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Pathophysiology of Leptospirosis
Article in Shock (Augusta, Ga.) March 2013
DOI: 10.1097/SHK.0b013e31828fae49 Source: PubMed
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2 authors:
Antonio Carlos Seguro
Lucia Andrade
University of So Paulo
University of So Paulo
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PATHOPHYSIOLOGY OF LEPTOSPIROSIS
Antonio Carlos Seguro* and Lucia Andrade*
*Laboratorio de Investigacao Medica (LIM-12) Hospital das Clnicas Faculdade de Medicina Universidade de
Sao Paulo; and Instituto de Infectologia Emlio Ribas, Sao Paulo, Brazil
ABSTRACTLeptospirosis is an acute septicemic illness that affects humans in all parts of the world. Approximately
10% of patients with leptospirosis develop severe disease, the Weil syndrome, with jaundice, acute kidney injury (AKI), and
pulmonary hemorrhage. Leptospirosis-induced AKI is typically nonoliguric with a high frequency of hypokalemia. Experimental and clinical studies demonstrated that tubular function alterations precede a drop in the glomerular filtration rate and
are mainly in the proximal tubule. Studies in humans and animals have demonstrated a decrease in the expression of
proximal sodium (NHE3) and water tubular transporter, aquaporin 1 (AQP1) together with higher renal expression of the
Na-K-2Cl cotransporter NKCC2. In an experimental model, at the initial phase of the disease, the expression of AQP2,
the water transport of the collecting duct, is decreased, which explains the higher incidence of nonoliguric AKI. During the
recovery phase of AKI, AQP2 expression increased in human and animals as a compensatory mechanism. Alveolar
hemorrhage, pulmonary edema, acute respiratory distress syndrome, or a combination of these features may accompany
AKI and is associated with high mortality. Studies with hamsters demonstrated that in leptospirosis a noncardiogenic
pulmonary edema occurs consequently to a decrease in the clearance of alveolar fluid, due to a decrease in sodium
transporter in the luminal membrane (ENaC) and an increase in the NKCC1 basolateral membrane transporter. Antibiotic
treatment is efficient in the early and late/severe phases and revert all kidney transporters. Early and daily hemodialysis,
low daily net fluid intake, and lung-protective strategies are recommended for critically ill patients with leptospirosis.
KEYWORDSLeptospirosis, acute kidney injury, acute lung injury, kidney transporters, lung transporters
INTRODUCTION
RENAL INVOLVEMENT
The reported incidence of AKI in severe leptospirosis varies
from 40% to 60%. The kidney is one of the principal target
organs of Leptospira. Leukocytes, as well as, to a lesser extent,
erythrocytes, are seen in the urinary sediment of patients with
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leptospirosis. Urinary protein excretion, when present, is typically less than 1 g/d. Bile pigments and granular casts can also
be seen. Under dark-field illumination, leptospires can be seen
in urine between weeks 1 and 4 of infection (4).
Interstitial nephritis is the mainly pathological alteration in
patients with leptospirosis even in those without AKI or tubular necrosis. The infiltration is mainly due to mononuclear
cells. Immunohistochemistry demonstrated intact leptospires
throughout the tubular basement membrane, among tubular cells,
within the tubular lumens, within the interstitium, and, in some
cases and in limited numbers, within glomeruli. Fragments of
spirochetes have been found within histiocytes, in the interstitium, and in tubules. Glomeruli maintain a normal aspect (6).
Leptospirosis-induced AKI is typically nonoliguric and
often includes hypokalemia. Seguro et al. (7) studied 56 patients with leptospirosis-AKI and found a higher frequency of
nonoliguric renal failure. The authors also found that morbidity and mortality were lower in those with nonoliguric AKI
than in those with oliguric AKI. The time to reach a serum
creatinine level of 1.5 mg/dL, a parameter of recovery from
AKI was shorter in nonoliguric patients. Nonoliguric patients
required dialysis less frequently than did oliguric patients.
Interesting observation was that of the 30 oliguric patients
on the first day of hospitalization, 16 became nonoliguric on
the second day after volume expansion (if not with pulmonary
edema) and furosemide administration, none of these nonoliguric patients died, whereas 50% of the remaining oliguric
died, mainly from pulmonary involvement.
An interesting finding was that 45% of the patients were
hypokalemic (potassium [K] G3.5 mEq/L) on the first day of
hospitalization, and none were hyperkalemic.
To explain a possible mechanism to the high frequency of
hypokalemia, 11 of these 56 patients were studied prospectively by measuring fractional excretion of sodium (FENa) and
K (FEK) on the first and eighth days of hospitalization. The
urinary K/Na ratio was also calculated. Because practically all
K filtered by the kidneys is reabsorbed in proximal tubule and
in the thick ascending limb of Henle, the urinary K is due to
secretion of this ion in distal and cortical collecting tubules,
consequently to lumen negative potential generated by Na reabsorption, the urinary K/Na ratio is considered an indirect evaluation of distal segments function.
The data showed that mean serum creatinine decreased from
6.0 mg/dL to 1.6 mg/dL, and serum K increased from 3.5 to
4.3 mEq/L. The mean FENa (normal value 1%) was elevated
on the first day (6.0%) and decreased to 1.2%, whereas FEK
(normal value, 8%Y12%) decreased from 102.5% to 12%, and
the mean urinary K/Na ratio decreased from 0.62 to 0.34. The
elevated FEK, which fell concomitantly with the FENa and
urinary K/Na ratio, suggests that the initially increased distal
K secretion is secondary to an increase in the delivery of Na to
distal segments consequently to a decrease in NaCl reabsorption in the proximal tubule, and the elevated urinary K/Na
ratio on the first day suggests that the distal segments are
preserved in leptospirosis.
In an experimental study with guinea pigs inoculated with
Leptospira icterohaemorrhagiae, Magaldi et al. (8) evaluated
the renal tubular function, using clearance and microperfusion
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PATHOPHYSIOLOGY OF LEPTOSPIROSIS
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PATHOPHYSIOLOGY OF LEPTOSPIROSIS
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to increased NKCC1 expression, might have significant deleterious effects in the context of increased pulmonary permeability such as that observed in ARDS.
Similar findings are observed in sepsis, a common cause of
AKI and ALI. Rats submitted to cecal ligation and puncture
(CLP), a model of sepsis, developed AKI and ALI, with pulmonary edema, downregulation of !-ENaC expression, and
upregulation of NKCC1 (26). These findings explain that although a positive water balance is considered, a major predictor of outcome in patients with sepsis, pulmonary edema,
can occur even when the water balance is normal or negative.
Rabb et al. (27) showed that, in rats without lung injury and
submitted to bilateral nephrectomy, there is a decrease in Na
cotransporter expression, followed by increases in vascular
permeability and interstitial edema, providing evidence of the
crosstalk between the lungs and kidneys.
Oxidative stress plays an important role in AKI and ALI related to sepsis. Campos et al. (26) demonstrated that the administration of the antioxidant, N-acetylcysteine, 2 days before
CLP ameliorates AKI, decreases pulmonary edema by !-ENaC
upregulation and NKCC1 downregulation associated with a
decrease in oxidative stress markers (plasma thiobarbituric acidY
reactive substances and 8-isoprostane in lung and kidney tissue).
Future studies are needed to verify the beneficial effect of
N-acetylcysteine in an animal model of severe leptospirosis.
Experimental studies demonstrated that glucocorticoids also
increase !-ENaC expression in the lung and may be an additional therapy to leptospirosis ALI (28). Clinical studies are
controversial, and until this moment, there is no consensus
about the use of glucocorticoids in patients with leptospirosis
with pulmonary involvement.
Furosemide inhibits NKCC1 and may contribute to control
ALI in leptospirosis. It is possible that the findings observed
by Seguro et al. that treatment of initially oliguric patients with
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expression, IKK-! activation, nuclear factor .B (NF-.B) activation, and inflammatory cytokine levels, thereby increasing
survival. They concluded that this protection, which appears to
be dependent on EPO receptor expression activation and on
endothelial NOS expression, is attributable, in part, to inhibition
of the inflammatory response via NF-.B downregulation (34).
Continuous EPO receptor activator (CERA) is an EPO with
a unique pharmacologic profile and long half-life. Rodrigues
et al. (35) hypothesized that pretreatment with CERA would be
renoprotective in the CLP model of sepsis-induced AKI. They
found that pretreatment with CERA preserved renal and tubular function, as well as the expression of NKCC2 and AQP2.
In addition, CERA maintained plasma lactate at normal levels,
as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-.B
was lower in CLP rats that received CERA than in CLP rats, as
were CD68-positive cell counts, whereas renal EPO receptor
expression was higher. Plasma levels of all measured cytokines were lower in CLP + CERA rats than in CLP rats (35).
The question is whether these new therapies could be in
some way effective in Weil syndrome.
FUTURE PERSPECTIVES
The complete genomes of L. interrogans serovar Lai, strain
56601, and L. interrogans serovar copenhageni, strain Fiocruz
L1-130, were sequenced in China and Brazil, respectively. The
genome of Leptospira consists of two circular chromosomes
and is highly conserved between the two serovars (32, 33). The
sequencing of these genomes may contribute to development
of specific culture media, identification of antibiotic resistance
mechanisms, identification of virulence factors, and clarification of host-pathogen interactions mechanisms, as well as the
development of monoclonal antibodies and vaccines.
Weil disease is a classic model of sepsis. Patients with Weil
disease typically develop severe lung injury (diffuse alveolar
hemorrhage, pulmonary edema, ARDS, or a combination of
these features) accompanied by AKI. Despite improved strategies for supporting vital organs and resuscitating patients, the
incidence and mortality rates of septic patients remain quite
high. The prevention of multiorgan dysfunction related to sepsis
in intensive care settings continues to represent a great challenge.
Recently, there are studies, mainly in CLP animal model,
to determine whether drugs that are able to reducing apoptosis, oxidative stress, lipid peroxidation, and also promoting renal tubular cell regeneration, vascular regeneration, and
neoangiogenesis could prevent the multiorgan dysfunction seen
in the CLP model of sepsis. These drugs are also being tested
whether they could be used as therapeutic agents after the induction of the CLP sepsis.
Erythropoietin (EPO) has emerged as a major tissue-protective
cytokine in the setting of stress. De Souza et al. (34) investigated the role of EPO in sepsis-related AKI using a CLP
model. At post-CLP procedure hour 24, septic rats that received EPO presented significantly higher inulin clearance
(criterion standard to measure renal function) than did CLP
rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as
well as preserving endothelial NOS expression, EPO receptor
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