Immunoglobulin A nephropathy associated with Plasmodium falciparum malaria.
ABSTRACT Glomerulonephritis occurs as a rare form of renal manifestation in Plasmodium falciparum malaria. Herein, we report a case of falciparum malaria-associated IgA nephropathy for the first time. A 49-yr old male who had been to East Africa was diagnosed with Plasmodium falciparum malaria. Microhematuria and proteinuria along with acute kidney injury developed during the course of the disease. Kidney biopsy showed mesangial proliferation and IgA deposits with tubulointerstitial inflammation. Laboratory tests after recovery from malaria showed disappearance of urinary abnormalities and normalization of kidney function. Our findings suggest that malaria infection might be associated with IgA nephropathy.
- SourceAvailable from: wjgnet.com[show abstract] [hide abstract]
ABSTRACT: To investigate the role of hepatitis B virus (HBV) in the pathogenesis of IgA nephropathy (IgAN). HBV antigens (HBAg, or HBsAg, HBcAg, and HBeAg) in renal tissues with IgAN were detected by immunohistochemical technique. The distribution and localization of HBV DNA were observed by using in situ hybridization. Southern blot analysis was performed to reveal the state of renal HBV DNA. Among 100 patients with IgAN, HBs antigenemia was detected in 18 patients (18.00 %). HBAg in renal tissues was detected in 31 patients (31.00 %), the positive rate of HBAg, HBsAg and HBcAg was 64.52 % (20/31), 32.26 % (10/31), 32.26 % (10/31), respectively in glomeruli. HBcAg was also found in tubular epithelia and interstitia, which was 45.16 % (14/31) and 6.45 % (2/31), respectively. Five out of six cases with positive HBV DNA by in situ hybridization were proved to be HBV DNA positive by Southern blot analysis, and all were of the integrated form. Eight specimens were demonstrated to be HBV DNA positive by in situ hybridization, which was localized in the nuclei of tubular epithelial cells and glomerular mesangial cells as well as in infiltrated interstitial lymphocytes. There is a relationship between HBV infection and IgAN. In addition to the humoral immune damage mediated by HBAg-HBAb immune complex, the cellular mechanism mediated by HBV originating from renal cells in situ may be also involved in the pathogenesis of IgAN.World Journal of Gastroenterology 10/2003; 9(9):2004-8. · 2.55 Impact Factor
Article: Pathogenesis of IgA nephropathy.[show abstract] [hide abstract]
ABSTRACT: In IgA nephropathy (IgAN), there is dysregulation of the IgA response to a wide range of antigens. The dysregulation promotes synthesis of polymeric IgA1 (pIgA1) with physicochemical characteristics that favor mesangial deposition, including altered O-glycosylation of the hinge region. This may be the synthesis of IgA in the systemic compartment, which has the phenotype of mucosal IgA. There is not a change in IgA1 structure to an entirely abnormal form; rather, there is a shift that results in a proportional increase in forms of IgA1 also found in healthy individuals. Altered O-glycosylation could favor pIgA1 deposition by promoting formation of macromolecular IgA and immune complexes. Mesangial injury follows through interactions of pIgA1 with the cells and extracellular matrix proteins of the mesangium and the activation of complement. The final clinical expression of IgAN also depends on generic factors, including hypertension and proteinuria, and a fibrotic renal response. No single "IgAN gene" has been identified, and it is likely that multiple interacting genes will eventually prove to underlie susceptibility to IgAN and the risk of progressive renal disease. These new pathogenic insights have not yet led to new therapeutic opportunities.Seminars in Nephrology 06/2004; 24(3):197-217. · 2.83 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The importance of carbohydrate moieties for the antigenicity of purified soluble Plasmodium falciparum antigens from the asexual blood stage was tested. Digestion of the soluble antigens with alpha-D-galactosidase clearly affected the ability of the antigen to react with malaria-immune sera from different geographical origins in crossed immunoelectrophoresis and immunoblotting. Antigens of 220, 180, 80, and 74 kilodaltons were affected by the enzyme treatment. Furthermore, the enzyme digestion reduced the ability of the purified soluble antigen to stimulate lymphocytes from malaria-immune donors. The results might have important implications for the strategy of developing a malaria vaccine.Journal of Clinical Microbiology 12/1987; 25(11):2075-9. · 4.07 Impact Factor
© 2012 The Korean Academy of Medical Sciences.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Immunoglobulin A Nephropathy Associated with Plasmodium
Glomerulonephritis occurs as a rare form of renal manifestation in Plasmodium falciparum
malaria. Herein, we report a case of falciparum malaria-associated IgA nephropathy for
the first time. A 49-yr old male who had been to East Africa was diagnosed with
Plasmodium falciparum malaria. Microhematuria and proteinuria along with acute kidney
injury developed during the course of the disease. Kidney biopsy showed mesangial
proliferation and IgA deposits with tubulointerstitial inflammation. Laboratory tests after
recovery from malaria showed disappearance of urinary abnormalities and normalization
of kidney function. Our findings suggest that malaria infection might be associated with
Key Words: Glomerulonephritis; IgA nephropathy; Malaria; Plasmodium falciparum
Dong Eun Yoo1, Jeong Ho Kim2,
Jeong Hae Kie3, Yoonseon Park2,
Tae Ik Chang2, Hyung Jung Oh1,
Seung Jun Kim1, Tae-Hyun Yoo1,
Kyu Hun Choi1, Shin-Wook Kang1,
and Seung Hyeok Han1
1Department of Internal Medicine, Yonsei University
College of Medicine, Seoul; Departments of
2Internal Medicine and 3Pathology, National Health
Insurance Corporation Ilsan Hospital, Goyang, Korea
Received: 4 October 2011
Accepted: 12 December 2011
Address for Correspondence:
Seung Hyeok Han, MD
Department of Internal Medicine, Yonsei University College of
Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea
Tel: +82.2-2228-1975, Fax: +82.2-393-6884
http://dx.doi.org/10.3346/jkms.2012.27.4.446 • J Korean Med Sci 2012; 27: 446-449
Malaria is one of the most common parasitic infection in tropi-
cal areas, and 243 million cases were reported worldwide in
2008 (1). Renal involvement is particularly common in Plasmo-
dium malariae and Plasmodium falciparum infections and is
generally manifested as chronic progressive glomerulopathy in
the former and acute kidney injury (AKI) in the latter (2). In en-
demic areas, AKI occurs as a complication of falciparum malar-
ia, mostly caused by acute tubular necrosis (ATN) and/or inter-
stitial nephritis, in 1% to 4.8% of native patients, and its inci-
dence increases up to 25% to 30% in European patients. Anoth-
er less common form of renal involvement in falciparum ma-
laria is acute glomerulonephritis, which is characterized by
mesangial proliferation and matrix expansion (3). To date, only
IgM, IgG, and C3 deposits within the mesangium have been
detected, and immunoglobulin A (IgA) nephropathy associated
with falciparum malaria has not yet been reported. Herein, we
present a case of falciparum malaria-associated IgA nephropa-
thy accompanied by AKI that was resolved after recovery from
the malaria infection.
A 49-yr-old Korean male visited our hospital on February 22,
2010 because of persistent fever for three days despite repeated
use of antipyretics. The patient had a 6-yr history of diabetes
and had been receiving treatment at our hospital. Clinical eval-
uations performed 2 months earlier showed serum creatinine
level of 0.9 mg/dL [corresponding to estimated glomerular fil-
tration rate (eGFR) of 95.3 mL/min/1.73m2, calculated using
the 4-variable Modification of Diet in Renal Disease (MDRD)
Study equation] and random urine albumin-creatinine ratio
(ACR) of 42.5 mg/g without microhematuria. Serial urine anal-
yses since the first visit to the clinic consistently showed no mi-
croscopic hematuria. Ophthalmologic evaluation revealed mild
non-proliferative diabetic retinopathy. Two weeks before the
illness, he traveled Uganda in East Africa.
Upon admission, the patient was dehydrated and lethargic.
Blood pressure, pulse rate and body temperature were 110/60
mmHg, 98 beats/min and 38.3°C, respectively. Initial laboratory
tests showed the following values: hemoglobin, 9.0 g/dL; plate-
lets, 57 × 103/µL; serum creatinine, 1.8 mg/dL; aspartate/ala-
nine aminotransferase, 101/90 U/L; total bilirubin, 6.0 mg/dL;
prothrombin time international normalized ratio, 1.03. The pa-
tient tested negative for hepatitis B surface antigen, and anti-
hepatitis C virus antibody. Urine dipstick examination showed
microhematuria (2+) and proteinuria (2+). Spot urine protein-
creatinine ratio (UPCR) and ACR were 2.92 g/g and 1,064 mg/g,
respectively, and 24-hr urinary protein and creatinine excretion
Yoo DE, et al. • IgA Nephropathy Associated with P. falciparum
was 953 and 1,158 mg/day, respectively, with mixed glomerular
and tubular proteinuria on urine electrophoresis. Serum IgA
was elevated to 606 mg/dL, but other serologic tests for antinu-
clear antibody and antineutrophil cytoplasmic antibodies were
negative. C3 and C4 were 95 and 32 mg/dL, respectively.
Based on his travel history and clinical features, malaria was
suspected, and a peripheral blood smear revealed 6% hyperpar-
asitemia with Plasmodium falciparum. The patient was immedi-
ately prescribed intravenous quinine dihydrochloride with oral
doxycycline on the second day of admission. However, he be-
came anuric with increase in serum creatinine up to 4.7 mg/dL
on the third day of admission, and was started on hemodialysis.
To further ascertain the cause of AKI and proteinuria, a kid-
ney biopsy was performed on the 14th day after admission. On
light microscopy, 11 glomeruli showed mild mesangial prolifer-
ation and expansion. In addition, some tubular lumens were
packed with hemosiderin casts, and the interstitium was infil-
trated with many inflammatory cells. Seven glomeruli processed
for immunofluorescence analysis showed mesangial staining
for IgA (1+ to 2+) and C3 (1+). In addition, 3 glomeruli examined
by electron microscopy showed multifocal electron-dense de-
posits within the mesangium and thickened glomerular base-
ment membrane ranging from 800 nm to 1,200 nm in thickness
The patient underwent hemodialysis until the 25th day after
admission. In the meantime, he became negative for P. falci-
parum and his kidney function recovered with increased urine
output. Serum creatinine and UPCR decreased to 2.2 mg/dL
and 0.47 mg/g on the 33rd day after admission, and the patient
was discharged in good condition. Two months later, his serum
creatinine level had decreased to 1.2 mg/dL with UPCR of 0.07
mg/g. Three consecutive urinalyses revealed no microhematu-
ria (Fig. 2). Serum IgA was also normalized to 301 mg/dL.
IgA nephropathy is the most common primary glomerulone-
phritis worldwide. It is characterized by mesangial cell prolifer-
Fig. 1. Pathologic findings in a patient with P. falcifarum-associated immunoglobulin A (IgA) nephropathy. (A) The renal biopsy specimen showed mild mesangial proliferation
and expansion (original magnification × 400). (B) Acute and chronic inflammatory cell infiltration in the tubulointerstitium with multifocal hemosiderin casts (original magnifica-
tion × 200). (C) Direct immunofluorescence showed mesangial staining for IgA (2+). (D) Electron microscopy showed multifocal electron-dense deposits within the mesangium
and irregularly thickened glomerular basement membrane ranging from 800 nm to 1,200 nm in thickness. Diffusely effaced foot processes were also observed.
Yoo DE, et al. • IgA Nephropathy Associated with P. falciparum
ation, expansion of the extracellular matrix, and predominant
IgA deposition within the mesangium (4). Although the etiolo-
gy of the disease has not been clearly elucidated, some infec-
tious organisms have been reported to be associated with IgA
nephropathy. These include Haemophilus parainfluenzae,
Staphylococcus species, Mycoplasma pneumoniae, and the
Hepatitis B and Dengue viruses, but no individual bacterial or
viral organism has been specifically associated with the devel-
opment of IgA nephropathy (5-9). Meanwhile, in an previous
experimental study, mesangial IgA deposits were rarely noted
in mouse malaria nephropathy caused by Plasmodium berghei
(10). However, similar findings were not reported among hu-
man malaria nephropathy to date. To our best knowledge, this
is the first case suggesting a possible link between IgA nephrop-
athy and Plasmodium falciparum infection.
In line with the previous studies, AKI due to ATN and inter-
stitial nephritis was clearly evident, which clearly explains our
patient’s clinical features. Notably, IgA nephropathy developed
after Plasmodium falciparum infection. One might question
whether the patient had glomerulonephritis or latent IgA ne-
phropathy before the infection. However, the patient had been
followed for 6 yr at our clinic for diabetes management, and
previous blood and urine tests consistently had revealed no evi-
dence of glomerulopathy. In addition, his urine analysis from
2 months before the illness showed no microscopic hematuria
but only microalbuminuria suggesting that glomerulonephritis
such as IgA nephropathy was less likely. Presumably, microal-
buminuria at that time could have been attributed to underly-
ing diabetic nephropathy. In fact, he might have diabetic ne-
phropathy, as evidenced by the biopsy finding showing a thick-
ened glomerular basement membrane and history of coexist-
ing mild non-proliferative diabetic retinopathy. Moreover, sub-
sequent blood and urine tests after recovery from malaria showed
a disappearance of urine abnormalities along with normaliza-
tion of both kidney function and serum IgA level. These find-
ings taken together suggest that Plasmodium falciparum may
have been associated with IgA nephropathy in this patient.
It is uncertain how malaria infection is involved in the devel-
opment of IgA nephropathy. In general, undergalactosylated
IgA1 is reported to play a role in the pathogenesis of idiopathic
IgA nephropathy (11). Such aberrantly glycosylated polymeric
IgA1 are prone to form circulating immune complexes, leading
to mesangial deposition and proliferation (12, 13). The underly-
ing mechanism responsible for this IgA1 abnormality is poorly
understood. However, it is possible that anti-α-galactosyl (anti-
Gal) antibodies may contribute to the development of immune
complexes with aberrantly glycosylated IgA1. Anti-Gal antibod-
ies are originally natural human polyclonal antibodies that spe-
cifically bind to the mammalian carbohydrate structure Galα1,
3Galβ1,4GlcNAc-R (α-galactosyl epitope) on glycoproteins and
glycolipids (14). Some investigators showed that anti-Gal was
associated with IgA nephropathy and Henoch-Schonlein pur-
pura (15). Interestingly, the titers of these antibodies were also
found to be elevated in many of the sera collected from subjects
living in malaria endemic areas or patients with falciparum
malaria (16). It was reported that terminal α-linked galactosyl
residues in some of the carbohydrate side chains of glycopro-
teins of the asexual blood stages of Plasmodium falciparum
could provoke increased anti-Gal production (17, 18). There-
fore, in the present case, it can be surmised that Plasmodium
falciparum might have induced augmented production of anti-
Gal, and in turn, might have caused formation of aberrantly
glycosylated polymeric IgA1. Unfortunately, we could not per-
form any pertinent study to confirm the presence of abnormal
IgA1 because the patient’s serum was not available by the time
the biopsy revealed IgA nephropathy.
Another possible explanation for IgA nephropathy in our re-
port is that clearance of IgA and immune complexes were re-
duced due to liver and/or renal dysfunction. However, such as-
sumptions cannot fully explain why IgA deposits were more
prominent than other immune-complexes within the mesangi-
um in our patient because only IgG, IgM, and C3 deposits have
been reported in malarial nephropathies to date although most
reported cases involved both renal failure and hepatitis.
As in some previous reports on IgA nephropathy associated
with infection (9, 19), the glomerulopathy in our patient ap-
peared to be transient. It is possible that removal of the caus-
ative organism from circulation and improvements in renal and
hepatic dysfunction might result in increased clearance of im-
mune-complexes, thus leading to the resolution of IgA nephrop-
athy. Unfortunately, a second biopsy to prove the complete res-
olution of IgA nephropathy was not feasible because the patient
did not agree to a repeated test. However, based on the results
from consecutive blood and urine tests after recovery from ma-
laria infection, it is likely that such glomerulopathy was resolved.
In addition, although it is not easy to discriminate between true
Serum creatinie, mg/dL
Urine protein-creatinine ratio (mg/g)
-3 y -6 m -2 m
0 3 d 1 m 2 m 4 m 6 m 8 m
Fig. 2. Changes in kidney function and urine findings during the course of disease. d;
day, m; month, y; year, PCR; protein-creatine ratio.
Yoo DE, et al. • IgA Nephropathy Associated with P. falciparum
IgAN and IgA-dominant postinfectious glomerulonephritis, the
latter was less likely because hypocomplementemia, diffuse
glomerular endocapillary hypercellularity, and subepithelial
humps (20) were not found in our case (Fig. 1).
In conclusion, our findings suggest that Plasmodium falci-
parum may be involved in the development of IgA nephropathy.
However, this report is limited to a single case and the mecha-
nism responsible for this remains speculative. Further investiga-
tion to elucidate the underlying pathogenesis is required.
1. World Health Organization. World malaria report 2009. Geneva: World
Health Organization, 2009.
2. Barsoum RS. Malarial nephropathies. Nephrol Dial Transplant 1998;
3. Barsoum RS, Sitprija V. Tropical nephrology. In: Schrier RW, editor. Dis-
eases of the kidney and urinary tract. Philadelphia: Lippincott Williams
& Wilkins, 2001, p2013-20.
4. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; 347: 738-48.
5. Sunaga H, Oh M, Takahashi N, Fujieda S. Infection of Haemophilus
parainfluenzae in tonsils is associated with IgA nephropathy. Acta Oto-
laryngol Suppl 2004: 15-9.
6. Satoskar AA, Nadasdy G, Plaza JA, Sedmak D, Shidham G, Hebert L,
Nadasdy T. Staphylococcus infection-associated glomerulonephritis mim-
icking IgA nephropathy. Clin J Am Soc Nephrol 2006; 1: 1179-86.
7. Suzuki K, Hirano K, Onodera N, Takahashi T, Tanaka H. Acute IgA ne-
phropathy associated with mycoplasma pneumoniae infection. Pediatr
Int 2005; 47: 583-5.
8. Wang NS, Wu ZL, Zhang YE, Guo MY, Liao LT. Role of hepatitis B virus
infection in pathogenesis of IgA nephropathy. World J Gastroenterol 2003;
9. Upadhaya BK, Sharma A, Khaira A, Dinda AK, Agarwal SK, Tiwari SC.
Transient IgA nephropathy with acute kidney injury in a patient with
dengue fever. Saudi J Kidney Dis Transpl 2010; 21: 521-5.
10. George CR, Parbtani A, Cameron JS. Mouse malaria nephropathy. J
Pathol 1976; 120: 235-49.
11. Barratt J, Feehally J, Smith AC. Pathogenesis of IgA nephropathy. Semin
Nephrol 2004; 24: 197-217.
12. Coppo R, Amore A. Aberrant glycosylation in IgA nephropathy (IgAN).
Kidney Int 2004; 65: 1544-7.
13. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J.
Circulating immune complexes in IgA nephropathy consist of IgA1 with
galactose-deficient hinge region and antiglycan antibodies. J Clin Invest
1999; 104: 73-81.
14. Hamadeh RM, Galili U, Zhou P, Griffiss JM. Anti-alpha-galactosyl im-
munoglobulin A (IgA), IgG, and IgM in human secretions. Clin Diagn
Lab Immunol 1995; 2: 125-31.
15. Davin JC, Malaise M, Foidart J, Mahieu P. Anti-alpha-galactosyl anti-
bodies and immune complexes in children with Henoch-Schönlein pur-
pura or IgA nephropathy. Kidney Int 1987; 31: 1132-9.
16. Ravindran B, Satapathy AK, Das MK. Naturally-occurring anti-alpha-ga-
lactosyl antibodies in human Plasmodium falciparum infections: a pos-
sible role for autoantibodies in malaria. Immunol Lett 1988; 19: 137-41.
17. Ramasamy R, Reese RT. Terminal galactose residues and the antigenicity
of Plasmodium falciparum glycoproteins. Mol Biochem Parasitol 1986;
18. Jakobsen PH, Theander TG, Jensen JB, Mølbak K, Jepsen S. Soluble Plas-
modium falciparum antigens contain carbohydrate moieties important
for immune reactivity. J Clin Microbiol 1987; 25: 2075-9.
19. Han SH, Kang EW, Kie JH, Yoo TH, Choi KH, Han DS, Kang SW. Spon-
taneous remission of IgA nephropathy associated with resolution of hep-
atitis A. Am J Kidney Dis 2010; 56: 1163-7.
20. Nasr SH, D’Agati VD. IgA-dominant postinfectious glomerulonephritis:
a new twist on an old disease. Nephron Clin Pract 2011; 119: c18-25.