Acute kidney injury secondary to severe delayed haemolysis in intravenous artesunate use for severe malaria

Background

Intravenous artesunate remains the treatment of choice for severe malaria due to its rapid parasite clearance, relatively safe profile and demonstrated efficacy in reducing mortality compared with other agents.1 However, postartesunate delayed haemolysis can occur and is potentially under-recognised.2 3 Additionally, although acute kidney injury (AKI) is a common complication of severe malaria, the incidence of renal impairment secondary to postartesunate delayed haemolysis is currently unknown.

Case presentation

A 50-year-old Australian man presented with 8 days of fever, headaches and gastrointestinal symptoms following 3 weeks of travel to Uganda, Sri Lanka, Dubai and Bali. He initially developed severe unilateral headache with associated fevers and malaise while travelling in Sri Lanka 7 days prior to returning to Australia. On returning to Australia, he sought medical treatment for worsening headaches with associated phonophobia and photophobia. Further history revealed that he was travelling with his partner on a combined business and leisure trip. He denied any exposure to street food, non-bottled water, animals, intravenous drug use and unprotected sexual intercourse. The patient had all recommended pre travel vaccinations but did not take malaria prophylaxis during his trip. He had no significant medical history and took no regular medications.

On initial presentation, a diagnosis of falciparum malaria was made with a peak parasite density of 12% on blood film (figure 1). The patient had an altered conscious state and thrombocytopaenia meeting the clinical criteria for severe disease. He was commenced on intravenous artesunate for severe malaria in the intensive care unit and received four doses before being switched to oral artemether–lumefantrine on day 4. Treatment was well tolerated and the patient was discharged on day 6, with a haemoglobin (Hb) of 99 g/L. Follow-up in the outpatient clinic on day 10 revealed an improving Hb of 112 g/L. However, he represented 3 days later to the emergency department with dark urine (figure 2) and fatigue.

Investigations

On initial presentation, arterial blood gas results showed a normal blood glucose of 6.7 mmol/L and pH of 7.43. Additional blood tests revealed a thrombocytopaenia (platelet count of 18×10⁹/L), while serial blood cultures were negative. A screen for vector borne disease was performed including a malaria smear, as well as serology for dengue and chikungunya. Blood films on day 1 revealed the presence of developing trophozoites of Plasmodium falciparum with a parasite density of 0.1%. Repeat blood films showed a parasite density of 12% on day 2 subsequently decreasing to <0.001% on day 4. During this time, the patient developed a mild anaemia with Hb between 120 g/L and 96 g/L. Haptoglobin <0.1 g/L and downtrending lactate dehydrogenase (LD) (1010–535 U/L) were supportive of a resolving mild haemolysis. On discharge, his Hb was stable (99 g/L) and renal function was preserved (estimated glomerular filtration rate (eGFR) >90 mL/min/1.73 m², creatinine 63 μmol/L).

At readmission 10 days after ceasing intravenous artesunate, laboratory findings were consistent with haemolytic anaemia (Hb 79 g/L, LD 2071 units/L, haptoglobin <0.1 g/L) and AKI (eGFR 49 mL/min/1.73 m², creatinine 143 μmol/L). Repeat blood smears for P. falciparum were negative. His anaemia continued to worsen despite transfusions, with a nadir Hb of 65 g/L on day 18 with ongoing reticulocytosis (135×10⁹/L). A direct antiglobulin test was negative. During this time, his renal function deteriorated (creatinine peak 559 μmol/L, eGFR nadir 9 mL/min/1.73 m²). Serum complement levels were preserved (C3 1.79 g/L and C4 0.32 g/L) and urinalysis showed haemoglobinuria (red blood cells 38×10⁶/L). An albumin creatinine ratio of 23 and protein creatinine ratio of 150 were consistent with a predominantly tubular cause of AKI. Renal ultrasound scan demonstrated moderately increased echogenicity with reduced cortical medullary differentiation bilaterally suggestive of an interstitial process.

Treatment

On readmission, the patient was adequately fluid resuscitated and hydration status was closely monitored with a strict fluid balance chart. He was transfused five units of packed red blood cells during days 1–5 of the second admission. Renal replacement therapy was not required as the creatinine remained stable and urine output was preserved.

Outcome and follow-up

Following an initial response, there was no significant increment in Hb with subsequent blood transfusions. His Hb remained stable in the 48 hours following the last transfusion and his renal function stabilised. He was discharged home on day 8 after readmission (Hb 84 g/L, creatinine 534 μmol/L, eGFR 10 mL/min/1.73 m²). Follow-up on day 50 post readmission demonstrated a full recovery of his renal function and haemolytic anaemia (Hb 126 g/L, eGFR 76 mL/min/1.73 m², creatinine 99 μmol/L).