Outcome in severe acute renal failure associated with malaria

Rubina Naqvi, Ejaz Ahmad, Fazal Akhtar, Anwar Naqvi and Adib Rizvi

Sindh Institute of Urology and Transplantation, Dow Medical College and Civil Hospital, Karachi, Pakistan

Correspondence and offprint requests to: Dr Rubina Naqvi, Assistant Professor, Sindh Institute of Urology and Transplantation, Dow Medical College and Civil Hospital, Karachi 74200, Pakistan. Email: rnaqvi{at}super.net.pk



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Malaria, a common health problem in certain parts of the world, has a considerable morbidity and mortality. This study reports its occurrence with a serious complication, acute renal failure (ARF), at a Third World tertiary care centre.

Methods. All registered patients with ARF who had history and clinical findings suggestive of malaria and had malarial parasites on peripheral blood smears were included in this study. The data on their modes of presentation, management and outcome have been analysed.

Results. Between January 1990 and December 1999, a total of 2098 patients with ARF were seen at the centre. Of these, 124 (5.9%) developed ARF due to malaria (falciparum in 121 and vivax in three). The male:female ratio was 4:1 and 84 (68%) patients were oligo- or anuric on presentation. Mean serum creatinine on admission was 9.43 ± 5.39 mg/dl and 99 (79.8%) patients required renal replacement therapy. Of the cohort, 32 (25.8%) died, most within 48 h of admission. Age, oliguria, central nervous system involvement and presence of disseminated intravascular coagulopathy emerged as bad prognostic factors in simple univariate analysis. Of the survivors, 77 (62%) had complete recovery of renal function, while 15 (12%) were progressing towards recovery when lost to follow-up. The number of dialysis sessions did not differ significantly between the oliguric and non-oliguric groups.

Conclusions. In patients who do not succumb early to ARF of severe malaria, treatment with antimalarials and dialysis brings about recovery of renal function.

Keywords: acute renal failure; falciparum malaria; malaria



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Malaria is endemic throughout South and South-East Asia, South America and Africa. It accounts for 1 000 000–3 000 000 deaths per year in those areas [1]. Clinically significant renal involvement is associated with infections by Plasmodium falciparum and P.malariae. The latter can cause an immune complex-mediated glomerular disease, leading to nephrotic syndrome. Infection with P.falciparum produces only acute manifestations, ranging from asymptomatic urinary abnormalities and mild electrolyte disturbances to acute renal failure (ARF) requiring dialysis support. ARF occurs in 1–5% [2,3] of cases of falciparum malaria, whose contribution to the total of admissions with ARF depends to a large extent on the prevalence of disease, referral pattern and other aetiological factors present in that area. Renal failure is multifactorial and carries a high mortality, especially in late referrals or if renal replacement therapy is not available. We have tried to analyse the risk factors associated with outcome in a large cohort of patients referred to us with established and fairly advanced malarial ARF, the majority of whom required dialysis.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The study was carried out at the Sindh Institute of Urology and Transplantation in Karachi, Pakistan. This centre serves as a tertiary referral centre for the southern portion of Pakistan.

All cases referred to the Institute during the 10 year period between January 1990 and December 1999 were reviewed. Those suffering from malarial ARF were selected for further study on the basis of the following criteria: (i) acute febrile illness compatible with malaria and demonstration of malarial parasites in blood smears; (ii) documented serial rise in creatinine or improvement in renal function after antimalarial treatment; (iii) normal-sized kidneys on ultrasound; and (iv) absence of any other condition leading to ARF.

The study includes patients diagnosed and treated primarily at the Institute as well as patients already diagnosed before presentation who had received partial or complete treatment with antimalarials before referral to us for the management of ARF. Serum creatinine >2 mg/dl was taken to be indicative of renal failure.

Cerebral involvement in malaria commonly manifests as drowsiness progressing into coma. These features may also be present in advanced uraemia. Due to difficulty in segregating the relative contribution of these two factors to central nervous system (CNS) symptoms in malarial ARF, CNS depression alone was selected as a marker of poor prognosis in the context of the present study.

Peripheral blood smears stained with Giemsa were available for all patients. Quantification of parasitaemia, however, was not available for all patients and, therefore, it was not considered during data analysis.

Complete blood count was performed on a Coulter machine (Coulter Electronics). Blood urea, creatinine and electrolytes were all analysed on a Hitachi 407 autoanalyser. Liver function tests were performed whenever jaundice was present or haemolysis was suspected. Prothrombin time, partial activated thromboplastin time and D-dimer were analysed based on clinical suspicions of coagulopathy. Lactate dehydrogenase (LDH) and reticulocyte count were requested if haemolysis was suspected to be a cause of severe anaemia. Patients who had documented haemolysis and who later were found to be deficient in glucose-6-phosphate dehydrogenase (G6PD) were excluded from this study. Urine, when available, was examined by dipstick (Selfstik; Chungdo Pharmaceutical Co., Korea) and microscopy of centrifuged sediments.

Patients who were afebrile on presentation, had received antimalarials elsewhere and had fresh Giemsa stains negative for parasitaemia did not receive additional antimalarials.

One-hundred patients were treated with quinine sulphate for 7 days, while 20 patients, in the early part of study, and those initially managed outside, received chloroquine or Fansidar (sulphamethoxazole + pyrimethamine). Halofantrine was briefly used in the later part of study in four patients.

Renal replacement therapy in the form of haemodialysis was performed if clinically indicated. Broadly, those so treated were patients with advanced uraemia, acidosis, hyperkalaemia, fluid overload and rising creatinine with or without oliguria. Double-lumen catheters inserted into the subclavian, internal jugular or femoral veins were used as vascular access. Cellulose membranes were used for dialysis and the frequency and duration of dialysis were adjusted according to clinical or biochemical parameters.

Statistical analysis
To assess factors adversely affecting outcome, patients were divided into those who survived and those who expired during the course of their illness. Age, oligo- or anuria, jaundice and CNS involvement were chosen as clinical variables while serum creatinine, urea, haemoglobin, platelets, LDH, hyponatraemia and coagulopathy were chosen as laboratory parameters to compare the two groups in univariate analysis.

A multiple logistic regression model was constructed to process data by both forwards and backwards selection using software package SPSS. A P-value of <0.05 was taken as significant for all statistical analyses.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Of a total of 2098 patients with ARF seen between January 1990 and December 1999, 124 had renal failure due to malaria. Plasmodium falciparum was responsible for 121. The remaining three had P.vivax on peripheral blood smears.

There were 99 males and 25 females with a mean age of 33.5 ± 17.2 years (range: 5–75 years). Their presenting clinical features are shown in Table 1. All were febrile and a majority had oligo- or anuria; jaundice was detected in 62 (50%) patients on presentation. CNS involvement of varying severity, ranging from depressed sensorium to frank coma, was present in 50 patients. Laboratory parameters are shown in Tables 2 and 3. Moderate reduction in haemoglobin was common. Thrombocytopenia, a platelet count <150 000/mm3, was present in 87 patients. Serum LDH was tested in 39 patients and in 31 it was >500 IU/l. The hyperbilirubinaemia of almost all icteric patients was of the conjugated variety. They had significant elevations in serum alkaline phosphatase. Increases in transaminases to more than double the normal were seen less frequently.


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Table 1. Presenting and clinical features of malarial ARF

 

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Table 2. Laboratory features in patients with malarial ARF

 

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Table 3. Laboratory features in patients with malarial ARF

 
Markedly elevated levels of urea and creatinine, partly due to late referral, were common (mean values: 323.5 ± 123 and 9.4 ± 5.3 mg/dl, respectively). All patients who were able to provide urine sample had urinalysis. Microscopic haematuria was present in 53 patients and dipstick-positive proteinuria was seen in 42.

Of the patients in ARF, 99 (79.8%) required renal replacement therapy (only haemodialysis). On average, six haemodialysis sessions were performed, with a per patient minimum of two to a maximum of 21 sessions. The remaining patients were managed without dialysis.

Of the total, 77 (62%) patients had complete renal recovery, 15 (12%) were lost to follow-up (after discontinuation of dialysis, in a state of partial recovery) and 32 (26%) died. Most of the deaths (78%) occurred within the first 48 h of admission. Among the 92 patients who survived, 56 (61%) were oliguric, but the proportion of dialysed patients did not differ much between the oligurics and non-oligurics (82 and 80%, respectively). Similarly, the number of dialysis sessions required was not significantly different between oliguric and non-oliguric patients, with oliguric patients requiring a median of 4.46 dialysis sessions and non-oliguric requiring 3.5 sessions.

There were no deaths among the 21 patients whose biochemical derangements were not severe enough to require dialysis. The median value of serum creatinine on presentation was 6 mg/dl in this group in comparison with the median value of 9 mg/dl in those who required dialysis.

Tables 4 and 5 compare parameters between patients who survived and those who expired. The severity of renal impairment, as judged by serum creatinine, did not differ significantly between the two groups. Older age, oliguria or anuria, CNS involvement and disseminated intravascular coagulopathy (DIC) were significantly associated with poor outcome on univariate analysis. On logistic regression, only CNS involvement and DIC emerged as factors influencing survival significantly.


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Table 4. Indicators of mortality in malarial ARF

 

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Table 5. Indicators of mortality in malarial ARF

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
ARF is a serious complication of malaria, carrying a high reported mortality of 15–45% [4]. The contribution of malaria to the number of cases of ARF in any particular setting depends to a large extent on the local prevalence of malaria and on the pattern of referral to a specialized centre. In this respect, the results of our study, 6% of ARF due to malaria, is close to the 4.8% found in a recent single-centre study in India with similar malarial transmission rates [3].

Patients with oliguric renal failure were more common in our series, which is different from the rather high 50–70% proportion of non-oliguric renal failure found in other studies. This may simply reflect higher referrals of patients with decreasing output to a tertiary care dialysis facility. ARF in falciparum malaria is multifactorial. Ischaemic acute tubular necrosis (ATN) is by far the most common pathology resulting from hypovolaemia, peripheral pooling of blood, blockage of microcirculation by parasitized red blood cells and non-specific effects of infection. Massive intravascular haemolysis itself is uncommon and confined to patients with G6PD deficiency or those receiving a combination of treatments [46]. Although the present study did not undertake to analyse the factors predisposing to ARF, evidence of intravascular haemolysis, in the form of brown or red urine, unconjugated bilirubinaemia and highly elevated LDH with reticulocytosis, was distinctly uncommon. The exclusion of patients from this study who later were found G6PD deficient may well have been one reason for this finding, but there were only two such patients.

Almost all patients with jaundice had conjugated hyperbilirubinaemia with cholestasis. This association with malarial ARF is well described and may contribute to the reduction of GFR or development of ATN [4].

In developing countries, limited medical resources at primary health care centres and late referrals compound outcomes. This is reflected in the need for immediate dialysis at presentation of 80% of patients referred to our centre; slightly higher than in other reports, which show a need of dialysis in only 60% of patients with malarial ARF [5,7]. Availability of renal replacement therapy for malarial ARF has been shown to improve outcome [8]. In our present study, mortality was 25.9%, which is in agreement with other studies where renal replacement therapy was available.

Factors associated with high mortality have been analysed previously in African children with falciparum malaria (none of whom had renal impairment) and impaired consciousness was a strong risk factor for death [9]. In the present study of patients with renal failure, CNS involvement was a strong risk factor for mortality, though it is difficult to be certain about the cerebral effect of malaria in patients with advanced uraemia. We could not study the effect of the degree of parasitaemia on mortality, lacking quantity data on most of the patients.

It is interesting to note that there were no deaths among patients who did not require dialysis and were managed conservatively, suggesting either a less severe generalized disease or an independent effect of the severity of renal failure per se on outcome. In those who survived, recovery of renal function was quick; dialysis-free status was achieved in the group as a whole after a median of four dialysis sessions. Non-oliguric patients required fewer dialysis sessions, but this was not statistically significant.

The prevention of malarial infection and early diagnosis are the only measures likely to decrease malarial ARF in developing countries. Early referral to centres equipped to provide renal replacement therapy, if necessary, along with antimalarial therapy and support, could further reduce mortality and enhance recovery of renal function. In this particular situation, dialysis is needed for only a brief period.



   Acknowledgments
 
We are indebted to Mr Amir Umair, Mr Aijaz Alam and Ms Sakina Yousuf for assistance in statistical analysis and to Mr Imran Sultan for correction of typographical errors.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Breman JG, White NJ. Malaria and Babesiosis. In: Isselbacher KJ, Eugene B, Wilson JD, eds. Harrison's Principles of Internal Medicine, 13th edn. McGraw-Hill, New York, 1994; 887–896
  2. Sheehy TW, Reba RC. Complications of falciparum malaria and their treatment. Ann Int Med 1967; 66: 807–809[ISI][Medline]
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  4. Barsoum RS. Malarial acute renal failure. J Am Soc Nephrol 2000; 11: 2147–2154[Free Full Text]
  5. Sitprija V. Nephropathy in falciparum malaria. Kidney Int 1988; 34: 867–877[ISI][Medline]
  6. Barsoum RS. Malarial nephropathies. Nephrol Dial Transplant 1998; 38: 1588–1597
  7. Stone WJ, Hanchett JE, Knepshield JH. Acute renal insufficiency due to falciparum malaria. Review of 42 cases. Arch Intern Med 1972; 129: 620–628[CrossRef][ISI][Medline]
  8. Trang TT, Phu NH, Vinh H et al. Acute renal failure in patients with falciparum malaria. Clin Infect Dis 1992; 15: 874–880[ISI][Medline]
  9. Marsh K, Forster D, Waruiru C et al. Indicators of life threatening malaria in African children. N Engl J Med 1995; 332: 1399–1404[Abstract/Free Full Text]
Received for publication: 5. 4.02
Accepted in revised form: 12. 3.03





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