| Abstract|| |
Background: Malaria has protean clinical manifestations and acute kidney injury (AKI) is one of its serious and life threatening complications. This study was carried out to describe the clinical characteristics, and factors associated with adverse outcomes, in patients with malarial AKI. Materials and Methods: Data of 100 patients with AKI and smear positive malaria was retrospectively analyzed to evaluate the incidence, clinical profile, outcome and predictors of mortality among all cases presented to us at the Nephrology unit of Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh between November 2010 to October 2011. Results were expressed as mean, standard deviation (SD) and range. Results: One hundred (22.1%) (68 males, 32 females) cases of malaria induced AKI, amongst 452 total cases of AKI, were evaluated. The mean age (± SD) was 30 ± 11.23 years. Male to female ratio was 3.3:1. Plasmodium falciparum was reported in 76%, P. vivax in 11%, and both in 13% patients. The mean serum creatinine was 8.7 ± 3.7 mg%, and oligo/anuria was present in 84% of the patients. 78% of the patients required hemodialysis. 67% of the patients recovered completely, 12% did not show full recovery, and 6% developed chronic kidney failure. Mortality occurred in 15% of the patients. Conclusion : Malarial AKI most commonly occurs in patients infected by Plasmodium Falciparum. Falciparum malaria associated with AKI is a life threatening condition. Prolonged disease duration, low hemoglobin, oligo/anuria on admission, hyperbilirubinemia, cerebral malaria, disseminated intravascular coagulation, and high serum creatinine were the main predictors of mortality in our study.
Keywords: Acute kidney injury, falciparum malaria, mortality
|How to cite this article:|
Khan R, Quaiser S, Haque SF. Malarial acute kidney injury: Prognostic markers. Ann Trop Med Public Health 2013;6:280-4
| Introduction|| |
Malaria is a major public health concern in the tropical countries. According to the World Malaria Report 2010, there were 225 million cases of malaria and an estimated 781 000 deaths worldwide in 2009.  Almost all complications and deaths from malaria are caused due to Plasmodium Falciparum.  Recently there is a changing trend not only in the clinical manifestations but also the pattern of complications in malaria. Over a decade ago, cerebral malaria was the predominant manifestation of severe malaria, whereas today the combination of jaundice and renal failure is more common.  Acute kidney injury (AKI) is one of the most dreaded complications of severe malaria.  The overall prevalence of AKI in falciparum malaria varies between <1 and 60%, with the mortality rate as high as 45%. , AKI occurs commonly in Plasmodium Falciparum malaria, and rarely in malaria caused by Plasmodium Vivax. ,, The management of malaria-induced AKI includes the use of appropriate antimalarials (parenteral artesunate or quinine), fluid electrolyte management, adequate supportive therapy, avoidance of nephrotoxic drugs, and renal replacement therapy (RRT) at the earliest. , Haemodialysis (HD) is effective for malaria-associated AKI. , This retrospective study was conducted to describe the clinical characteristics, laboratory parameters, predictors of mortality and outcome in patients with malarial AKI.
| Materials and Methods|| |
A retrospective study of 452 AKI patients admitted to nephrology unit was undertaken in our hospital from November 2003 to October 2011. Hundred patients having AKI with peripheral smear displaying malarial parasites were selected. Clinical history and assessment was recorded in all the study patients, and all other known etiological causes of fever and jaundice were excluded by relevant investigations. All the patients were subjected to complete hemogram with reticulocyte counts. Thick and thin peripheral smear examination using Geimsa stain was carried out for the type and grading of parasitemia. Urine samples were examined for routine and microscopy examination. Serum was tested for sodium, potassium, alkaline phosphatase, alanine aminotransaminase (ALT), bilirubin, lactic acid dehydrogenase and glucose 6-phosphate dehydrogenase. Serological tests for Human Immunodeficiency Virus (HIV) and hepatitis B and C were performed. Estimation of blood sugar, coagulation profile for disseminated intravascular coagulation (DIC), cerebrospinal fluid examination, blood cultures and arterial blood gas analysis were carried out when indicated. Chest radiographs and ultrasonography (USG) of abdomen were recorded in all the patients. AKI was defined as serum creatinine (SCr) of ± 3 mg%, and urine output <400 mL/day, with normal kidney size on USG, as per the definition by the World Health Organization (WHO). 
| Results|| |
A total of 100 (22.12%) (68 males, 32 females) patients with malaria induced AKI (amongst 452 AKI patients) were included in the study. The mean age (± SD) was 30 ± 11.23 years. P. falciparum was reported in 76% patients, P. vivax in 11%, and mixed infection was reported in 13% of the cases. The clinical findings included fever (97%), nausea-vomiting (89%), oligo/anuria (84%), abdominal pain/tenderness (46%), jaundice (61%), altered sensorium (36%), diarrhea (11%), splenomegaly (62%) and hepatomegaly (57%), as shown in [Table 1]. The mean duration of illness was 6.07 ± 2.33 (range 3-15) days.
|Table 1: Clinical findings among 100 malarial Acute Kidney Injury patients as seen in the study|
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The mean bilirubin level was 09.22 ± 6.52 mg/dl (range 0.63-31 mg/dl), and it was predominantly of the the conjugated variety. Serum transaminases were not significantly raised when compared to serum bilirubin. Serum alanine aminotransferase (ALT) <132 IU/L and serum aspartate aminotransferase (AST) at levels <310 IU/L was noted in all patients. The mean levels of urea and creatinine on admission were 268.5 ± 79.31 mg/dl and 8.73 ± 3.22 mg/dl, respectively. Positive correlation was found between duration of illness and impairment of renal function. Only 05 (5%) patients had blood sugar <55 mg/dl. Compared with patients with short duration of illness (<7 days), those with prolonged duration (>7 days) were more likely to have higher degree of derangement of urea and creatinine, (P = 0.001). Only 04 (4%) of our patients showed serum potassium >5 mEq/L. Urine examination showed presence of granular cast in 11 (%), proteinuria (++) in 19 (%), and microscopic haematuria in 14 (%) patients. Over all, haemodialysis treatment was performed in 78 (78%) of the patients. The remaining 22 (22%) patients were treated conservatively. Among 78 patients requiring the haemodialysis, 62 (62%) were oliguric and 16 (16%) non-oliguric.
Compared with nonoliguric subjects, the oliguric patients had higher need of dialysis (P = 0.001). The average number of dialysis sessions required per patient was 05, with a minimum of 03 to a maximum of 12. The oliguric patients also needed more haemodialysis sessions than the non-oliguric patients (mean SD = 6 ± 3.4 versus 2.3 ± 1.1 haemodialysis treatment, respectively), (P = 0.04). Twenty two (22%) patients were treated conservatively, where the biochemical parameters were not severe enough to require dialysis. In this group, the mean value of serum creatinine on presentation was 4.32 ± 1.51 mg/dl (range 3.4-6.8), as compared with the mean value of 8.39 ± 3.62 mg/dl (range 4-17 mg/dl) in patients requiring dialysis (P = 0.001). In survivors, the course of illness lasted 4-26 days depending upon the severity of AKI. The time taken for serum creatinine level to return to within the normal range was 11.76 ± 6.40 days in the oliguric patients, and 8.45 ± 4.17 days in non-oliguric (P = 0.021). Fifteen (15%) of total 100 malarial AKI patients succumbed to the disease while 67 (67%) had complete recovery. [Table 2] and [Table 3] compare the parameters between patients who survived and those who expired. Death occurred at a mean time of 1.92 ± 0.63 days (range 1-2 days) after admission. All deaths were in the dialysis group. Serum creatinine (mean ± SD) value was significantly higher in patient who died (12.93 ± 4.74 mg/dl), compared to those who survived (7.41 ± 2.88) (P = 0.001). Eight of the patients who died were suffering from jaundice, and 11 of them had cerebral malaria. Presence of jaundice was not predicted as a marker of mortality. Instead, it was the severity of hyperbilirubinaemia which appeared as a risk factor and was associated with adverse outcomes [Table 2] (P = 0.001). Patients who were oliguric on admission had a significantly higher mortality rate (P = 0.001) [Table 3]. Compared with those without cerebral malaria, patients with cerebral malaria were more likely to die (P = 0.001). When altered sensorium alone was taken as a marker of mortality in malarial AKI, it could not prove itself as a predictor of mortality. Acidosis in combination with AKI increased the risk of dying (P = 0.001). Multiple complications of falciparum malaria were responsible for death in individual patients. Prolonged duration of illness, oliguria on admission, hyprebilirubinaemia, cerebral malaria, DIC, and acidosis were the main causes of mortality in our patients [Table 2] and [Table 3].
|Table 2: Predictors of mortality in malarial Acute Kidney Injury patients in our study|
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|Table 3: Associated complications as predictors of mortality in malarial Acute Kidney Injury patients in our study|
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| Discussion|| |
The incidence of malarial AKI was 22.12% in our study which is comparable to results of other studies conducted in India and Ethiopia. , AKI is a serious and life threatening complication of falciparum malaria, and has been seen commonly in South East Asia.  Our study showed a 15% mortality rate due to malarial AKI, consistent with 15-45% mortality rate reported by other studies.  Several factors including various chemical mediators, catecholamine release, cytoadherence of parasitized erythrocytes, dehydration, intravascular hemolysis, intravascular coagulation, sepsis, hyperbilirubinemia and hyperparasitemia have been implicated in the pathogenesis of AKI in malaria. 
Men were more affected in our study as compared to women, similar to observations of other groups. , This could be explained by the fact that men are more mobile, and move around in the swampy areas more as compared to women, especially in the Asian countries. Also, in these regions, women are more confined to their homes, and being near the cooking fire offers them protection from biting mosquitoes. P. falciparum was observed in 76% of our cases and only 24% had P. vivax or mixed infections, as seen in other studies. , P. falciparum parasitemia is known to be associated with a significantly greater reduction in endogenous creatinine clearance.  AKI in P. falciparum can occur in three ways: Acute Tubular Necrosis (ATN), the commonest presentation, followed by acute tubulo-interstitial nephritis or less commonly acute Glomerulonephritis (GN). ATN may be monitored in 1-4% of P. falciparum malarial Acute Renal Failure (ARF) cases, and may also reach up to 60% in severe malaria. , AKI in falciparum malaria is usually oliguric and hyper-catabolic; the oliguric phase lasting for a few days to several weeks. This was also found in our study.
Hyperbilirubinemia in falciparum malaria possibly predisposes to AKI, which may be revealed only by laboratory investigations.  All patients of AKI and jaundice had conjugated hyperbilirubinemia. This well described association may contribute to the reduction of glomerular filtration rate or development of ATN. , AKI associated with jaundice had high mortality in comparison with AKI patients who did not have jaundice.  Cerebral symptoms were observed in 63.04% of our cases. The severity of these symptoms ranged from impaired consciousness to coma. We used score on Glasgow coma scale (GCS) to assess the severity of these symptoms. High proportion of impaired consciousness in patients with malarial ARF is documented in the past studies. , Surprisingly, significant hyperkalemia was not seen in the present study. Only two patients showed hyperkalemia which was mild and did not require the treatment. The reason for this is not clear.
However, this finding is supported from the study conducted in India in which out of 24 patients with malarial ARF, none showed serum potassium >5 mEq/L.  Anti-malarial therapy was the main stay of treatment of malaria associated with AKI along with the symptomatic and dialysis support. Although peritoneal dialysis has been used in the treatment of malarial AKI, its effectiveness in severe cases is limited because of peritoneal dysfunction and low clearance due to the impaired microcirculation.  For this reason, hemodialysis appears to be beneficial for AKI associated with malaria, particularly when started earlier in the course of illness.  We used only hemodialysis technique in our patients who required dialysis. The need for dialysis was seen in 78% of cases and most of them were oliguria. Greater proportion of patients requiring the haemodialysis in malarial AKI has been documented in the past studies. ,,, In non-oliguric patients, dialysis was also needed for additional removal of waste products since the remaining renal function could not cope with hyper-catabolic state. However, the number of such patients was small and we could not compare the difference in number of dialysis sessions required for the oliguric and nonoliguric. The recovery of renal function was quick in survivors, especially those who were non-oliguric on admission and had less severe renal dysfunction. The serum creatinine levels significantly decreased after three sessions of haemodialysis. In malarial AKI, prognosis depends on the severity of the condition, associated extra-renal complications, and early institution of anti-malarial therapy along with dialysis support. Availability of renal replacement therapy for malarial AKI has been shown to improve the outcome.
In a study performed in Vietnam, mortality in patients with malarial AKI was 75% without dialysis, and 26% when dialysis was available. Moreover, the authors stated that more effective dialysis or ultrafiltration might further reduce the mortality rate.  In our study, mortality was 15%, which is comparable with other studies conducted in areas with similar pattern of malaria transmission and where dialysis support was available, as in our study. ,, Majority (51.2%) deaths in the study patients occurred in the first 24 hours after admission, after dialysis was started. Prolong duration of illness before reaching the dialysis facility unit and severity of AKI probably explained the early deaths in our patients. A nearly similar observation was documented in a study conducted in Thailand, in which 58.3% patients died during the first 24 hours after admission. 
The severity of hyperbilirubinemia significantly predicted the adverse out come in present study. It is documented that total bilirubin level >20 mg/dl is often associated with severe renal failure and adverse out comes.  Peripheral neutrophil leucocytosis has been observed in severe falciparum malaria, even in the absence of detectable bacterial infection, and is associated with poor prognosis. , Thrombocytopenia is a common feature in falciparum and vivax malaria, whether mild or severe, but profound thrombocytopenia is more common in severe falciparum malaria.  Significant leucocytosis and severe thrombocytopenia was seen in fatal cases in this series. But due to the presence of high proportion of DIC in expired group, these both were not considered as independent predictors of mortality in our patients. In present study prolonged duration of illness, oliguria, higher concentration of bilirubin, Severity of AKI (higher urea and creatinine with acidosis), cerebral malaria and DIC were associated with poor prognosis. Most of these findings, as a predictor of mortality in malarial AKI and in complicated falciparum malaria, are consistent with other studies. ,
| Conclusion|| |
Thus, it can be concluded that malaria is an important cause of AKI in Asian countries, and particularly in tropical areas. Malarial AKI most commonly occurs in infections by Plasmodium falciparum. Falciparum malaria associated with AKI is a life threatening condition. Prolonged disease duration, low hemoglobin counts, oligo/anuria on admission, hyperbilirubinemia, cerebral malaria, disseminated intravascular coagulation and high serum creatinine were the main predictors of mortality in our study. Haemodialysis is an effective treatment for malarial AKI. Early referral of malarial AKI patients to dialysis facility unit, and early institution of haemodialysis in complicated falciparum malaria may further reduce mortality and enhance recovery functions.
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Department of Medicine, AMU, Aligarh, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]