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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2019  |  Volume : 30  |  Issue : 2  |  Page : 540-544
Complement factor H gene polymorphisms and vivax malaria associated thrombotic microangiopathy


1 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatric Allergy Immunology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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Date of Submission16-Apr-2018
Date of Acceptance07-Mar-2018
Date of Web Publication23-Apr-2019
 

   Abstract 


Acute kidney injury (AKI) occurs in about 1% of cases of malaria; however, in these cases, the mortality rate can be as high as 45%. Thrombotic microangiopathy (TMA) as a cause of AKI in malaria is rare with only a handful cases documented in literature so far. Alternate complement pathway (ACP) dysregulation as a major mechanism of injury in the development of thrombotic microangiopathies is well known. It is proposed that patients with preexisting defects in ACP are usually clinically silent, until stress condition such as infections help manifest them. Herein, we describe the presence of two complement factor H (CFH) variants in an 8-year-old female with vivax malaria associated TMA. The complement workup confirmed dysregulated ACP and revealed two single-nucleotide polymorphisms in CFH gene, i.e. exon-7 rs1061147 (p.Ala243Ala) and exon-9 rs1061170 (p.His402Tyr) which predisposed this patient to develop TMA precipitated by vivax malaria.

How to cite this article:
Agrawal P, Kumar A, Parwaiz A, Rawat A, Tiewsoh K, Nada R. Complement factor H gene polymorphisms and vivax malaria associated thrombotic microangiopathy. Saudi J Kidney Dis Transpl 2019;30:540-4

How to cite this URL:
Agrawal P, Kumar A, Parwaiz A, Rawat A, Tiewsoh K, Nada R. Complement factor H gene polymorphisms and vivax malaria associated thrombotic microangiopathy. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 May 24];30:540-4. Available from: http://www.sjkdt.org/text.asp?2019/30/2/540/256865



   Introduction Top


Malaria is a common infectious disease in tropical countries. The most common renal manifestation is acute tubular necrosis due to pigment cast nephropathy resulting from intra-vascular hemolysis. A proportion of malaria cases develop thrombotic microangiopathy TMA). Alternate complement pathway dysregulation (ACP) has been etiopathogenetically associated with TMA; however, ACP workup in cases of malaria with TMA has not been evaluated. Herein, we document the first case of vivax malaria precipitated renal TMA in a patient with complement factor H (CFH) gene single-nucleotide polymorphisms (rs1061170, rs1061147).


   Case Report Top


An 8-year-old female child presented with the complaints of fever and abdominal pain for 10 days, black-colored stools for four days, bloody vomitus, yellowish discoloration of body, high-colored urine, and generalized body swelling for two days and decreased urine output of one day duration. On examination, the child had pallor and icterus, facial puffiness, and hepatomegaly. The laboratory investigations revealed a positive vivax malaria card test. Hemoglobin was 7.3 g/dL, total leukocyte count 9000/uL, platelet count 63000/uL, serum creatinine 10.6 mg/dL, urea 238 mg/dL, and urine albumin 1+. Serology for HIV, hepatitis B surface antigen, anti-HCV, hepatitis A, and leptospira was negative. antinuclear antibody and antineutrophil cyto-plasmic antibodies were not present.

Kidney biopsy included 22 glomeruli, of which 11 showed the features of acute to subacute TMA in the form of endothelial swelling with the presence of red blood cells (RBCs) and fibrin, mesangial reticulation. Five glomeruli showed features of chronic TMA in the form of bland sclerosis of capillary tuft and collapse. No vascular TMA was noted. The tubule-interstitium showed marked edema with numerous foci of interstitial hemorrhages, loss of proximal convoluted tubules, and the presence of RBC casts. Perls’ stain highlighted hemosiderin pigment in the interstitium, tubular epithelial cells, and glomeruli indicating old hemorrhages. No parasitized RBCs were identified. A malaria pigment bleach using alcoholic solution of picric acid was performed at 4 h and 24 h to confirm hemozoin pigment. A diagnosis of ongoing TMA leading to acute cortical necrosis was made [Figure 1].
Figure 1: (a) Photomicrograph showing subacute glomerular thrombotic microangiopathy, interstitial edema and hemorrhages along with the loss of proximal convoluted tubules (H and E, ×400). (b) Perls' stain highlights Prussian blue color hemosiderin deposits in the tubules and interstitium (Perls'stain, ×200). (c) Perls' stain highlights Prussian blue color hemosiderin in the glomerulus, while the brownishblack hemozoin pigment is unstained (Perls'stain, ×oil immersion). (d) Alcoholic picric acid bleach at the end of 4 h shows persistence of hemozoin pigment (H and E, ×Oil immersion). (e) Alcoholic picric acid bleach at the end of 24 h shows disappearance of hemozoin pigment (H and E, ×oil immersion).

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Complement workup was performed before the initiation of treatment and revealed C3 1.17 g/L (normal range 0.89–1.87 g/L), C4 6.5 g/L (normal range 0.165–0.38 g/L), anti-factor H antibodies 12.1 AU/mL (normal <24 AU/ mL), Factor H 732 ug/mL (normal range 225–760 ug/mL), Factor I 42 ug/mL (normal range 42–78 ug/mL), and Factor B 164 ug/mL (normal range 85–227 ug/mL). Alternate complement pathway functional assay was 20.9% (normal range 30%–113%).

The patient was treated with artesunate and primaquine along with six cycles of hemodialysis. After one month of presentation the serum creatinine improved to 2.6 mg/dL, urea to 135 mg/dL, platelet count to 481,000/uL, and hemoglobin to 8.1 g/dL.

In addition to serology, genomic DNA was extracted from blood using DNA extraction kit (Qiagen) followed by polymerase chain reaction (PCR). All the exons of CFH and CHF related 5 genes were amplified. PCR products were purified followed by Sanger sequencing which revealed two single-nucleotide polymorphisms in CFH gene [Figure 2], i.e., exon-7 rs1061147 (p.Ala243Ala) and exon-9 rs1061170 (p.His402Tyr).
Figure 2: Sequence chromatograms showing two Complement Factor H variants in exon-7 (rs1061147) and exon-9 (rs1061170) in this patient.

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   Discussion Top


Malaria is a disease of public importance, especially in the tropics. According to the World Malaria Report 2015, there were 214 million cases of malaria, of which 438,000 succumbed to disease globally in the year 2015.[1] As per the National Vector Borne Disease Control Programme Annual Report 2014–2015, there were 0.85 cases of malaria per million population in India.[2] In India, about 65% of malaria is caused by Plasmodium vivax and 35% by Plasmodium falciparum[3] Although complicated malaria is more frequent in P. falciparum infection; however, a significant proportion of P. vivax infected cases also develop complicated malaria.[3] Acute kidney injury (AKI) occurs in about 1% of cases of malaria, wherein the mortality rate is reported to be about 45%.[4]

A variety of renal lesions have been described in malaria, the most common being acute tubular necrosis due to pigment cast nephropathy resulting from intravascular hemolysis. The other renal manifestations are acute interstitial nephritis, proliferative glomerulonephritis due to immune complex deposits[5] and rarely nephrotic syndrome.[6] TMA as a cause of AKI in malaria is rare, with only handful cases documented from India in literature so far, including our institution.[7],[8],[9],[10],[11] The question as to why only a few patients suffering from malaria develop TMA remains unanswered.

The three important pathogenetic mechanisms in infection-associated TMA are endothelial injury/activation, complement dysregulation and secondary ADAMTS13 deficiency. The cytoadhesive property of P. falciparum-infected red cells with other red cells, monocytes, platelets, and endothelium is well documented.[5] Carvalho et al have demonstrated cytoadhesive property in P. vivax in an in vitro model.[12] The binding of P. vivax-infected red cells to endothelium results in its injury/activation. Ohnishi has described increased serum levels of endothelial activation markers (thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) in patients suffering from vivax malaria.[13] Therefore, the interaction of P. vivax-infected red cells with the endothelium results in its injury/activation which contributes in the pathogenesis of TMA.

ACP dysregulation as a major mechanism of injury in the development of TMA is being rigorously evaluated in recent times. Qualitative or quantitative defects in various complement factors, anti-complement factor antibodies, mutations in complement factor genes can precipitate complement-mediated TMA.[14] Srichaikul et al have documented that P. falciparum directly activates C3 through ACP.[15] However, direct ACP activation by P. vivax has not been documented till date.

Patients with pre-existing defects in complement pathway and its regulatory mechanisms are usually clinically silent and manifest in stress conditions such as infection, as exemplified in the present case. In the present case, although C3 and C4 levels were not decreased and Factor H, Factor I and Factor B levels were within the normal limits along with absence of anti-Factor H antibody, the decreased ACP functional assay suggests ACP dysregulation. Sequencing of all exons of CFH gene was then performed to explain ACP dysregulation, which revealed two CFH variants, namely, rs1061147 and rs1061170 that predisposed the patient to develop TMA precipitated by vivax malaria infection. The above-mentioned CFH variants are significant and also associated with dense deposit disease,[16] atypical hemolytic uremic syndrome,[17] dengue,[18] age-related macular degeneration,[19] lupus nephritis,[20] and Rift valley fever.[21]

Reduced ADAMTS 13 activity and antigen levels is known to occur during infections. de Mast et al have described ADAMTS13 deficiency and elevated levels of ultra large von Willibrand factor in P. falciparum and P. vivax infection.[22] However, thrombotic thrombo-cytopenic purpura is unlikely in the present case due to renal dominant disease and the absence of platelet rich thrombi on histology; although, ADAMTS13 antigen levels and functional assay were not performed.


   Conclusion Top


This is the first study to document CFH variants,namely, rs1061147 and rs1061170in a case of renal TMA associated with vivax malaria. The patients with underlying complement factor gene polymorphisms are prone to develop TMA in the setting of malaria. Therefore, it is imperative to test complement pathway defects by serological and molecular genetic analysis. A normal complement work-up by serology does not exclude an underlying ACP dysregulation; therefore, mutational analysis is a must.

Conflict of interest: None declared.



 
   References Top

1.
World Health Organization World Malaria Report. Available from: http://www.who.int/ malaria/publications/world-malaria-report-2015/ report/en/.  Back to cited text no. 1
    
2.
National Vector Borne Disease Control Programme Annual Report; 2014-2015. Available form: http://www. nvbdcp.gov.in/doc/ annual-report-nvbdcp-2014-15.pdf.  Back to cited text no. 2
    
3.
Aashish A, Manigandan G. Complicated vivax malaria, an often underestimated condition – Case report. J Family Community Med 2015; 22:180-2.  Back to cited text no. 3
    
4.
Mishra SK, Das BS. Malaria and acute kidney injury. Semin Nephrol 2008;28:395-408.  Back to cited text no. 4
    
5.
Barsoum RS. Malarial nephropathies. Nephrol Dial Transplant 1998;13:1588-97.  Back to cited text no. 5
    
6.
Gilles HM, Hendrickse RG. Possible aetiological role of Plasmodium malariae in “nephrotic syndrome” in Nigerian children. Lancet 1960;1:806-7.  Back to cited text no. 6
    
7.
Keskar VS, Jamale TE, Hase NK. Hemolytic uremic syndrome associated with Plasmodium vivax malaria successfully treated with plasma exchange. Indian J Nephrol 2014;24:35-7.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Sinha A, Singh G, Bhat AS, et al. Thrombotic microangiopathy and acute kidney injury following vivax malaria. Clin Exp Nephrol 2013;17:66-72.  Back to cited text no. 8
    
9.
Jhorawat R, Beniwal P, Malhotra V. Plasmodium vivax induced hemolytic uremic syndrome: An uncommon manifestation that leads to a grave complication and treated successfully with renal transplantation. Trop Parasitol 2015;5:127-9.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Saharan S, Kohli U, Lodha R, Sharma A, Bagga A. Thrombotic microangiopathy associated with Plasmodium vivax malaria. Pediatr Nephrol 2009;24:623-4.  Back to cited text no. 10
    
11.
Saini A, Dogra S, Devidayal, Nada R, Ramachandran R, Doraiswamy A. Glomerular thrombotic microangiopathy caused by Plasmodium vivax infection. J Pediatr Sci 2012;4:e123.  Back to cited text no. 11
    
12.
Carvalho BO, Lopes SC, Nogueira PA, et al. On the cytoadhesion of Plasmodium vivax-infected erythrocytes. J Infect Dis 2010;202: 638-47.  Back to cited text no. 12
    
13.
Ohnishi K. Serum levels of thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the acute phase of Plasmodium vivax malaria. Am J Trop Med Hyg 1999;60:248-50.  Back to cited text no. 13
    
14.
George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654-66.  Back to cited text no. 14
    
15.
Srichaikul T, Puwasatien P, Karnjanajetanee J, Bokisch VA, Pawasatien P. Complement changes and disseminated intravascular coagulation in Plasmodium falciparum malaria. Lancet 1975;1:770-2.  Back to cited text no. 15
    
16.
Abrera-Abeleda MA, Nishimura C, Frees K, et al. Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol 2011;22:1551-9.  Back to cited text no. 16
    
17.
Bouatou Y, Bacchi VF, Villard J, Moll S, Martin PY, Hadaya K. Atypical hemolytic uremic syndrome recurrence after renal transplantation: C3-glomerulonephritis as an initial presentation. Transplant Direct 2015; 1:e9.  Back to cited text no. 17
    
18.
Kraivong R, Vasanawathana S, Limpitikul W, et al. Complement alternative pathway genetic variation and dengue infection in the Thai population. Clin Exp Immunol 2013;174:326-34.  Back to cited text no. 18
    
19.
Francis PJ, Schultz DW, Hamon S, Ott J, Weleber RG, Klein ML. Haplotypes in the complement factor H (CFH) gene: Associations with drusen and advanced age-related macular degeneration. PLoS One 2007;2: e1197.  Back to cited text no. 19
    
20.
Wang FM, Song D, Pang Y, Song Y, Yu F, Zhao MH. The dysfunctions of complement factor H in lupus nephritis. Lupus 2016;25: 1328-40.  Back to cited text no. 20
    
21.
Hise AG, Traylor Z, Hall NB, et al. Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways. PLoS Negl Trop Dis 2015;9:e0003584.  Back to cited text no. 21
    
22.
de Mast Q, Groot E, Asih PB, et al. ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria. Am J Trop Med Hyg 2009;80:492-8.  Back to cited text no. 22
    

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Correspondence Address:
Ritambhra Nada
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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DOI: 10.4103/1319-2442.256865

PMID: 31031394

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