with severe FM and ARF (n = 25), renal failure was non-oliguric in 28% and oliguric in 72%. The average duration of renal failure was 10.53 ± 4.0 days. Sixty percent recovered and 40% died. All patients with non-oliguric presentation recovered. The mean serum malondialdehyde (MDA) levels were 0.82 ± 0.43 μmol/L, 2.97 ± 1.11 μmol/L, and 6.86 ± 2.62 μmol/L, respectively, in healthy con­trols, in patients with uncomplicated FM, and in those with severe FM with ARF. The Acute Physiology Age and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, and the Acute Tubular Necrosis-Individual Severity Index (ATN-ISI) score were all significantly higher in the expired group (19 ± 5.49) when compared to the survivor group (14.4 ± 3.15) (P = 0.014). Kaplan-Meier survival analysis showed that survival was low in patients with delayed hospitalization and longer duration of symptoms. Also, we observed a high occurrence of acute respiratory distress syndrome and central nervous system involvement among the patients who expired.

How to cite this article:
Krishna CR, Rao PS, Das G C, Kumar V S. Acute renal failure in falciparum malaria: Clinical characteristics, demonstration of oxidative stress, and prognostication. Saudi J Kidney Dis Transpl 2012;23:296-300

How to cite this URL:
Krishna CR, Rao PS, Das G C, Kumar V S. Acute renal failure in falciparum malaria: Clinical characteristics, demonstration of oxidative stress, and prognostication. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2014 Oct 21];23:296-300. Available from: http://www.sjkdt.org/text.asp?2012/23/2/296/93160

   Introduction Top


Malaria is a parasitic disease of great epide-miological importance in tropical countries. The incidence of malaria is estimated to be 300-500 million clinical cases each year, with about 90% of these occurring in sub-Saharan Africa. Also, there are approximately one mil­lion deaths related to malaria each year. [1],[2],[3] Acute renal failure (ARF) in falciparum ma­laria (FM) infection occurs almost exclusively in adults and older children, with an incidence of 1-4%. [4] The incidence of ARF may reach up to 60% in patients with severe FM, resulting in increased mortality. [3] In India, the incidence of malarial ARF has been reported to be 13% in North India, 17.8% in New Delhi, and 17.2% in Orissa. ARF associated with severe FM is usually oliguric or anuric and hyper-catabolic. The pathogenesis of ARF as well as other serious complications in FM is multi-factorial, involving a complex interaction of mecha­nical, immunological, cytokine and humoral factors, and acute phase reactants, apart from certain nonspecific and hemodynamic com­ponents. Mechanical factors such as erythrocyte sequestration in the microvasculature cause impairment in renal microcirculatory flow and metabolism. Additionally, massive monocyte activation resulting in elaboration of reactive oxygen species into the circulation has been shown to play an important role in the patho-genesis of ARF and other vital organ dysf­unction in acute severe FM. Several factors including intravascular hemolysis, disseminated intravascular coagulation (DIC), and rhabdo-myolysis are also found in falciparum infec­tion and might result in impaired renal func-tion. [5],[6],[7] ARF usually occurs simultaneously with impairment of other vital organs, resul­ting in jaundice, acute respiratory distress syn­drome (ARDS), cerebral malaria, DIC, and thrombocytopenia. The eventual prognosis of patients with ARF would be influenced by the presence of other co-morbid features. [4]

Herein, we present the data of our study, which was conducted to assess the clinical characteristics of ARF, demonstrate the role of oxidative stress (OS), and to predict the out­come in patients with acute FM.


   Objectives Top


The objectives of this study were to assess the clinical characteristics of ARF, demonstrate the role of OS, and also to predict the outcome in patients with acute FM by scoring systems including Acute Physiology Age and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Acute Tubular Necrosis-Individual Severity Index (ATN-ISI).


   Methods Top


The prospective study included a total of 75 subjects and consisted of 25 adult patients with acute severe FM and ARF and 25 adult pa­tients with uncomplicated FM, admitted in our institute. The remaining 25 patients served as age- and sex-matched controls. FM was con­firmed by examination of Geimsa-stained peri­pheral smear and quantitative buffy coat (QBC) test. The erythrocyte parasitemia index (EPI) was determined by the number of infected red blood cells (RBC) per 100 red cells in a thin smear. ARF was diagnosed according to WHO criteria, i.e. urine output <400 mL/day, failure to improve after rehydration and/or rise in se­rum creatinine to greater than 3 mg/dL. Each blood sample was analyzed for serum mal-ondialdehyde (MDA), vitamin A, and vitamin E. The serum MDA, vitamin A, and vitamin E levels were measured in the 25 control sub­jects also. Free MDA in serum was estimated as thiobarbituric acid reactive substances (TBARS) as an index of changes in lipid peroxidation; this was measured spectrogra-phically after precipitating the proteins with trichloroacetic acid (TCA). Vitamin A and vi­tamin E were measured by High Performance Liquid Chromatography (HPLC). All the sub­jects were tested for renal dysfunction, liver dysfunction, serum electrolytes, arterial blood gas analysis, complete blood picture including coagulation profile, serum calcium, phospho­rus, albumin, cholesterol, and urinalysis. Se­rum chemistry was measured by standard methods using commercial kits on Beckman CX9 analyzer. APACHE II, SOFA, and ATN-ISI scoring were determined in patients with ARF and severe FM. [8],[9],[10]


   Statistical Analysis Top


All numerical values were entered in Micro­soft excel spread sheet and transferred to SPSS 11.5 Chicago Inc. data editor for carrying out computations. Mean values were compared by student's independent "t" test and categorical variables with chi-square and Fisher exact test. Association between variables was assessed by linear regression. Survival rate of patients with ARF was correlated with the duration of symptoms by Kaplan-Meier survival curve. P values <0.05 are considered significant.


   Results Top


The total number of patients studied was 75, which included 25 patients with acute severe FM and ARF, 25 patients with uncomplicated FM, and 25 age- and sex-matched controls. Patients with acute severe FM and ARF also manifested impairment of other vital organs: hepatic (96%), central nervous system (CNS; 56%), ARDS (28%), and hypotension (12%). The ARF was non-oliguric in seven patients (28%) patients and oliguric in the remaining 18 patients (72%). Metabolic acidosis was observed in all patients with acute severe FM and ARF. Hyponatremia (<135 meq/L) was found in 16 patients (64%) with severe FM. Among them, three patients had severe hypo-natremia (<125 meq/L). Four patients (16%) had proteinuria of <1 g/day. Five patients (20%) had hypoglycemia (plasma glucose level of <40 mg/dL). Severe anemia (<5 g/dL) was seen in four patients (16%) and severe thrombocytopenia (<50,000/mm [3] ) in 18 pa­tients (72%). The mean EPI in patients with ARF was 4.53 ± 0.82.

Patients with uncomplicated FM presented with typical manifestations of high fever with chills and rigors. All had normal renal func­tions and five patients (20%) showed hypo-natremia. The mean EPI in these patients was 3.50 ± 0.90. There was no statistically signi­ficant difference in the EPI between patients with ARF (4.53 ± 0.82) and those without ARF (3.50 ± 0.90).

The mean serum MDA levels were 0.82 ± 0.43 μmol/L, 2.97 ± 1.11 μmol/L, and 6.86 ± 2.62 μmol/L, respectively, in healthy controls, patients with uncomplicated FM, and in those with severe FM and ARF. The serum MDA levels were significantly higher in patients with FM when compared with controls (P < 0.01). We did not find any significant difference in the antioxidant levels (serum vitamin A and serum vitamin E) between patients with acute severe FM with ARF and those with FM with­out ARF.

All patients were treated with quinine or artesunate and doxycycline. Patients who had severe thrombocytopenia were given platelet transfusion. Packed red cell transfusion was needed in 11 patients (44%).

Twenty patients (80%) needed hemodialysis (HD) support: This included four patients (57.1%) with non-oliguric ARF and 16 pa­tients (88.8%) with oliguric ARF. Seven pa­tients (28%) had ARDS and all required me­chanical ventilator support.

Out of the 25 patients with severe FM and ARF, 15 (60%) recovered and the remaining 10 patients (40%) died. Among the patients who died, 16% succumbed within 48 hours of admission to the intensive care unit. All pa­tients (7 patients, 28%) with non-oliguric ARF recovered. Of the 15 patients who recovered from the illness, 14 attained normal renal func­tion (mean serum creatinine: 1.0 ± 0.24 mg/dL). One patient who had persistent hypotension during the illness had residual renal dysfunc­tion with serum creatinine of 1.9 mg/dL after follow-up of three months. The average dura­tion of renal failure was 10.53 ± 4.0 days. The APACHE II score was significantly higher in the expired group (19 ± 5.49) when compared with the survivor group (14.4 ± 3.15; P = 0.014). The SOFA score on day one was also significantly higher in the expired group when compared with the patients who survived (16.4 ± 2.4 vs. 11.4 ± 3.0; P < 0.05). The ATN-ISI score was significantly higher in patients who died in comparison with those who recovered (0.8776 ± 0.1323 vs. 0.4419 ± 0.1276; P < 0.05) [Table 1]. Kaplan-Meier survival ana­lysis showed that the survival was low in pa­tients who had delayed hospitalization and longer duration of symptoms. We also ob­served higher occurrence of ARDS and CNS involvement in the patients who expired. All patients (28%) who developed ARDS died. Also, all patients who expired had oliguric ARF.
Table 1: Comparison of the prognostic scoring in patients with acute severe Falciparum malaria between those who expired and the patients who survived.

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   Discussion Top


ARF is a common complication in severe FM in adults as well as in older children. It may occur simultaneously with involvement of other vital organs. [11],[12] In our study, ARF was found along with hepatic dysfunction in 96%, severe thrombocytopenia in 72%, CNS mani­festations in 56%, ARDS in 56%, hypogly-cemia in 20% and hypotension in 12%.

OS is defined as tissue damage resulting from an imbalance between an excessive generation of oxidant compounds and insufficient anti-oxidant defense mechanisms. OS occurs when the formation of reactive oxygen species (ROS) exceeds the body's ability to metabo­lize them. Since ROS are non-specific effector molecules, they can cause damage not only to malarial parasites, but also to "innocent by­standers" like non-parasitized erythrocytes and various parenchymatous organs including kid­ney, liver, and endothelial cells, which is often observed in severe FM. Free iron and hemo­globin released from lysed RBC are powerful pro-oxidants which enhance the oxidative damage. [5],[6],[7]

The serum MDA levels were measured as a marker of OS in our study. Elevated serum bilirubin can interfere with the measurement of serum MDA and a correction factor of 0.008 should be reduced, for every unit rise in serum bilirubin beyond 4 mg/dL. [13] We observed significantly elevated levels of MDA in pa­tients with FM, with and without ARF, in comparison to controls, suggesting increased oxidative stress in these patients (P < 0.05), as observed in other studies. [13],[14] We also found that patients with FM had significantly lower levels of serum vitamins A and E when compared to controls. However, we did not find any significant difference in the anti-oxidant status between patients with severe FM and ARF and those with uncomplicated FM (P > 0.05). The ARF was non-oliguric in seven patients (28%) and oliguric in the remaining 18 pa­tients (72%). HD support was required in 57.1 and 88.8% of patients with non-oliguric and oliguric ARF, respectively. Of the 25 patients with ARF, 60% recovered from the illness and 40% died. All patients with non-oliguric ARF recovered in our study. ARF in malaria has been reported to carry a high mortality of 15- 45%.15,16

ARF in severe FM generally occurs in association with dysfunction of various other vital organs, which could influence the out­come of disease. In our study, ARDS and CNS dysfunction were found to be significantly associated with mortality. In one study, the survival rate was found to be strongly in­fluenced by CNS dysfunction in patients of FM and ARF. [11] In our study, the scores of all the three systems (APACHE II, SOFA, and ATN-ISI) were found to be significantly higher in the expired patient group compared to the survivor group, which is in accordance with other existing reports. [17],[18],[19],[20]

In our study, we found higher level of OS in patients with FM compared to controls. Also, we found significantly higher serum MDA levels in patients with severe FM and ARF when compared to those without ARF. The APACHE II, SOFA, and ATN-ISI scores were significantly higher in patients who died, indi­cating their prognostic value in predicting the outcome.

 
   References Top

1.Park K. Text book of preventive and social medicine. 18 th ed. India: Banarasi Das Bhanot Publishers; 2005;201-11.  Back to cited text no. 1
    
2.White NJ. Malaria. In: Manson's tropical diseases, 21 st ed. Cook GC, Zumla A, eds. Saunders, London: 2003;1205-95.  Back to cited text no. 2
    
3.Eiam-Ong S. Malarial nephropathy. Semin Nephrol 2003;23:21-33.  Back to cited text no. 3
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4.Murthy GL, Sahay RK, Srinivasan VR, Upadhaya AC, Santharam V. Clinical profile of falciparum malaria in a tertiary care hospital. J Indian Med Assoc 2000;98:160-9.  Back to cited text no. 4
    
5.Mishra SK, Das BS. Malaria and Acute kidney injury. Semin Nephrol 2008;28:395-408.  Back to cited text no. 5
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6.Das BS, Nanda NK. Evidence of erythrocyte lipid peroxidation in acute falciparum malaria. Trans Royal Soc Trop Med Hyg 1999;93:58-62.  Back to cited text no. 6
    
7.Eiam-Ong S, Sitprija V. Falciparum malaria and the kidney: A model of inflammation. Am J Kidney Dis 1998;32:361-75.  Back to cited text no. 7
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8.Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A Severity of disease classification system. Crit Care Med 1985;13:818-29.  Back to cited text no. 8
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9.Carbonell N, Biasco M, Ferreres J, et al. Sepsis and SOFA score: related outcome for critically ill renal patients. Clin Nephrol 2004;62:185-92.  Back to cited text no. 9
    
10.Liano F, Gallego A, Pascual J, et al. Prognosis of acute tubular necrosis: an extended pros-pectively contrasted study. Nephron 1993; 63:21-31.  Back to cited text no. 10
    
11.Naqvi R, Ahmad E, Akhtar F, Naqvi A, Rizvi A. Out come in severe acute renal failure asso­ciated with malaria. Nephrol Dial Transplant 2003;18:1820-3.  Back to cited text no. 11
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12.Mehta KS, Halankar AR, Makwana PD, Torane PP, Satija PS, Shaw VB. Severe acute renal failure in malaria. J Postgrad Med 2001; 47:24-6.  Back to cited text no. 12
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13.Nanda R, Misra PK, Das UK, Rout SB, Moha-patra PC, Panda A. Evaluating role of oxi-dative stress in determining the pathogenesis of falciparum malaria induced acute renal failure. Indian J Clin Biochem 2004;19:93-6.  Back to cited text no. 13
    
14.Rath RN, Panigrahy N, Das BK, Das PK. Lipid peroxidation in acute falciparum malaria. Indian J Med Res 1991;93:303-5.  Back to cited text no. 14
    
15.Barsoum RS. Malarial acute renal failure. J Am Soc Nephrol 2000;11:2147-54.  Back to cited text no. 15
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16.Prakash J, Gupta K, 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;11:2414-6.  Back to cited text no. 16
    
17.Parker RA, Himmelfarb J, Rubin NT, Chandran P, Wingard RL, Hakim RM. Prognosis of patients with acute renal failure requiring dialysis: Results of a multi center study. Am J Kidney Dis 1998;32:432-43.  Back to cited text no. 17
    
18.Ahistrom A, Kuitunen A, Peltonen S, et al. Comparison of 2 acute renal failure severity scores to general scoring systems in the critically ill. Am J Kidney Dis 2006;48:262-8.  Back to cited text no. 18
    
19.Abosaif NY, Tolba YA, Heap M, Sussell J, EL Nahas AM. Outcome of acute renal failure in the intensive care unit according to RIFLE: Model application, sensitivity and predicta­bility. Am J Kidney Dis 2005;46:1038-48.  Back to cited text no. 19
    
20.Liano F, Junco E, Pascual J, Madero R, Verda E; the Madrid acute renal failure group. Spectrum of acute renal failure in intensive care unit compared with that seen in other settings. Kidney Int 1998;53:s16-24.  Back to cited text no. 20
    

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Correspondence Address:
V Siva Kumar
Department of Nephrology, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati 517507, Andhra Pradesh
India
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PMID: 22382222

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