RENAL DATA FROM ASIA - AFRICA
|Year : 2014 | Volume
| Issue : 6 | Page : 1352-1358
|Black water fever associated with acute renal failure among Congolese children in Kinshasa
Joseph M Bodi1, Célestin N Nsibu1, Michel N Aloni2, Guy N Lukute1, Thomas S Kunuanuna2, Pierre M Tshibassu3, Nestor Pakasa4
1 Pediatrics Emergency and Intensive Care Unit, University of Kinshasa, Democratic Republic of Congo
2 Pediatrics Nephrology Unit, University of Kinshasa, Democratic Republic of Congo
3 Pediatric Gastroenterology Unit, Department of Pediatrics, University of Kinshasa, Democratic Republic of Congo
4 Anatomopathology Unit, Department of Medical Biology, University of Kinshasa, Democratic Republic of Congo
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|Date of Web Publication||10-Nov-2014|
| Abstract|| |
Acute renal failure (ARF) is reported in some severe forms of malaria such as black water fever (BWF). It is associated with a high mortality rate and can be managed effectively with adequate renal replacement. A prospective survey of children with dark urine after a malarial infection with Plasmodium falciparum was coupled with a chart review study of patients managed in the past 11 years in the Pediatrics' Kinshasa University Hospital. Eighty-nine cases of ARF were identified, but data from only 63 patients were available, of whom 44 (69.8%) had severe malaria (39 with BWF and 5 with cerebral malaria). The mean age of the patients was 8.2 ± 1.73 years. Of the 39 cases of BWF, an association with quinine ingestion was observed in 32 children (82%). Urea and creatinine levels were elevated in all cases (135.4 ± 88.2 and 3.83 ± 2.81 mg/dL, respectively). Oligo-anuria was observed in 44.4%, severe metabolic acidosis (bicarbonate <15 mEq/L) in 61.5% and hyponatremia (<130 mEq/L) in 33.3%. Peritoneal dialysis was required in 36 patients, including 20 with BWF. The remaining patients were managed with conservative treatment. Twenty-eight children (44.4%), including 20 on dialysis, fully recovered and 14 died (22.2%), including eight cases of BWF. Our study suggests that ARF is commonly associated with BWF in Congolese children. Elevated urea and creatinine and severe metabolic acidosis were observed more often than other clinical/metabolic disturbances. Severe renal impairment remains a significant complication with a high mortality rate in low-resource settings.
|How to cite this article:|
Bodi JM, Nsibu CN, Aloni MN, Lukute GN, Kunuanuna TS, Tshibassu PM, Pakasa N. Black water fever associated with acute renal failure among Congolese children in Kinshasa. Saudi J Kidney Dis Transpl 2014;25:1352-8
|How to cite this URL:|
Bodi JM, Nsibu CN, Aloni MN, Lukute GN, Kunuanuna TS, Tshibassu PM, Pakasa N. Black water fever associated with acute renal failure among Congolese children in Kinshasa. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2017 Nov 17];25:1352-8. Available from: http://www.sjkdt.org/text.asp?2014/25/6/1352/144326
| Introduction|| |
Black water fever (BWF) is one of the severe forms of malaria described among non-immune expatriates who have lived for a long time in malaria endemic countries and has been reportedly related to the inappropriate prophylactic use of quinine. ,,, The local native population seem to be protected, but many cases have been described, particularly in children older than five years, since the change of the anti-malarial policy in Africa promoting the use of quinine due to the increasing resistance of Plasmodium falciparum to other anti-malarial drugs. ,,,,,,, This severe form of malaria can result in acute renal failure (ARF), which seems extremely rare in children but common in adults, and which is associated with a high mortality if incorrectly managed. ,,,,,,
Falciparum malaria is complicated by ARF in less than 1-4.8% of native patients in endemic areas. , The ARF has the clinical and biochemical features of acute tubular necrosis (ATN) and is associated with liver dysfunction. , Oligo-anuria, hyper-catabolism, jaundice, anemia, thrombocytopenia and reduction of peripheral vascular resistance have all been reported. Proteinuria and hyponatremia are common and, when hyperkalemia is present, it can be fatal. Most patients die from complications related to renal failure, and the recovery of renal function does not appear to be correlated with hemoglobinuria or parasitemia.
Resurgence of BWF is observed in many parts of the world such as Africa, Asia and Europe. ,,, Most studies have reported the occurrence of ARF in association with BWF in adults. In Kinshasa, according to studies conducted in the last 10 years, majority of the patients were children aged more than six-years, who are supposed to have acquired immunity to malaria.
The aim of this study was to evaluate the renal function of children with BWF due to severe falciparum malaria in an endemic area, Kinshasa (DRC), during the last decade.
| Methods|| |
This descriptive study was conducted at the Intensive Care and Nephrology Units of the Pediatrics' University Hospital of Kinshasa, a large tertiary referral hospital in the capital city of the Democratic Republic of Congo (DRC). This area is endemic for severe forms of malaria, predominantly seen in children younger than five years.  A retrospective chart review study focused on a 10-year period (January 1994 to December 2003) and was coupled to a prospective selection of patients with ARF (January 2004 to December 2007) admitted in these two units.
BWF was defined as the presence of hemoglobin in the urine in a febrile jaundiced patient with anemia, Plasmodium falciparum malaria and acute intravascular hemolysis. Children with hemoglobinopathy (sickle cell trait) and glucose-6-phosphate-dehydrogenase (G6PD) deficiency were excluded. Other potential causes of hemoglobinuria such as viral infections, leptospirosis and toxic agents were not screened. ARF was defined as impaired renal function with creatinine clearance <50 mL/min/1.73 m² with or without oligo-anuria <0.5 mL/kg/h. 
The study included patients with renal failure diagnosed and treated primarily at the pediatrics department of the University Hospital of Kinshasa as well as patients already diagnosed before admission who had received partial or complete anti-malarial treatment or antibiotics before referral to the Intensive Care Unit for the management of ARF. Children younger than 14 years with hemoglobinuria, fever, jaundice, anemia with positive Plasmodium falciparum documented on thin blood film and impaired renal function were included in the study. Parents' or guardians' consent was obtained before each inclusion.
Thick and thin blood smear preparations for detection of malaria parasite were performed using Giemsa staining. The activity of G6PD was evaluated by a spectrophotometer and sickle cell trait was excluded using the acetate cellulose method for hemoglobin electrophoresis (Chemetron, Belgium). Hemoglobin measurement was made using the spectrophotometer method. Dipstick reagent strips were used for rapid determination of hemoglobin in the dark brown colored urine (Cypress Diagnostics-Belgium). We performed Coomb's anti-globulin test to evaluate the possible presence of quinine-dependent antibodies using the agglutination method. Serum creatinine, urea and electrolytes were determined by a semi-automated analyzer (CYAN plus, Belgium); acid-base balance status was evaluated by a titrimetric method (Van SLYKE).
Patients with ARF were managed according to the published World Health Organization guidelines.  They received dextrose fluid 5% with electrolytes in case of dehydration and diuretics if they were oligo-anuric. Quinine was stopped and replaced with parenteral derivate of artemisin.
The results from the collected data were recorded in a computerized database (Microsoft Excel) and then analyzed using SPSS 6.0. Age, oligo- or anuria, jaundice, referral time and drugs received before the occurrence of BWF were considered as clinical variables while serum creatinine, urea, hemoglobin, hyponatremia and base excess were the laboratory parameters assessed to compare the outcome of the ARF cases (survivors and non-survivors) in univariate analysis. A P-value <0.05 was considered significant for all statistical analyses.
| Results|| |
Of the 89 patients with ARF studied from January 1994 to December 2007, complete data were available for 63 children; 39 of them had BWF (61.9%), six patients (9.5%) had sepsis and five had cerebral malaria (7.9%) [Table 1].
|Table 1: Different causes of acute renal failure during the study period.|
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Plasmodium falciparum was the cause of all cases of BWF; there was associated documentation of quinine ingestion in 32 children (82%). There were 20 male and 19 female (sex-ratio: 1.0) patients, with a mean age of 8.2 ± 1.73 years (range: 3.5-13.5 years). Thirty-six of the 39 cases of ARF (85.7%) associated with BWF had severely impaired renal function (clearance creatinine <50 mL/min/1.73 m² associated with oligo-anuria <0.5 mL/kg/h).
The clinical features of the 63 cases with ARF and the 39 patients with BWF are shown in [Table 2] and [Table 3], respectively. Fifty-one patients were febrile (80.9%) and jaundice was detected in 54 children (85.7%). Twenty-eight patients with ARF (71.7%) were referred to the Intensive Care Unit of the University Hospital of Kinshasa after 72 h of the onset of malaria.
|Table 2: Presenting clinical features of children with acute renal failure.|
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|Table 3: Presenting and clinical features of children with acute renal failure associated with black water fever.|
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Laboratory parameters are shown in [Table 4]. Severe reduction in hemoglobin (<5 g/dL) was observed in 37 patients and 42 children (66.6%) had an increased white cell count (>22,000/ mm³). Thrombocytopenia with a platelet count <150,000/mm 3 was present in 13 patients. The hyper-bilirubinemia of the icteric patients was of the non-conjugated variety. The Coombs anti-globulin test was positive in three of 14 patients tested.
We observed a significant rise in serum alkaline phosphate levels; markedly elevated levels of urea and creatinine were also noted (mean values: 135.4 ± 88.2 and 3.83 ± 2.81 mg/dL, respectively).
Among the 36 patients with severe ARF associated with BWF, 20 (55.5%) received renal replacement therapy and the remaining patients were managed conservatively due to financial constraints. The median value of serum creatinine at admission was 3.38 mg/dL in patients treated conservatively in comparison with the median value of 5.4 mg/dL in those who received dialysis. Four patients with ARF and cerebral malaria (9.5%) had severe hyperkalemia (K 6.5 mEq/L), 24/42 (57.1%) had severe metabolic acidosis (<15 mEq/L) and 13/42 (30.9%) had dilutional hyponatremia (Na <130 mEq/L). An average of three peritoneal dialysis sessions was carried out in the study patients (range, two to five sessions). Among the 36 cases with severe ARF, 28 patients (77.7%) had complete renal recovery and eight died (22.2%). Most of the deaths (n = 6) occurred within the first 72 h of admission. There were no deaths among the patients whose biochemical changes were not severe enough to require dialysis and there was no death among ARF patients associated with cerebral malaria. Six patients who presented with sepsis, acute glomerulonephritis and hemolytic uremic syndrome died. [Table 5] illustrates between survivors and non-survivors with BWF.
|Table 5: Differences in key laboratory values between survivors and non-survivors with black water fever.|
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| Discussion|| |
BWF has rarely been encountered since 1950 when quinine was replaced by chloroquine in the treatment of malaria. The re-emergence of BWF occurred after 1990, when use of chloroquine was discontinued in the treatment of malaria because of increased resistance of Plasmodium falciparum to this drug.
Many published reports have incriminated the irregular use of quinine in the pathogenesis of BWF. ,,, There is evidence that repetitive use of quinine in the prophylaxis of malaria is more likely to precipitate BWF than use of any other synthetic anti-malarial drugs because of the direct effect of quinine on the abnormal erythrocytes.
Immunologic as well as non-immunologic mechanisms could explain damage to the red blood cells (RBCs) during severe malaria, leading to acute massive intravascular hemolysis. In the immunologic mechanism, antibodies directed against the RBCs require presence of the compound to interact. The degree of hemolysis depends on the affinity of the antibodies binding to the RBC (quantity, specificity, temperature range, ability to fix tissue and macrophages) as well as those of the target antigen (density, expression and the patient age). Intravascular hemolysis occurs when IgM antibodies activate the classical complement pathway leading to cell lysis. 
The mean age of our patients was 8.2 ± 1.73 years. Previous studies from this part of the world proposed that full immunity to malaria is reached at around seven to eight years of age. Hence, those children are protected and severe malaria is less common. , Jelliffe in Nigeria reported that BWF was three times more prevalent among children than in adults, a finding indicating an absence of immunity.  BWF in patients with a sufficient level of acquired immunity should raise a differential diagnosis with other etiologies of hemolysis and dark urine.
ARF can occur in the setting of severe malaria. Its incidence and prevalence in African children is not well known. ,,,, In areas of intense malarial transmission from Sub-Saharan Africa, the incidence of ARF appears to be very low in younger children worst affected by malaria. ,, In contrast, in semi-immune patients, especially older children such as those included in our study, cases of ARF have been reported. ,,,,, However, in that study, malaria was not considered to be the primary etiology of the renal disturbance, in contrast to our report. ,,
When associated with BWF, renal dysfunction probably occurs due to massive intra-vascular hemolysis and sudden onset of hypovolemia. Marked decrease of hemoglobin and high levels of unconjugated bilirubin are also indicators suggesting the onset of massive hemolysis. As the precise mechanism of ARF in falciparum malaria is not known, several mechanisms have been proposed, including the effect of plasmodium RBC (pRBC) in the microcirculation, the release of chemical mediators and the increase of plasma viscosity. The pathology of renal involvement is variable; in mild cases, mild tubular degeneration can be observed. In severe cases, however, tubular epithelial injury is present with distal tubular necrosis. ,,,
The ARF in BWF has been reported to have a high mortality rate of 15-45%, especially in late referrals or if renal replacement therapy is not available. In our study, 66% of patients with BWF had impaired renal function. The exact incidence of this entity is not well documented in African children and different figures have been reported in these endemic areas. ,,,,
Once BWF is documented, correction of imbalance of fluids and electrolytes becomes imperative because dehydration results in a rapid onset of renal failure. Ischemic ATN is by far the most common feature resulting from hypovolemia, peripheral pooling of blood and the blockage of microcirculation by the parasitized RBCs. This association with malarial ARF is well described and may contribute to ATN. ,,, Patients with oligo-anuric renal failure were common in our study, similar to the high proportion also reported in other series. ,
The use of renal replacement therapy for malarial ARF has been shown to improve the outcome.  In our series, the mortality rate was 22.2%, which is in agreement with previous studies where renal replacement therapy was available. Only peritoneal dialysis was used in this study, rather than hemodialysis, which has been reported as being more efficient. No death was reported among patients who did not require dialysis and were conservatively treated, suggesting either a less-severe systemic disease or an independent effect of the severity of renal impairment. In patients who survived, the recovery of the renal function was quick and complete. Many studies have reported that limited medical resources at primary health-care centers and late referrals worsen the outcome. The need for immediate dialysis at presentation in our series was slightly lower (55%) than in other series, which documented the need for dialysis in 60- 80% of patients with malarial ARF. ,,, Thus, transfer of the patient to a well-equipped center is an urgent option.
Factors associated with high mortality have been previously analyzed in African children with severe falciparum malaria. A strong association was found between ARF and impaired consciousness. ,,,, In the present study, only the standard base deficit was statistically different between survivors and non-survivors. Prevention of malaria, early diagnosis and prompt and efficient treatment are the only measures likely to decrease the incidence of BWF and malarial ARF in developing countries. Early referral to well-equipped centers to provide renal replacement therapy is required and effective therapy and support can reduce the mortality and enhance the recovery of renal function.
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Joseph M Bodi
Pediatrics Emergency and Intensive Care Unit, Department of Pediatrics, University of Kinshasa
Democratic Republic of Congo
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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