Plasmodium vivax induced hemolytic uremic syndrome: An uncommon manifestation that leads to a grave complication and treated successfully with renal transplantation.

We are reporting a case of hemolytic uremic syndrome, a rare manifestation of Plasmodium vivax malaria. A young driver was admitted with acute febrile illness, decreased urine output, anemia, thrombocytopenia, jaundice, and increased serum lactate dehydrogenase. He showed a partial response to antimalarial drugs. However, he was readmitted with worsening renal parameters. His kidney biopsy revealed chronic thrombotic microangiopathy. He remained dialysis dependent and later underwent renal transplantation successfully, with excellent graft function at 1-year.

INTRODUCTION

Generally, severe malaria is associated with Plasmodium falciparum. Plasmodium vivax infection has been considered as benign, however, many studies have been published that had shown that clinical manifestation and its severity are not different from Plasmodium falciparum, at least in Indian sub-continent.[12]

Thrombotic microangiopathy (TMA) is primarily due to congenital complement dysregulation, acquired autoantibody against ADAMTS13 or secondary due to pregnancy, infection or drug- induced like quinine, mefloquine, oral contraceptive, calcineurin inhibitors, etc. However, TMA due to P. vivax is uncommon.[3] We are reporting a case of nonrecovering acute renal failure secondary to hemolytic uremic syndrome (HUS) in a young driver due to P. vivax malaria. He became dialysis dependent and underwent renal transplant successfully.

CASE REPORT

A 28-year-old young married male driver had repeated history of mosquito bites in the during the monsoon season. He presented with high-grade fever and headache for 8 days and decreased urine output, nausea, and vomiting for last 3 days. He was initially admitted in a private hospital; the malaria card test was positive, and peripheral blood smear was showing schizonts of P. vivax. He was referred to our center for worsening uremic symptoms. On examination, his pulse rate was 88/min, blood pressure was 136/86 mmHg, and he has pallor. Systemic examination was normal.

He received an antimalarial course with artesunate and clindamycin combination for 7 days. The laboratory investigations were showing azotemia as detailed in Table 1. He was in uremia and received 4 sessions of hemodialysis. His urine output started improving and reached to around 2–2.5 L/day after 15 days of his illness. His serum creatinine improved to 3.46 mg/dl at discharge on the 17th day.

Table 1

Laboratory investigations

He was readmitted after 20 days of his discharge with the symptom of nausea and vomiting, and he was hypertensive at this time. Urine output was adequate. On investigation, his serum creatinine was 16.2 mg/dl and serum urea 198 mg/dl. He was dialyzed. The kidney biopsy was done after adequate dialysis, was showing chronic thrombotic microangiopathy with chronicity >70% both in glomerular and interstitial compartments as shown in Figure 1.

Figure 1

(a) Fibrin thrombi in the glomerulus (black arrow) (b) “onion peeling” with RBC in the arteriole. (c and d) Chronic changes-tubulointerstitial inflammation (red arrow) with tubular atrophy (yellow arrow) and glomerular atrophy and sclerosis (green arrow) associated with interstitial inflammation (H and E)

Follow-up

He was remained on hemodialysis for 3 months. After 3 months (4½ months after his illness), he underwent renal transplantation. He received the renal allograft from his 50-year-old mother and immunosuppressed with tacrolimus-based therapy. At 1-year, his allograft function was excellent without an episode of renal dysfunction or rejection with serum creatinine 0.7 mg/dl.

DISCUSSION

The clinical manifestation of P. vivax, both benign and severe are increasingly observed overlapping with P. falciparum. Asymptomatic renal dysfunction to a morbid complication like TMA-HUS or renal cortical necrosis has been reported in P. vivax malaria.[4] TMA is caused by both P. falciparum and P. vivax. However, the pathogenic mechanism is better described and understood in P. falciparum compared to P. vivax malaria. However, the pathogenesis of TMA between these two species, similar or different is still unanswered.

P. falciparum-infected RBC expressed P. falciparum erythrocyte membrane protein 1 recognized by endothelial counter-receptor CD-36. Endothelium activation lead to expression on the surface of P- and E-selectin, intercellular cell adhesion molecules-1, vascular cell adhesion molecule-1, and exocytose storage granules (Weibel-Palade bodies) containing large amount of ultra-large von Willebrand factor (ULvWF) which bind to platelets and cause platelet aggregation.[56] Accumulation of ULvWF almost always results from failure of its processing by metalloproteinase ADAMTS13, which has been reported deficient in malaria.[7] Bridge et al. showed that P. falciparum-infected erythrocytes are able to bind platelets attached to ULvWF stand in a CD-36 dependent manner, and the attachment can be prevented by antibodies against vWF.[8]

P. vivax also have similar reported pathogenic mechanism like greater inflammatory response and cytokines production, Weibel-Palade bodies exocytosis, altered thrombosis, platelet activation, endothelial cell injury, and impairment of vasomotor responses, as well as decrease in ADAMTS13 level similar to P. falciparum malaria.[6789] This indicates that mechanisms underlying TMA in P. falciparum and P. vivax are not different, however, we need a “thread” which binds all steps of the pathogenic mechanism together, in P. vivax induced TMA.

Possibility of atypical HUS due to congenital complement dysregulation was also considered. However, complement levels were only transient decreases, which were normalized after an acute febrile illness. Family history of similar disease was absent and post renal transplant allograft function was excellent at 1-year. However, the genetic studies for complement pathway mutations were not done in our case.

Severe complications such as renal cortical necrosis, HUS/thrombotic thrombocytopenic purpura, and increased mortality with P. vivax malaria are more frequently reported in Indian sub-continent. Is it because of the geography, climatic condition or genetic variation in the local population, does still need to be answered.

CONCLUSION

P. vivax is as severe as P. falciparum though the frequency of severe manifestation like TMA may vary. Early recognition and plasma exchange therapy has been reported to be effective in malaria-induced TMA and should be instituted early. Further research is warranted to elucidate the role of the complement system and association of complement dysregulation in malaria-induced TMA.

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Conflicts of interest

There are no conflicts of interest.