1. Nuclear factor kappa B in urine
sediment: a useful indicator to detect
acute kidney injury in Plasmodium
falciparum malaria
Author: Chuchard Punsawad and Parnpen Viriyavejakul
Malaria Journal 2014, 13:84 doi:10.1186/1475-2875-13-84
speaker：邱以涵
advisor：張永宗
Date: 2015.04.07
1
2. CONTENTS
• ABSTRACT
• MALARIA LABORTARY DIAGNOSIS
• INTRODUCE ACUTE KIDNEY INJURY
• BIOMARKERS OF RENAL FUNCTION
• METHODS
• RESULTS
• CONCLUSIONS
• TAKE HOME MESSAGE
2
3. ABSTRACT
• Acute kidney injury (AKI) is one of the major
complications of Plasmodium falciparum malaria.
• Activation of transcription factor nuclear factor
kappa B (NF-κB) involved in the development of
progressive renal inflammatory diseases.
3
4. THE AIM of
THE STUDY
was to determine
whether urinary
sediment NF-κB p65
can act as a
biomarker for AKI in
patients with P.
falciparum malaria.
NF-κB P65
P.
falciparum
malaria
biomarker
acute
kidney
injury
4
5. MALARIA LABORTARY DIAGNOSIS
• Microscopy (morphologic analysis)
This technique remains the gold standard for
laboratory confirmation of malaria.
• Molecular Diagnosis
PCR is for confirming the species of malaria after the
diagnosis either smear microscopy or RDT.
5
6. • Antigen Detection
Rapid Diagnostic Test(RDTs)
• Serology
Using either indirect immunofluorescence (IFA) or
enzyme-linked immunosorbent assay (ELISA).
11. •Renal tubular epithelial
cells and muddy brown
casts(granular casts)
suspect acute tubular
necrosis.
Possible Urine Sediment Findings in
Acute Kidney Injury
11
12. Possible Urine Sediment Findings in
Acute Kidney Injury
• Urinary eosinophils
suggest acute
interstitial nephritis.
• RBC casts indicate
glomerulonephritis or
vasculitis.
13. Biomarkers of Renal Function
Biomarker Type Biomarker
Functional marker Serum creatinine
Up-regulated proteins Neutrophil gelatinase-associated lipocalin
(NGAL)
Kidney injury molecule 1 (KIM-1)
Interleukin 18 (IL-18)
13
14. Creatinine
• At present, serum creatinine, which is used to
measure the glomerular filtration rate (GFR),
is the most commonly used marker of renal
function.
14
15. Why we search for new biomarker?
• Serum creatinine is a delayed and unreliable
indicator of acute kidney injury (AKI).
a) The creatinine level is influenced by multiple non-renal
factors.
b) Serum creatinine measurement does not allow differentiation
between hemodynamically mediated changes in renal
function.
15
16. THE AIM of
THE STUDY
was to determine
whether urinary
sediment NF-κB p65
can act as a
biomarker for AKI in
patients with P.
falciparum malaria.
NF-κB P65
P.
falciparum
malaria
biomarker
acute
kidney
injury
16
22. DAY 0 DAY 7
CREATININE
BLOOD UREA
NITROGEN
URINE WBC
Positive
correlation
22
23. • A significant positive correlation was found
between NF-κB p65 in the urinary sediment
cells and serum Cr.
DAY 0 DAY 7
Rs:0.9000; p:0.037 Rs: 0.975; p:<0.005
23
24. CONCLUSIONS
• the urinary level of NF-κB p65 has a potential
role as a disease biomarker for renal tubular
epithelial cells and AKI among complicated P.
falciparum malaria patients.
• Early diagnosis and prompt management
including dialysis can reduce mortality .
24
26. Liver changes in severe Plasmodium falciparum
malaria: histopathology, apoptosis and nuclear
factor kappa B expression
Parnpen Viriyavejakul12*, Vasant Khachonsaksumet1 and Chuchard Punsawad3
Malaria Journal 2014, 13:106 doi:10.1186/1475-2875-13-106
• Results
Hyperplastic Kupffer cells and portal tract inflammation are two
main features found in the liver tissues of severe P. falciparum
malaria cases. In addition, NF-κB is associated with Kupffer cells
and lymphocyte apoptosis in severe P. falciparum malaria.
26
27. Take home
message
the urinary level of
NF-κB p65 has a
potential role as a
disease biomarker in
AKI among
complicated P.
falciparum malaria
patients.
NF-κB P65
P.
falciparum
malaria
biomarker
acute
kidney
injury
27
30. Recent studies show that NF-κB p65 activation has also been
detected in peripheral blood mononuclear cells (PBMCs) from
complicated P. falciparum malaria patients.
30
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The renal epithelial cells that makeup a renal epithelial cell cast can degrade while they are present free in the tubular lumen. In this case, they can form a pigmented or granulated cast. These are less specific than a true renal epithelial cell cast, since other structures such as red cells or white cells can also degrade and form granular casts. Usually, however, large numbers of pigmented granular casts, so called muddy brown casts, are indicative of ongoing acute tubular necrosis (ATN).
"typical" dysmorphic red cells in glomerular haematuria.
Up-regulated 正向調控
accumulation of nitrogenous products in the blood (azotemia)氨血症
Hemodynamically血液動力
1.The creatinine level is influenced by multiple non-renal factors, such as age, gender, muscle mass, muscle metabolism and diet.
2.An increase in the serum creatinine level can take several hours or days to reach a new steady state, represents a delayed indication of a functional change in GFR that occur in the kidney during the early stage of AKI.
3. Serum creatinine measurement does not allow differentiation between hemodynamically mediated changes in renal function, such as pre-renal azotemia from intrinsic renal failure or obstructive uropathy.
The source of NF-κB p65 in urine sediment possibly originated from renal tubular cells, which were detached from the basement membrane into the lumen of renal tubules and/or from the WBC.
NF-ĸB是由p50和p65所形成的heterodimer，存在於細胞質中，平時IĸB會附著在上面，抑制其活性 a. 可以啟動NF-ĸB活性的訊號因子有 i. 發炎激素(proinflammatory cytokine) ii. 細菌與病毒感染(bacterial and viral infection) iii. 氧化自由基(reactive oxygen species) iv. 生長刺激因子(mitogens)
b. 反應路徑： i. 外界活化因子(activators)會使IKK複合體活化 ii. 活化的IKK複合體接著磷酸化IĸB，使其失去與NF-ĸB的結合力，脫落的IĸB，最後會被Proteasome/ubiquitin系統分解掉 iii. 活化的NF-ĸB進入細胞核與基因結合，吸引共活化因子(coactivator)促進轉錄，進而影響基因表現
NF-κB作用機制。在此圖中，將以Rel與p50蛋白組成的NF-κB異質二聚體為例。當處於激活狀態時，NF-κB位於細胞質中且與抑制蛋白IκBα形成複合體。通過內在膜受體的介導，一些胞外信號物質可激活一種稱為IκB激酶（IKK）的酶。IKK轉而磷酸化IκBα蛋白，這將導致後者的泛素化，使得IκBα從NF-κB上脫離下來，最終IκBα被蛋白酶體所降解。被激活的NF-κB接下來轉移到細胞核內，在這裡會結合到DNA上被稱為反應元件（RE）的特異性序列上。DNA/NF-κB 複合體接下來會招募其它蛋白，如輔激活物與RNA聚合酶，這些蛋白將下游的DNA轉錄為mRNA並轉而被翻譯為蛋白質，這些蛋白最終導致細胞功能發生改變
CORRELATIONS BETWEEN URINARY SEDIMENT NF-KB P65 LEVEL AND CLINICAL DATA
Data suggest that NF-κB p65 levels may reflect the degree of renal tubular damage caused by PRBC sequestration, leading to restricted local blood flow and host cytokine response, contributing to progressive renal tubular injury.
