Severe acute renal failure in malaria.KS Mehta, AR Halankar, PD Makwana, PP Torane, PS Satija, VB Shah
Department of Nephrology, B.Y.L. Nair Hospital and T.N. Medical College, Mumbai, India. , India
BACKGROUND: We have noticed a recent rise in the incidence and severity of acute renal failure (ARF) in malaria. AIM: To study the incidence, severity and outcome of ARF in malaria. SETTING and DESIGN: It is a retrospective analysis of data of one year from a tertiary medical centre in a metropolitan city. MATERIALS AND METHODS: Patients with ARF and smear positive malaria were evaluated. STATISTICAL ANALYSIS: Results were expressed as mean, range and standard deviation. RESULTS: Out of 402 detected smear positive malaria, 24 had ARF. Eighteen were of the age group 21-40 years. Plasmodium falciparum (PF) was detected in 16, Plasmodium vivax in three, and mixed infection in five. Non-oliguric ARF was seen in 14. Eighteen showed severe ARF (Serum creatinine >5 mg%). Twenty-two patients needed dialysis. Prolonged ARF lasting for 2-6 weeks was seen in eight. Seventeen patients recovered completely, while seven showed fatal combination of disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), severe ARF and PF malaria. No response was seen to chloroquine and artesunate given alone and twenty patients required quinine. CONCLUSION: ARF necessitating dialysis was seen in 92% of patients with ARF in malaria. PF infection, severe ARF, DIC and ARDS were poor prognostic factors. Resistance was noted to both chloroquine and artesunate.
Keywords: Adult, Aged, Aged, 80 and over, Animal, Antimalarials, therapeutic use,Drug Resistance, Multiple, Human, Incidence, India, epidemiology,Kidney Failure, Acute, diagnosis,parasitology,Malaria, complications,diagnosis,drug therapy,epidemiology,Malaria, Falciparum, complications,diagnosis,Malaria, Vivax, complications,diagnosis,Middle Age, Plasmodium falciparum, isolation &purification,Plasmodium vivax, isolation &purification,Quinine, therapeutic use,Retrospective Studies,
Malaria is a major public health problem in tropical developing world. State-wide distribution of malaria cases reveals an incidence of 17.3% in Madhya Pradesh, 14.5% in Maharashtra and 13% in Orissa. Almost the entire population of India (95.9%) is now deemed to be under malaria risk.
Almost parallel to this, an upsurge in the incidence of ARF in malaria has been reported in India and varies from 13% to 17.8%. ARF is usually associated with intravascular haemolysis or heavy parasitaemia. ARF lasts from few days to several weeks and is occasionally non oliguric type. Several factors; including various chemical mediators, catecholamine release, cytoadherence of parasitised erythrocytes and associated haemorrhaeologic changes, intravascular coagulation, intravascular haemolysis, hyperbilirubinaemia and severe hyperpyrexia have been implicated in the pathogenesis of ARF in Malaria. 
We recently noticed a rise in the incidence and severity of ARF in malaria along with multidrug resistance (MDR). This study was conducted with the aim to study the incidence, severity and outcome of ARF in malaria.
It is a retrospective analysis and patients included were consecutive. 6306 cases of fever were evaluated for malaria during 1st January 1999 to 30th November 1999. 402 were detected to be smear positive malaria. Patients with ARF and Peripheral Smear(PS) positive for malarial parasite (MP) were included in the study, while patients with diseases other than malaria which involved liver and kidney simultaneously e.g. leptospirosis, septicaemia, hepatorenal syndrome, vasculitis, etc. were excluded. Details of history and clinical assessments were noted in all.
Blood was obtained by pricking finger. Thick and thin smears were prepared, stained with Giemsa and examined under the microscope. Severity of parasitaemia was assessed as parasitic index (PI) and was expressed as < 2, 2-5 and > 5.
All the patients were subjected to complete haemogram, routine examination of urine, urine cultures, estimation of blood sugar, renal and liver function tests, arterial blood gas, DIC profile, ultrasonography (USG) of abdomen, blood cultures, serum leptospira antibody, urine for leptospira, HIV, HBsAg and HCV. ANA, dsDNA, C3, ANCA and antiphospholipid antibodies were done when indicated.
Chloroquine and artesunate were the first line of treatment. Quinine was used as second line or in cases of severe malaria as first line. Quinine dose was not modified if serum creatinine (Scr) was < 3 mg%. When Scr exceeded 3 mg%; usual dose was continued for two days and then reduced as per creatinine clearance.
Acute Renal Failure: Those with Scr >1.5 mg% and normal size kidneys on USG were included and divided in 3 groups: mild (Scr < 2 mg%), moderate (Scr 2-5 mg%) and severe (Scr >5 mg%).
Dialysis was done when indicated. Early dialysis was considered in the presence of severe acidosis and/or fluid overload. Peritoneal dialysis (PD) was initial mode of RRT in all. All those in whom ARF persisted > 1 week, received haemodialysis (HD) subsequently.
Kidney biopsy was done when ARF lasted for more than three weeks.
Of total 402 PS positive malaria, PF infection was seen in 147 patients (36.6%), PV in 219 (54.5%) and mixed infection in 36 (8.9%). Twenty-four patients (5.9%, 19 males and 5 females) out of 402 had ARF and PS positive malaria. Eighteen were in the age group 21- 40 years; three each in 41-60 and 60-80 years. PF was the causative parasite in 16; P. Vivax (PV) in three and mixed infection was noted in five. Four patients showed MP on PS only on fourth to sixth day of admission in spite of repeated smear examinations. 60% had PI < 2, 10% had 2-5, while 30% had > 5.
Presenting clinical features were fever (22), oedema (4), oliguria (10), icterus (4), altered sensorium (10), pain in abdomen (4), headache and vomiting (8), loose motions (3), dyspnoea (7), and convulsions (2).
The haemoglobin was 7.6 + 2.7 gm% (mean + SD), blood urea nitrogen 100 + 32.48 mg%, Scr 10.2 + 5.8 mg%, and serum bilirubin: 10.43 + 7.75 mg%. Serum Transaminases were < 200 IU in all patients. None of our patient showed serum potassium > 5 mEq/liter.
None of the patients had mild renal failure. Six patients (25%) had moderate renal failure. PF was detected in four while PV and mixed infection were noted in one each.
Eighteen patients (75%) had severe renal failure. Twelve (67%) of these were PF positive, two (11%) were PV positive while four (22%) showed mixed infection. Six (25%) had Scr 5-8 mg% while 12 (75%) had Scr > 8 mg%.
Urine showed presence of granular cast and epithelial cells in 21 (88%) while remaining three (12%) showed 2+ albuminuria and microscopic haematuria.
Dialysis was necessary in 22 (92%) patients. All received PD initially. Eight of these 22 had prolonged course lasting 2-6 weeks and received HD subsequently.
Fourteen patients received single drug (Chloroquine - 4. artesunate - 4; quinine - 6). Twelve received > 2 drugs and total 20 received quinine. Three did not show response to artesunate.
Kidney biopsy was done in five patients. All showed ATN, pigment cast and mild mesangial proliferation.
Seven (29%) of total 24 patients succumbed to the disease. Scr (mean + SD) value was significantly higher in them (13.66 + 3.47 mg%) compared to those who survived (7.14 + 3.78 mg%) (P <0.05). All seven had fatal combination of disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), severe ARF and PF malaria. No significant difference was noted in these two groups for PI (mean + SD) values; (3.5 + 3.26 in those who died vs. 1.53 + 1.12 in survivors, P >0.05). Renal function recovered completely in surviving 17 patients.
Incidence of ARF in Malaria in our study group was 5.9%. ARF necessitating dialysis was seen in 92%. Non-oliguric ARF was noted in 58%. PF was the commonest but PV was also found to be the cause of severe ARF. PF Malaria, severe ARF, DIC and ARDS were poor prognostic factors. In addition to Chloroquine, resistance was seen to artesunate as well.
Incidence of ARF in malaria all over the world has been reported as 0.57% to 60%. 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.
Membrane of infected RBCs is altered to form electrodense protrusions. Infected erythrocytes begin to retreat from peripheral to visceral circulation as the knobs appear on the surface. This may explain why in some patients parasitaemia is not severe despite severe ARF. In our group, 75% had severe ARF while PI > 5 was seen in only 30%. Four patients (17%) showed malarial parasites on peripheral smear only on fourth to sixth day of admission inspite of repeated samples. Though explained on basis of microvascular clogging and knowing that interpretation requires considerable expertise, it emphasizes the need for early and prompt diagnosis. This is essential since many physicians hesitate to start intravenous quinine in ARF in suspected malaria. Newer, more advanced malaria diagnostics are now available. Fluorescent techniques are rapid and relatively easy to perform (when > 100 parasites/ml) and demonstrate sensitivities and specificities equivalent to examination of stained thick smears.
The most promising are new generation, antigen capture tests. Two parasite antigens currently used are histidine rich protein- 2 (HRP2): produced only by PF and parasite LDH: produced by all 4 plasmodium species. When there are more than 60-100 parasites/ml, the HRP2 based test are > 90% sensitive and specific compared with thick smeared microscopy. Sensitivity for detection of malaria using plasmodium LDH is 95.4%.
Three patients (12%) showed 2+ albuminuria and microscopic haematuria. Abnormal urine analysis has been described in 20-50%. Proteinuria was < 1 gm/day and disappeared as fever subsided usually within 2-3 weeks. Five of our subjects who underwent biopsy which showed mild mesangial proliferation in addition to ATN and pigment casts. Glomerular changes in PF are common, but alone are not sufficient to cause impaired renal function.
PD was the initial mode of dialysis in all 22 patients who needed RRT. Though PD is less effective due to impaired microcirculation in severe malaria which is a hypercatabolic state, it was the more readily available mode to seriously ill and haemodynamically unstable patients.
Multidrug resistance was observed by us and we feel, it was the main cause of severe ARF in 12 patients receiving more than two drugs. Chloroquine resistance has been reported from various parts of India, Thailand and Africa., Uppal et al found high percentage (61%) of R-I type of resistance in PF infections. Chloroquine resistance in PV malaria have been reported from New Guinea and Bombay. Three patients in our study group did not show response to artesunate alone. Failure of artesunate even in adequate dosages for a maximum of five days has been reported.
Quinine should be the first drug of choice in any complicated and suspected malaria. Though we have not used mefloquine in our patients, improved efficacy of artesunate combined with mefloquine have been documented in multidrug resistant PF malaria in Thailand.
Exchange transfusions has been used as a valuable adjunct to chemotherapy by Miller et al in United States. We propose and plan to use it henceforth in severe cases of malaria with parasitaemia > 10%.
Thus we have highlighted the high incidence of severe ARF in malaria along with multidrug resistance. Early and prompt diagnosis along with aggressive therapy can prevent progression to complicated malaria while we are waiting to combat other factors like vector control, administrative shortfalls, financial stringency etc.