Review

Acute Kidney Injury Associated with Severe Leptospirosis:

Fatal Re-Emerging Disease in Latin America
Elber Osorio-Rodríguez 1,2, * , Dairo Rodelo-Barrios 1 , Carlos Rebolledo-Maldonado 2,3 , Alberto Polo-Barranco 2 ,
Jhonny Patiño-Patiño 1,2 , Mauricio Aldana-Roa 1,3 , Valeria Sánchez-Daza 1 , Emily Sierra-Ordoñez 1
and Alfonso Bettin-Martínez 4,5

1 Group of Intensive Care and Comprehensive Care (GRIMICI), Barranquilla 080002, Colombia;
dairorodelo1992@gmail.com (D.R.-B.); jjpp0097@gmail.com (J.P.-P.); dr._aldana@hotmail.com (M.A.-R.);
valesanchezdaza@gmail.com (V.S.-D.); juliethsierraor@gmail.com (E.S.-O.)
2 Department of Intensive Medicine, Clínica Iberoamérica, Barranquilla 080002, Colombia;
carlos.rebolledo@unisimon.edu.co (C.R.-M.); dralbertopolob@gmail.com (A.P.-B.)
3 Departament of Critical Medicine and Intensive Care, Faculty of Medicine, Simón Bolívar University,
Barranquilla 080002, Colombia
4 Faculty of Health Sciences, Metropolitana University, Barranquilla 080002, Colombia;
abettin@unimetro.edu.co
5 Caribbean Research Group on Infectious Diseases and Microbial Resistance, Barranquilla 080002, Colombia
* Correspondence: osorioelver@gmail.com; Tel.: +53-3205240376

Abstract: Leptospirosis is a re-emerging zoonotic disease that has had an unprecedented impact on
most health systems in the world. The spectrum of symptoms is variable and usually ranges from
asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied
by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive
care assistance. Although early antibiotic treatment is usually effective, in severe cases, it may
require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive
Citation: Osorio-Rodríguez, E.;
Rodelo-Barrios, D.;
hemodynamic monitoring, increasing the risk of death. In Latin America, the real burden of acute
Rebolledo-Maldonado, C.; kidney injury in this condition is unknown and may be underestimated due to the rapid progression
Polo-Barranco, A.; Patiño-Patiño, J.; of the disease, similar to other vector zoonoses, and the low coverage of diagnostic tests in primary
Aldana-Roa, M.; Sánchez-Daza, V.; care, especially in rural regions. Therefore, below, we review the clinical aspects and describe the
Sierra-Ordoñez, E.; Bettin-Martínez, A. scientific, clinical, and therapeutic evidence of acute kidney injury attributed to Leptospira spp. and
Acute Kidney Injury Associated with its relevance in patients with severe leptospirosis in Latin America.
Severe Leptospirosis: Fatal
Re-Emerging Disease in Latin Keywords: leptospirosis; acute kidney injury; renal replacement therapy; zoonotic disease;
America. Kidney Dial. 2024, 4, 78–92.
antibiotic; death
https://doi.org/10.3390/
kidneydial4020006

Academic Editor: Raymond Vanholder

1. Introduction
Received: 3 December 2023
Revised: 22 March 2024
Leptospirosis is a re-emerging tropical zoonotic disease with worldwide distribution,
Accepted: 1 April 2024
caused by spirochetes of the genus Leptospira spp. [1]. According to estimates by the
Published: 3 April 2024 Pan American Health Organization (PAHO), leptospirosis is an endemic disease in Latin
America, and there have been an estimated 10,702 cases annually [2]. However, little is
known about the actual current burden, which has become a threat to public health in
the region. The incidence is expected to increase in the coming decades as a consequence
Copyright: © 2024 by the authors. of exposure in vulnerable areas, the peri-urban growth of marginal neighborhoods, and
Licensee MDPI, Basel, Switzerland. limited access to basic services (insufficient garbage collection, absence of drinking water,
This article is an open access article and sewage) recurrent in our region [3].
distributed under the terms and The spectrum of symptoms is variable and usually ranges from asymptomatic cases
conditions of the Creative Commons to fatal manifestations [4]. Although early antibiotic treatment is usually effective, late
Attribution (CC BY) license (https://
presentation during the immune phase of the disease often causes serious complications [5].
creativecommons.org/licenses/by/
These occur in 5–10% of cases and present as Weil’s disease, which involves multiple
4.0/).

Kidney Dial. 2024, 4, 78–92. https://doi.org/10.3390/kidneydial4020006 https://www.mdpi.com/journal/kidneydial

Kidney Dial. 2024, 4 79

organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney

injury (AKI) requiring intensive care assistance [1,6]. In addition, there may be pulmonary
involvement, and this is described as severe pulmonary hemorrhage syndrome, which
reaches a fatality rate greater than 50% [7]. The prognosis depends on early diagnosis,
severity, and timely intensive treatment [8]. However, the presentation is usually different
in different geographical areas of the world and is explained by variations in intrinsic
virulence between serovars and existing species [4].
In the initial clinical phase, the symptoms and signs may be nonspecific due to their
similarity to other tropical diseases such as Dengue, Zika, Chikungunya, Malaria, etc. [6].
Therefore, the early diagnosis of leptospirosis is essential to attenuate disease progression
and obtain better outcomes [9]. In clinical practice, the use of IgM through ELISA, the
microscopic agglutination test, and the polymerase chain reaction (PCR) are useful diag-
nostic tools for screening the disease [10]. Furthermore, detection via the direct growth of
Leptospira spp. in culture samples is useful as a diagnostic tool [6]; however, it is seldom
used in clinical practice due to the difficulty in achieving standardization.
The presence of AKI is an early manifestation of severe leptospirosis and its incidence
ranges from 10 to 60% of total cases [1]. This can occur due to the direct action of the etio-
logical agent, dehydration, rhabdomyolysis, and hemodynamic alterations [11]. Leptospira
spp. enters the host through the skin or mucous membranes, demonstrates hematogenous
spread, and then reaches target organs, such as the liver, lungs, and, mainly, the proximal
renal tubules [12,13]. By infiltrating the renal tubular cells, it leads to direct nephrotoxic
action and triggers an immune response that results in tubulointerstitial nephritis, acute
tubular necrosis, and a risk of renal fibrosis [6].
Renal manifestations are variable and range from mild changes in urinary sediment
to changes in tubular function, such as low urinary protein excretion to irreversible dam-
age [14]. In severe cases, there may be a drop in glomerular filtration rate, severe elec-
trolyte imbalance [15], and the need for renal replacement therapy (RRT) in up to 31.6%
of cases [16,17]. The recovery of kidney function may take several months; however, AKI
exposure from severe leptospirosis can lead to long-term end-stage chronic kidney disease
(CKD) [18–20].
Despite leptospirosis being a public health priority, estimates of AKI, identification,
and the need for RRT are unknown. Therefore, the objective of this review is to describe
the scientific, clinical, and therapeutic evidence of AKI attributed to Leptospira spp. and its
relevance in patients with severe leptospirosis in Latin America.

2. Etiology
The word Leptospira comes from the Greek words leptos (thin) and spira (coiled),
referring to the shape of the microorganism [21]. Leptospira spp. is an aerobic bacterium,
spirochete of the genus Leptospira [13], measuring approximately 0.15–0.3 µm in diameter
and 6–20 µm in length [22]. Its growth is slow, and, in its incubation phase, it may take up
to 90 days [23] with an ideal temperature that ranges between 27 and 30 degrees Celsius.
The axial filaments or endoflagella of the bacteria are what facilitate its mobility [22].
Leptospira species have a lipopolysaccharide layer in their structure and are classified
into three groups: pathogenic, intermediate (without demonstrated virulence), and non-
pathogenic [24]. To date, 13 pathogenic strains have been identified, the main one being
Leptospira interrogans. It is estimated that this species has more than 260 serovariants,
five intermediate strains, and six non-pathogenic or saprophytic strains with more than
60 serovariants [25].

3. Pathophysiology of Leptospirosis and Acute Kidney Injury

The most common complication of leptospirosis is AKI [26]. Leptospira spp. coloniza-
tion of the kidney can cause tubulointerstitial nephritis followed by fibrosis, and, if not
treated in time, it culminates in CKD [19,20,27]. Once Leptospira spp. enters the body, it can
cause direct nephrotoxicity, altering the sodium/phosphate cotransporter in the proximal
 3. Pathophysiology of Leptospirosis and Acute Kidney Injury
The most common complication of leptospirosis is AKI [26]. Leptospira spp. coloniza-
Kidney Dial. 2024, 4 tion of the kidney can cause tubulointerstitial nephritis followed by fibrosis, and, if not 80
treated in time, it culminates in CKD [19,20,27]. Once Leptospira spp. enters the body, it
can cause direct nephrotoxicity, altering the sodium/phosphate cotransporter in the prox-
imal tubule,
tubule, which
which favors
favors thethe generation
generation of of ammonia
ammonia and
and anan increase
increase inin urinary
urinary pHpH [10].
[10]. The
The pathophysiology spectrum is summarized in Figure
pathophysiology spectrum is summarized in Figure 1. 1.

Figure 1. Model of the biological effects on the proximal tubule caused by Leptospira spp. The per-
Figure 1. Model of the biological effects on the proximal tubule caused by Leptospira spp. The persis-
sistence of this microorganism in the kidney tissue causes interstitial inflammation, accumulation
tence of this matrix,
of extracellular microorganism in thetokidney
and damage tubulartissue causes
epithelial interstitial
cells. inflammation,
Abbreviations: accumulation of
LPS: lipopolysaccha-
extracellular matrix, and damage to tubular epithelial cells. Abbreviations: LPS:
rides; PG: peptidoglycan; GLP: Glycolipoprotein; OM: outer membrane proteins; IM: inner mem- lipopolysaccharides;
PG:proteins;
brane peptidoglycan;
AQP-1:GLP: Glycolipoprotein;
aquaporin 1 channel; OM:
H2O:outer
water;membrane proteins; IM:
HPO4: phosphoric acid;inner
NHE membrane
3: sodium–pro-
teins; AQP-1:
hydrogen aquaporin
exchanger; STAT3:1 Signal
channel; H2 O: water;
transducer andHPO :
activator
4 phosphoric
of acid;
transcription NHE
3; :
TGFβ1:
3 sodium–hydrogen
Transform-
ingexchanger;
growth factor betaSignal
STAT3: 1; NF-KB: Nuclear
transducer andFactor-kappa B; IL-6: interleukin
activator of transcription 6; IL-8:
3; TGFβ1: interleukin
Transforming 8;
growth
TNF-α: tumor necrosis factor-α; 3HCO : carbonic acid. Created with BioRender.com.
factor beta 1; NF-KB: Nuclear Factor-kappa B; IL-6: interleukin 6; IL-8: interleukin 8; TNF-α: tumor
3

necrosis factor-α; 3HCO3 : carbonic acid. Created with BioRender.com.

The epithelial cells of the renal tubules are the structures most affected by Leptospira
spp. [28].
TheThis microorganism,
epithelial inrenal
cells of the its outer membrane,
tubules has proteins
are the structures such
most as OmpL1,
affected lipo-
by Leptospira
protein LipL41,
spp. [28]. ThisLipL32, and lipopolysaccharides
microorganism, that can
in its outer membrane, hasadhere
proteinsand infiltrate
such as OmpL1,mononu-
lipopro-
teintubular
clear LipL41, LipL32, cells,
epithelial and lipopolysaccharides
activating complement thatand
cancausing
adhere and infiltrate
direct mononuclear
injury [29–31]. On
thetubular epithelial
other hand, cells,
during activating
the acute phasecomplement and
of the disease, thecausing
existingdirect injury
cytokine [29–31].
storm On the
amplifies
theother hand, during the
pro-inflammatory acute
state, thephase of theofdisease,
migration the existing
macrophages, cytokine
and it storm amplifies
favors kidney tissue in-the
pro-inflammatory state,
jury (Figure 1) [1,32,33]. the migration of macrophages, and it favors kidney tissue injury
(Figure 1) [1,32,33].
One of the preferred sites of the Leptospire spp. is the proximal tubule [30] due to its
affinity One of the
for the preferred sites
Na/K-ATPase pumps, Leptospire
of thewhich spp.
alters is the
their proximalby
functioning tubule [30] due
inhibiting to its
their
affinity for the Na/K-ATPase pumps, which alters their functioning by inhibiting their
activity, also reducing the sodium/hydrogen ion exchanger and aquaporin 1 (AQP-1) in
the apical and basolateral membrane (Figure 1) [34]. As a consequence, it favors the loss of
urinary sodium and potassium, while in the luminal part, there is an accumulation of free
water, thus causing polyuria and secondary to this hypovolemia and hypotension [35].
Kidney Dial. 2024, 4 81

The ascending branch of the loop of Henle is also affected by this microorganism [36].
When tubular cells are injured, they release nitric oxide, which facilitates a decrease in
systemic vascular resistance, thus reducing renal blood flow and the glomerular filtration
rate [37]. It can also reduce the expression of the Na/K/2Cl- cotransporter (NKCC2), which
explains the loss of sodium and potassium in the urine [38]. When control of this ion
channel is lost, the losses of positive electrical charges in the luminal space increase, leading
to a decrease in the reabsorption of calcium and magnesium [36]. The dysregulation of ion
pumps explains the hyponatremia, hypokalemia, hypomagnesemia, and non-oliguric AKI
characteristic of leptospiral nephropathy.
Glycolipoprotein (GLP) is an endotoxin with the capacity to store fatty acids that
contribute to the pathogenic action of Leptospira spp. [39,40]. Its main characteristic is its
specificity for the Na/K-ATPase pump [41] on the cytosolic surface of cell membranes
through the action of its lipid component on the cell membrane (oleic acid), and the
poor adsorption of the albumin toward these fatty acids [42–44]. Synergistic inhibition
reduces the co-transport activity of the Na/K-ATPase pump, increasing affinity for sodium
and potassium loss [45,46]. GLP also induces a systemic inflammatory response with an
increase in the production of IL-6, IL-8, and TNF-α from the expression of peripheral blood
mononuclear cells with the expression of CD69, HLA-DR, leukotriene B4, prostaglandin
E2, and nitric oxide; these contribute to cellular activation and cause a greater degree of
tissue damage (Figure 1) [47,48].
Other factors that facilitate AKI are myoglobinuria induced by rhabdomyolysis, caus-
ing direct toxicity to the kidney, obstruction of the renal tubules, and renal vasoconstric-
tion [6,49]. The persistence of this microorganism in the kidney tissue causes interstitial
inflammation, the accumulation of extracellular matrix, and damage to tubular epithelial
cells [18]. In addition, it has been reported that damage to these cells stimulates the medi-
ator of tubulointerstitial fibrosis (STAT3 transcription factor) that favors the secretion of
transforming growth factor beta (TGF β1) and the production of type II and IV collagen
that has been implicated in the progression of kidney disease [1,50,51].
After the initial injury, the residual and functional nephrons enter into a maladaptive
compensation process to replace the work of the injured glomeruli and tubules [52]. If
chronicity persists in the degree of inflammation, it can favor the invasion of immune cells,
the abnormal migration of fibroblasts, and can lead to fibrosis [52,53]. In patients with
existing chronic kidney disease, the repair and compensation processes are more limited
and the risk of progression to terminal disease increases [54,55].

4. Clinical Manifestations
The main manifestations of severe leptospirosis in AKI are oliguria, anuria, and renal
failure with the possibility of RRT [6]. Between 41 and 45% of patients with AKI are
non-oliguric and have hypokalemia, which determines the characteristic presentation of
leptospirosis [1]. Acute tubular nephritis and acute interstitial nephritis are the main
pathological findings [6]. This is accompanied by skin rash, fever, emesis, frequency, and
nocturia [56].
Laboratory findings are usually varied, finding hematological and urinary alterations.
Among the findings of the urinalysis are pyuria, hematuria, bile pigments, granular casts,
and mild proteinuria [6]. Hypokalemia and magnesiuria continue to be the most important
findings, which can be found in 40–87% and 75% of cases, respectively [57]. Hyponatremia
is also notable in leptospirosis (frequency); however, together with hypokalemia, it is
characteristic of the disease [10]. In atypical situations, the presence of Fanconi syndrome
characterized by the excretion of phosphate, uric acid, bicarbonaturia, glucosuria, and
defects in sodium reabsorption has been described [58].

5. Diagnosis
The early and accurate diagnosis of leptospirosis is essential to mitigate disease pro-
gression [9]. The use of IgM through ELISA and the microscopic agglutination test are
Kidney Dial. 2024, 4 82

useful diagnostic tools for screening the disease in Latin America [10]. In addition, there are
rapid tests valid for the detection of Leptospira spp. antibodies through a portable reagent
strip that provide immediate screening during the acute phase [59,60]. PCR tests continue
to be important in diagnosis, but poor availability and a high cost make them difficult to
apply in clinical practice in Latin America [10].
The early identification of AKI caused by severe leptospirosis is important to reduce
associated morbidity and mortality [61]. The use of serum markers such as creatinine
continues to be important in first care settings [62]. This marker of late kidney damage
is correlated with a drop in the glomerular filtration rate by up to 50% and if it rises to
1.5 times its baseline value, it increases the risk of imminent kidney failure [63]. The RIFLE
and AKIN stages are used to stratify the severity of patients with leptospirosis [64]. These
systems, through the measurement of creatinine, can achieve greater sensitivity (84%) and
specificity (48%) to determine severe AKI secondary to leptospirosis [65].
In recent decades, studies on the use of renal biomarkers to identify premature kid-
ney damage due to leptospirosis have increased enormously [26]. The action of Lep-
tospira spp. in the kidney involves the increased expression of proinflammatory molecules
such as neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemotactic pro-
tein 1 (MCP-1) [66], kidney injury molecule 1 (KIM-1), and N-acetyl-D-glucosaminidase
(NAG) [67]. Although these biomarkers are not specific for AKI and leptospirosis, their
measurement has been important in the early detection of AKI to reduce associated compli-
cations in patients with leptospirosis [11].

5.1. Cellular Immunoglobulin Mucin Domain 1 (KIM-1)

KIM-1 is a type I transmembrane glycoprotein that is expressed in the apical membrane
of proximal renal tubule cells [68]. This biomarker is characterized by appearing 12–24 h
after the onset of the injury [67], relating to the severity of the infection [69]. In a study
in Sri Lanka, KIM-1 was detected on the third day of fever after admission and was at its
highest concentration on the ninth day [63]. Furthermore, it has the particularity of not
being present in healthy individuals; it only increases once damage to the epithelial cells
of the proximal tubule begins [70]. Therefore, the measurement of this biomarker may be
useful in diagnosing AKI in severe leptospirosis [67].

5.2. Monocyte Chemoattractant Protein 1 (MCP-1)

This is expressed when AKI occurs secondary to ischemia [63]. In a study at the Seattle
hospital, they used kidney samples with kidney injury in rats and showed an increase in
MCP-1 4 h after the onset of failure [71]. Nisansala et al. [26], in a cross-sectional study,
verified the direct relationship between the increase in MCP-1 values in the presence of AKI
and leptospirosis. However, the sensitivity was lower compared to other renal biomarkers
such as KIM-1.

5.3. Neutrophil Gelatinase-Associated Lipocalin (NGAL)

This biomarker reaches a concentration of 20 ng/mL in plasma or urine and rises
after 2–4 h, initiating kidney damage. Srisawat et al. [72] determined that urinary NGAL
was associated with AKI with a sensitivity of 86.1% and a specificity of 85.1% in patients
with leptospirosis.

5.4. Urinary N-Acetyl-B-D-glucosaminidase (NAG)

An increase in values started 12 h after damage [67]. Two retrospective studies were
conducted in Thailand in 2016 and 2020, where urinary NAG was related to leptospirosis-
associated AKI [26].

6. Management Strategies
Antibiotic therapy is currently the cornerstone of managing severe leptospirosis [58].
Options include the use of intravenous penicillin [6], ceftriaxone [64], or doxycycline [73]
Kidney Dial. 2024, 4 83

for seven days. On the other hand, it has been shown that the use of ceftriaxone significantly
reduces hospital stay, admission to intensive care, and the risk of AKI and RRT [64,74,75].
In a cohort published in Colombia, it was found that non-administration of antibiotics
was associated with severe disease and admission to intensive care [76]. In the case of
neuroinfection due to leptospirosis, the antibiotic of choice is benzylpenicillin for 2 to
3 weeks [15].
Regarding fluid therapy, it should be guided by hemodynamic variables to reduce the
risk of perpetuating pulmonary, renal, and hemodynamic complications [77]. Guaranteeing
2–2.5 L per 24 h for a urinary output greater than 0.5 mL/kg/h reduces the risk of AKI [78].
After starting water therapy and the poor diuresis response, a diuretic stimulus should be
started, taking into account the high risk of requiring RRT [77].
If arterial hypotension is evident despite the administration of adequate fluid therapy,
the use of vasoactive agents should be resorted to [58]. This is because the hemodynamic
changes associated with severe leptospirosis are similar to a state of septic shock, finding a
high cardiac index and low systemic vascular resistance (hemodynamic behavior of septic
shock) [79]. Therefore, due to the little scientific evidence regarding therapy at this point, it
is advisable to follow the recommendations issued by the Surviving Sepsis Campaign for
the use of vasoactive agents [80].
From 50 to 93% of patients with leptospirosis present thrombocytopenia, and although
the mechanism of platelet consumption is not clear, it has been correlated with sepsis, AKI,
and the severity of the infection, for which platelet transfusions can play a fundamental
role in management [81,82]. Platelet transfusion should be considered if there is bleeding
and a platelet count <50,000/uL [83].
In the advanced stages of the infection, where sepsis and septic shock reveal organ
dysfunction [84], mechanisms mediated by immune complexes generate systemic tissue
damage, and antibiotic therapy produces an excessive release of endotoxins due to bacterial
death (Jarisch–Herxheimer reaction) [85]. The use of plasma exchange could be considered
a reasonable option [86]. This rapidly eliminates circulatory endotoxins, catabolic products,
and the inflammatory markers generated, reducing the risk of associated complications
such as acute tubular necrosis and AKI [86,87]. In addition, it favors clinical recovery and
a significant reduction in mortality in critically ill patients [87,88]. Regarding techniques
such as hemoabsorption, no literature was found.
When addressing the possibility of starting RRT in the context of severe leptospirosis,
in addition to AKI, the basic aspects that make up the dialysis emergency must be consid-
ered [77]. The latter, in patients with severe infection, is more frequently observed as severe
metabolic acidosis, water overload refractory to diuretics, and anuric renal failure [89]. The
indication of RRT should not be delayed, deferred, or underdosed if necessary since its early
use generates a reduction in mortality [77,89]. The continuous modality (continuous ven-
ovenous hemodialysis or continuous venovenous hemodiafiltration) has beneficial effects
in improving survival [16]. However, if this therapy is not available, peritoneal dialysis
has also been associated with excellent results [90,91]. Because paradoxical hypokalemia
is often present in patients with this type of AKI, kaliuretic diuretics and RRT methods
mentioned in the text should be used with caution.
In those patients with respiratory compromise who develop acute respiratory failure,
support for this condition will begin with oxygen therapy, devices such as a high-flow
nasal cannula, and non-invasive mechanical ventilation (CPAP/BPAP). In the case of
reaching the condition of severe ARDS, ventilatory support may be required and should be
administered early [77], and, in this case, invasive mechanical ventilation should follow the
current recommendations for protective ventilation for the management of ARDS [92–98].
In patients with severe ARDS, in conditions of refractory hypoxemia and multiple organ
dysfunction, successful cases have been described with the use of extracorporeal membrane
oxygenation therapy [99–101]; however, there is no strong scientific evidence or guidelines
for its use in these patients.
Kidney Dial. 2024, 4 84

7. Overview of Acute Kidney Injury Secondary to Severe Leptospirosis in Latin America

Leptospirosis is a disease of poor environments and high impact in Latin America [5].
This zoonosis is 100 times more common than in other parts of the world [102]. According
to PAHO estimates, leptospirosis reaches an estimated 10,702 cases annually [2]. Despite
this, until now, AKI secondary to leptospirosis was poorly reported on the continent,
making it difficult to determine the current incidence and burden of the disease.
Next, we describe, through a literature mapping, the studies on AKI associated with
severe leptospirosis in Latin America. We include original articles and case series published
in journals indexed in PubMed, Clinical Key, ScienceDirect, and Scielo with the terms Mesh
(“Weil Disease” AND “Acute Kidney Injury” AND Latin America”) and (“Leptospirosis” AND
“Acute Kidney Injury” AND “Latin America”). Articles were limited to English and Spanish.
Articles that presented bibliographic products with an unavailable abstract and duplicate article
were excluded. Table 1 summarizes the selected articles that met the search criteria.

Kidney Dial.7.1. Overall

2024, 4, Findings
FOR PEER REVIEW 10

Of the 18 published articles, 5 were published before 2010 (27.8%) [16,62,103–105],

11 between 20117.1.
and Overall
2020Findings
(61.1%) [17,28,64,65,102,106–111], and 2 studies were published
Of the 18 72.2%
after 2021 [11,76]. In total, published(Narticles, 5 wereofpublished
= 13/18) beforeincluded
the articles 2010 (27.8%) [16,62,103–105],
information 11
from
between 2011 and 2020 (61.1%) [17,28,64,65,102,106–111], and 2 studies were published
Brazil, 16.7% (N after
= 3/18) from Colombia, and 16.7% from Central America (N = 2/18) (see
2021 [11,76]. In total, 72.2% (N = 13/18) of the articles included information from Bra-
Table 1). In the extracted
zil, 16.7% (Narticles,
= 3/18) fromthe epidemiology,
Colombia, needCentral
and 16.7% from for RRT, and(Nmortality
America in the
= 2/18) (see Table
region were described.
1). In the extracted articles, the epidemiology, need for RRT, and mortality in the region
were described.
7.2. Epidemiology of Acute Kidney Injury
7.2. Epidemiology of Acute Kidney Injury
Of the 18 articles found, 10 publications described the prevalence of AKI secondary
Of the 18 articles found, 10 publications described the prevalence of AKI secondary
to severe leptospirosis,
to severe with 90% (Nwith
leptospirosis, = 9/10)
90% (Nof= articles beingbeing
9/10) of articles fromfrom
South America.
South When
America. When
studying the frequency
studying the offrequency
the selected articles,articles,
of the selected 52.3% (N (N
52.3% = 1124/2148) presented
= 1124/2148) presented AKI
AKI due
to severe leptospirosis.
due to severe leptospirosis. When When the manuscripts
the manuscripts were reviewed
were reviewed byby region in Brazil,
region a prev- a
in Brazil,
alence of 59.2% (N = 948/1602) [64,65,104,106,108,111] was found, and for Colombia it was
prevalence of 59.2% (N = 948/1602) [64,65,104,106,108,111] was found, and for Colombia it
found to be 29.3% (N = 122/416) [76,102,107]. However, only one article published by
was found to be Herrmann-Storck
29.3% (N = 122/416) [76,102,107].
et al. [105] described AKI However, only toone
corresponding thearticle
Centralpublished
American re-by
Herrmann-Storckgion,et al. [105]a prevalence
finding describedofAKI 41.5%corresponding
(N = 54/130). Thesetofindings
the Central American
are summarized region,
in Figure
finding a prevalence
2. of 41.5% (N = 54/130). These findings are summarized in Figure 2.

Figure 2. Epidemiology ofEpidemiology

Figure 2. acute kidney injury
of acute in patients
kidney with severe
injury in patients leptospirosis
with severe ininLatin
leptospirosis America.
Latin America.
Created with BioRender.com.
Created with BioRender.com.
7.3. Renal Replacement Therapy
Of the articles reviewed, the need for RRT was 34.9% (N = 1187/3402) in patients with
severe leptospirosis in Latin America [16,17,28,62,64,65,76,102–111]. Brazil was the coun-
try with the greatest scientific evidence, finding a prevalence of 40% (N = 1114/2785)
[11,16,17,28,62,64,65,103,104,106,108,110,111], followed by Colombia with 15.6% (N =
52/334) [76,102,107].
Early implementation of effective RRT is key to slowing the progression of AKI into
Kidney Dial. 2024, 4 85

Table 1. Acute kidney injury in patients with severe leptospirosis in Latin America.

Hydroelectrolyte
Author Type Study AKI (%) Imbalance Oliguria 1 (%) Dialysis (%) Global Mortality (%) Country
(Na or K)
Daher et al.,
1999 Retrospective Cohort - No n = 103/110 (93.6) n = 89/110 (81) n = 24/110 (22) Brazil
[62]
Andrade et al., Retrospective Total: n = 33/33 (100) Total: n = 13/33 (39.4)
2007 - No - DAdD: n = 15/33 (45.5) DAdD: n = 10/15 (66.7) Brazil
[16] Cohort PaDD: n = 18/33 (54.5) PaDD: n = 3/18 (16.7)
Daher et al., Total: n = 103/196 (52) Total: n = 27/196 (14)
2009 Retrospective Cohort - Yes n = 64/196 (32.7) Oliguric 1 : n = 43/103 (41.7) Oliguric 1 : n = 17/64 (27) Brazil
[103] Nonoliguric: n = 60/103 (58.3) Nonoliguric: n = 10/132 (8)
Daher et al.,
2010 Retrospective Cohort n = 175/201 (87) Yes n = 64/201 (31.8) n = 103/201 (51.2) n = 31/201 (15.4) Brazil
[104]
Herrmann-Storck et al.,
2010 Retrospective Cohort n = 54/130 (41.5) No n = 34/128 (26.6) n = 10/110 (9.09) n = 6/110 (5.45) Guadalupe
[105]
Damasco et al.,
2011 February Retrospective n = 13/27 (48.1) - - n = 3/27 (11.1) n = 3/27 (11.1) Brazil
[106]
Echeverri et al.,
2011 June Case series n = 2/14 (14.3) - - n = 1/14 (7.1) n = 2/14 (14.3) Colombia
[107]
Silva Júnior et al.,
2011 Retrospective Cohort RIFLE: n = 237/287 (82) Yes n = 55/287 (19) n = 105/287 (36.6) Total: n = 37/287 (13) Brazil
AKIN: n = 242/287 (84) Dialysis n = 21/37 (56.7)
[65]
Reis et al.,
2013 Septmeber Cases and controls - - n = 65/172 (37.8) n = 37/172 (21.5) n = 25/172 (14.5) Brazil
[28]
Daher et al.,
2014 February Retrospective Cohort n = 301/374 (80.5) - n = 79/374 (21.2) n = 124/374 (33.2) n = 47/374 (12.5) Brazil
[108]
Daher et al.,
2016 February Cross-sectional n = 162/206 (78.6) Yes n = 42/206 (20.4) n = 80/206 (38.8) n = 26/206 (12.7) Brazil
[64]
Sharp et al.,
2016 February Cases and controls - - - n = 11/173 (6.36) n = 21/173 (12.1) Puerto rico
[109]
Cleto S et al., Total: n = 39/138 (28.3) Total: n = 6/138 (4.3)
2016 Ago Prospective - - - SLED: n = 19/39 (48.7) SLED: n = 3/19 (15.8) Brazil
[110] SLEDf: n = 20/39 (51.3) SLEDf n = 3/20 (15)
Kidney Dial. 2024, 4 86

Table 1. Cont.

Hydroelectrolyte
Author Type Study AKI (%) Imbalance Oliguria 1 (%) Dialysis (%) Global Mortality (%) Country
(Na or K)
Echeverri-Toro et al.,
2017 Cross-sectional n = 60/201 (29.9) - - n = 14/119 (11.8) n = 6/119 (5) Colombia
[102]
Daher et al., Retrospective
2017 - Yes n = 130/507 (25.6) n = 193/507 (38.1) n = 72/507 (14.2) Brazil
[17] Cohort

Daher et al., Retrospective

2019 n = 60/507 (76.1) - n = 127/207 (25) n = 193/507 (39.2) n = 75/507 (14.8) Brazil
[111] Cohort

Meneses et al.,
2022 Prospective - - n = 4/27 (14.8) n = 12/27 (44) n = 2/27 (7.4) Brazil
[11]
Parra et al., Retrospective
2023 n = 60/201 (29.9) - n = 40/201 (19.9) n = 37/201 (18.4) n = 17/201 (8.5) Colombia
[76] Cohort

1 Urinary volume < 400 mL/day after 24 h of appropriate hydration. Abbreviations: AKI: acute kidney injury; K: potassium; Na: sodium; DAdD: delayed, alternate-day dialysis; PaDD:

prompt and daily dialysis; SLED: sustained low-efficiency dialysis; SLEDf: sustained low-efficiency dialysis via hemodiafiltration.
Kidney Dial. 2024, 4 87

7.3. Renal Replacement Therapy

Of the articles reviewed, the need for RRT was 34.9% (N = 1187/3402) in pa-
tients with severe leptospirosis in Latin America [16,17,28,62,64,65,76,102–111]. Brazil
was the country with the greatest scientific evidence, finding a prevalence of 40%
(N = 1114/2785) [11,16,17,28,62,64,65,103,104,106,108,110,111], followed by Colombia
with 15.6% (N = 52/334) [76,102,107].
Early implementation of effective RRT is key to slowing the progression of AKI into
more severe forms and is associated with decreased mortality [17,110]. However, when
evaluating the type of dialysis to use, i.e., sustained low-efficiency dialysis (SLED) vs.
sustained low-efficiency dialysis via hemodiafiltration (SLEDf), no significant differences
were found to reduce mortality; but the use of SLEDf reduced the levels of pro-inflammatory
cytokines faster, which may prevent disease progression [110].
Currently, the search for biomarkers to predict the need for RRT in patients with severe
leptospirosis has been of interest in the region. Meneses et al. [11], in a prospective study
carried out in Brazil, reported that patients with RRT presented significantly higher levels
of Syndecan-1, angiopoietin-2, and FGF-23 compared to those without RRT. However,
scientific progress is awaited to obtain more information on the use of these biomarkers in
patients with severe leptospirosis.

7.4. Mortality
In our review, we found an overall mortality of 12.9% (N = 440/3402) in pa-
tients with severe leptospirosis in Latin America. In Brazil, the prevalence was
13.9% (N = 388/2785) [11,16,17,28,62,64,65,103,104,106,108,110,111], Colombia 7.5%
(N = 25/334) [76,102,107], and 14.8% (N = 27/183) in Puerto Rico and Guadeloupe [105,109].
However, in one cohort, there was a decreasing trend in mortality found in recent years
(decreasing from 22% to 14% and to 11.6% in the last decade), which reflects the early
diagnosis of complications and the provision of appropriate treatment [17].
Advanced stages of the AKIN and RIFLE classification systems have been associated
with an elevated risk of mortality [64]. In a retrospective cohort, patients in AKIN 3 AND
RIFLE “Failure” stages were associated with higher mortality [65]. However, in a cohort
study published in Brazil, it was found that early intervention and the early initiation
of dialysis in these groups reduced mortality in critically ill patients [16]. On the other
hand, four articles were found where 13.5% (N = 44/327) of the patients in need of RRT
died [16,65,102,110]. From our experience in a care center on the northern coast of Colombia
(Barranquilla) during 2023, in patients with advanced stages according to AKIN, the use
of antibiotic therapy, fluid therapy, and diuretics reduced the need for RRT and mortality.
However, in three patients requiring RRT, two died (unpublished data).

8. Conclusions
AKI associated with leptospirosis is a serious complication that increases the need
for admission to intensive care and the likelihood of renal replacement therapy. In Latin
America, high exposure to risk factors for leptospirosis has caused AKI to disproportion-
ately affect all age ranges, exacerbated by the similarity in clinical manifestations to other
zoonoses, the absence of diagnostic tests, and the delay in the onset of antibiotic therapy. In
this region, there is a discrepancy between the data, which underestimates the real burden
of AKI associated with leptospirosis, making it a public health problem, particularly in
countries with weaker health systems. Therefore, it is necessary to improve surveillance
and notification systems and establish protocols for the management of AKI to reduce the
risk of end-stage CKD and death.
Kidney Dial. 2024, 4 88

Author Contributions: Conceptualization, E.O.-R. and D.R.-B.; writing—original draft preparation,

E.O.-R., D.R.-B., J.P.-P., V.S.-D. and E.S.-O.; project administration, E.O.-R.; writing—review and
editing, E.O.-R., D.R.-B., J.P.-P., C.R.-M., A.P.-B., M.A.-R. and A.B.-M. The corresponding author
attests that all listed authors meet authorship criteria and that no others meeting the criteria have
been omitted. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.

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