ABSTRACT
ATN
is the second most common cause of all categories of AKI
in hospitalized patients, with only prerenal azotemia occurring more frequently Acute Kidney Injury (AKI) is seen mostly in Plasmodium
falciparum infection, but P. vivax and P.malariae can
occasionally contribute for renal impairment. Malarial AKI is commonly found in
nonimmune adults and older children with falciparum malaria. Occurance of AKI in
severe falciparum malaria is quite common in southeast Asia and Indian
subcontinent where intensity of malaria transmission is usually low with
occasional microfoci of intense transmission. Since precise mechanism of
malarial ATN is not known, several hypotheses including mechanical obstruction
by infected erythrocytes, immune mediated glomerular and tubular pathology,
fluid loss due to multiple mechanisms and alterations in the renal
microcirculation, etc,
INTRODUCTION
Acute tubular necrosis (ATN) is
pathologically characterized by varying degrees of tubule cell damage and by
cell death that usually results from prolonged renal ischemia, nephrotoxins, or
sepsis.
ATN is clinically characterized by acute kidney injury (AKI), which is defined
as a rapid (hours to days) decline in the glomerular filtration rate (GFR) that
leads to retention of waste products such as BUN and creatinine.6
AKI is seen mostly in Plasmodium
falciparum infection. Malarial AKI is commonly found in no immune adults
and older children with falciparum malaria. Occurance of AKI in severe
falciparum malaria is quite common in southeast Asia and Indian subcontinent where
intensity of malaria transmission is usually low with occasional microfoci of
intense transmission1.
Since precise mechanism of malarial ATN
is not known, several hypotheses including mechanical obstruction by infected
erythrocytes, immune mediated tubular pathology, fluid loss due to multiple
mechanisms and alterations in the renal microcirculation, etc, have been
proposed.1 In this paper I will try to explain about Pathophysiology acute tubular necrosis
(ATN) on falciparum
malaria.
PATHOPHYSIOLOGY
Four species of the genus Plasmodium cause
nearly all malarial infections in humans. These are P.falciparum, P.
vivax, P. ovale, and P. malariae. Almost all deaths are caused by falciparum
malaria. Human infection begins when a female anopheline mosquito inoculates
plasmodial sporozoites from its salivary gland during a blood meal.
These microscopic motile forms of the malarial parasite are carried rapidly via
the bloodstream to the liver, where they invade hepatic parenchymal cells and
begin a period of asexual reproduction. By this amplification process (known as
intrahepatic or preerythrocyticschizogony or merogony), a
single sporozoite eventually may produce from 10,000 to >30,000 daughter
merozoites. The swollen infected liver cell eventually bursts, discharging
motile merozoites into the bloodstream. These then invade the red blood
cells (RBCs) and multiply six- to twentyfold every 48–72 h. When the parasites
reach densities of ~50/ L of blood, the symptomatic stage of the infection
begins. 6
The first symptoms and signs of malaria
are associated with the rupture of erythrocytes when erythrocytic-stage
schizonts mature. This release of parasite material presumably triggers a host
immune response. The cytokines, reactive oxygen intermediates, and other
cellular products released during the immune response play a prominent role in
pathogenesis, and are probably responsible for the fever, chills, sweats,
weakness, and other systemic symptoms associated with malaria. In the case of
falciparum malaria (the form that causes most deaths), infected erythrocytes
adhere to the endothelium of capillaries and postcapillary venules, leading to
obstruction of the microcirculation and local tissue anoxia. In the brain this
causes cerebral malaria, in the kidneys
it may cause acute tubular necrosis and renal failure; and in the intestines it
can cause ischemia and ulceration, leading to gastrointestinal bleeding and to
bacteremia secondary to the entry of intestinal bacteria into the systemic
circulation. The severity of malaria-associated anemia tends to be related to
the degree of parasitemia. 7
ATN usually occurs after an acute
ischemic or toxic event, and it has a well-defined sequence of events. The
initiation phase is characterized by an acute decrease in GFR to very low
levels, with a sudden increase in serum creatinine and blood urea nitrogen
(BUN) concentrations. The maintenance phase is characterized by a sustained
severe reduction in GFR, and this phase continues for a variable length of
time, most commonly 1-2 weeks. Because the filtration rate is so low during the
maintenance phase, the creatinine and BUN continue to rise. The recovery phase,
in which tubular function is restored, is characterized by an increase in urine
volume (if oliguria was present during the maintenance phase) and by a gradual
decrease in BUN and serum creatinine to their preinjury levels.
Ischemic acute tubular necrosis
Restricted
local blood flow in the kidneys is considered a major contributor for malarial
AKI. Low intake of fluids, loss of fluids because of vomiting and pyrexial
sweating may be responsible for dehydration and renal ischemia. Depending on
the degree of renal hypoperfusion, the spectrum of manifestations varies from
milder forms like pre-renal azotemia to more severe forms of ischemic AKI.
Pre-renal azotemia is the most common form of renal impairment esulting from
mild to moderate renal hypoperfusion1. Under these conditions,
hypoperfusion initiates cell injury that often, but not always, leads to cell
death. Injury of tubular cells is most prominent in the straight portion of the
proximal tubules and in the thick ascending limb of the loop of Henle,
especially as it dips into the relatively hypoxic medulla.
2
The reduction in GFR that occurs
from ischemic injury is a result not only of reduced filtration due to
hypoperfusion but also of casts and debris obstructing the tubule lumen,
causing back leak of filtrate through the damaged epithelium (ie, ineffective
filtration) 2. Cytoadherence
of P. falciparum infected red blood cells (IRBCs) to the vascular
endothelial cells of different host organs along with rosette formation is
considered as a most important mechanism of severe malaria. IRBCs preferentially
sequester in the deep vascular beds of vital organs, including the brain,
liver, lung, spleen, intestine, and kidney. Parasite proteins referred to as
variant surface antigens (VSA) expressed on the IRBC surface mediate adhesion
of infected erythrocytes to host vascular endothelial receptors. Significantly
more IRBCs were seen in renal vasculature of malaria patients with ARF than
those without ARF. 1
Ischemia leads to decreased
production of vasodilators (ie, nitric oxide, prostacyclin [PGI2]) by the
tubular epithelial cells, leading to further vasoconstriction and
hypoperfusion.
On a cellular level, ischemia causes
depletion of adenosine triphosphate (ATP), an increase in cytosolic calcium,
free radical formation, metabolism of membrane phospholipids, and abnormalities
in cell volume regulation. The decrease or depletion of ATP leads to many
problems with cellular function, not the least of which is active membrane
transport. With ineffective membrane transport, cell volume and electrolyte regulation
are disrupted, leading to cell swelling and intracellular accumulation of
sodium and calcium. Typically, phospholipid metabolism is altered, and membrane
lipids undergo peroxidation. In addition, free radical formation is increased,
producing toxic effects. Damage inflicted by free radicals apparently is most
severe during reperfusion.
The earliest changes in the proximal
tubular cells are apical blebs and loss of the brush border membrane followed
by a loss of polarity and integrity of the tight junctions. This loss of
epithelial cell barrier can result in the above-mentioned back leak of
filtrate. Another change is relocation of Na+/K+ -ATPase
pumps and integrins to the apical membrane. Cell death occurs by both necrosis
and apoptosis. Sloughing of live and dead cells occurs, leading to cast
formation and obstruction of the tubular lumen.
The maintenance phase of ATN is characterized by a
stabilization of GFR at a very low level, and it typically lasts 1-2 weeks.
Complications (eg, uremic and others,) typically develop during this phase. The
mechanisms of injury described above may contribute to continued nephron
dysfunction, but tubuloglomerular feedback also plays a role. Tubuloglomerular
feedback in this setting leads to constriction of afferent arterioles by the
macula densa cells, which detect an increased salt load in the distal tubules.
The recovery phase of ATN is
characterized by regeneration of tubular epithelial cells 7. During
recovery, an abnormal diuresis sometimes occurs, causing salt and water loss
and volume depletion. The mechanism of the diuresis is not completely
understood, but it may in part be due to the delayed recovery of tubular cell
function in the setting of increased glomerular filtration. In addition,
continued use of diuretics (often administered during initiation and
maintenance phases) may also add to the problem.
Histology
ATN has been found as the most
consistent histological finding. Variable degrees of altered tubular cell
morphology, beginning from cloudy swelling to cellular necrosis are seen.
Tubular changes include deposits of hemosiderin granular deposits, presence of
hemoglobin casts in the tubular lumen, and edematous interstitium with
mononuclear cellular infiltration. The venules may contain IRBCs and rosettes.
A recent study from Vietnam and Thailand found that most patients showed
mononuclear cells in glomerular and peritubular capillaries. Phagocytosed
malarial pigment was seen in the cytoplasm of mononuclear cells in some
patients.1
RESUME
Most
intrinsic AKI cases are associated with ATN from prolonged ischemia or toxic
injury, and the terms ischemic and nephrotoxic ATN are frequently used
synonymously with ischemic or nephrotoxic AKI.
The mechanism of renal injury in falciparum malaria is not
clearly known. Low intake of fluids, loss of
fluids because of vomiting and pyrexial sweating, cytokine and NO mediated
arterial vasodilatation specifically organ specific release of NO, resistance
to vasoactive hormones, cytopathic hypoxia leading to decreased ATP synthesis,
cytoadherence of PRBCs, etc all may contribute singly or in combination towards
malarial AKI.
REFERENCES
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2010
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3. Acute
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4. Acute renal failure.
Available at: http://emedicine.medscape.com/article/243492-overview.
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Conquering Malaria.
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Pathogenesis of
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Accessed on 20th 2010
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