Acute Kidney Injury in Severe Dengue: Current Evidence and a Latin American Overview

1. Introduction

Dengue virus (DENV) infection is an arboviral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes, endemic to tropical and subtropical regions [1]. In the Americas, according to estimates from the Pan American Health Organization (PAHO), more than 10 million cases were reported in 2024, and in 2023, the region accounted for 80% of global cases [2]. This recent increase reflects a marked rise compared with previous reporting periods and underscores that dengue burden in the Americas has reached historically unprecedented levels [3]. The rapid growth of DENV, with the co-circulation of multiple serotypes and the resulting variability in clinical outcomes, represents a priority threat to public health in the Americas [4]. Its transmission is determined by vector density, climate change, and the susceptibility of human populations [5,6]. This entails significant economic and health costs associated with hospitalization, intensive care use, and lost productivity [7].

DENV belongs to the Flaviviridae family and consists of four antigenically distinct serotypes (DENV1-4) [8]. These serotypes are genetically similar and share approximately 65% of their genome [9]. The viral genome has three structural proteins (C, prM, and E) that form the components of the virion and seven non-structural proteins (NS1, NS2A/B, NS3, NS4A/B, NS5) involved in viral RNA replication [10]. The incubation period for dengue varies from 3 to 10 days (average 4–7 days) [11]. Once inside the host, DENV infects a variety of cells and tissues, including monocytes/macrophages, lymphocytes, and endothelial cells, as well as organs such as the lungs, stomach, and kidneys [4].

The clinical spectrum of the disease is heterogeneous and can range from mild, self-limiting illnesses to severe, fulminant forms [12]. The severity of dengue depends on immunopathological mechanisms involving both viral and host factors, leading to microvascular and circulatory damage [13]. The disease can progress during the critical phase, with severe plasma loss, contributing to dengue shock syndrome and multiple organ dysfunction [14]. Furthermore, the genetic background associated with the immune response, including antibody-dependent amplification in secondary infections with heterologous serotypes, has been linked to worse outcomes [13].

The pathophysiological mechanisms underlying DENV-induced kidney injury remain incompletely understood [15]. However, several etiologies have been proposed that frequently coexist, including hemodynamic instability, direct viral invasion and tubular cytotoxicity, rhabdomyolysis, and immune-mediated mechanisms [1]. No single mechanism appears to predominate, and two or more pathogenic mechanisms often coexist [16]. Histopathologically, acute tubular necrosis in the proximal convoluted tubules is the main finding [8]. Clinically, acute kidney injury (AKI) may be accompanied by elevated serum creatinine (CrS), proteinuria, and, in some cases, hematuria. Glomerular patterns (nephrotic syndrome) and, less frequently, hemolytic uremic syndrome have also been described [17]. Currently, no specific antiviral therapy is approved to modify the course of dengue; therefore, the treatment of AKI involves supportive care, with goal-directed hemodynamic resuscitation and renal replacement therapy (RRT) when indicated [13].

In Latin America, clinical information on AKI secondary to dengue is scarce and scattered. This gap is particularly relevant because AKI has also been recognized as an important complication in other severe tropical infectious diseases in the region [18]. The objective of this review is to describe and synthesize the epidemiological, pathophysiological, and therapeutic evidence on AKI attributed to DENV, and to assess its relevance in patients with severe dengue in Latin America, identifying knowledge gaps and operational considerations for health systems with heterogeneous access to laboratory testing, renal monitoring, intensive care, and RRT. This manuscript was developed as a narrative review. The global sections on pathophysiology, clinical manifestations, diagnosis, management, and prognosis were based on a non-systematic, topic-driven literature review. In contrast, the Latin America-specific overview was based on a focused structured search.

2. Etiological Agent and Transmission Cycle

DENV is a positive-sense, single-stranded RNA flavivirus responsible for one of the most widespread tropical infectious diseases in recent decades [6,19]. Its genome is encapsulated and surrounded by a lipid envelope. The virion expresses three structural proteins: C, prM/M, and E [10,20]. prM is crucial for preventing premature fusion of the E protein before the virions mature [21]. Non-structural (NS) proteins include NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 [13]. These lipid-associated structures are essential for transcription, assembly, replication, invasion, and immune evasion in the host [20,22,23]. See Table 1.

The virus has four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) and is transmitted by female mosquitoes of the genus Aedes, primarily Aedes aegypti and, less frequently, Aedes albopictus (adapted to colder climates) [8]. The serotypes are genetically similar and share approximately 65% of their genomes [9]. The incubation period in humans is 3 to 10 days (average of 4–7 days) [11]. During viremia (usually ~5 days), mosquitoes become infected by feeding on the blood of viremic individuals [37]. The virus replicates in the mosquito’s midgut and reaches the salivary glands after an extrinsic incubation period [38]; infectious saliva is inoculated during feeding, introducing the virus into the bloodstream of the new host and initiating another cycle [4,9].

3. Immunity and Determinants of Severity

Following initial infection with any DENV serotype, immunological memory develops, providing homotypic protection and partial, transient heterotypic protection [13]. The host’s genetic background, certain viral variants, and immune responses modulated by prior infections have been associated with an increased risk of severe disease [13]. In Latin America, multiple analyses have identified DENV-2 as a determinant strongly associated with severe dengue in different contexts [39], partly due to its high replicative efficiency and the intensification of inflammatory and apoptotic responses in host cells [40,41]. Furthermore, secondary heterotypic infections are associated with severe forms and a higher risk of mortality [42].

In addition to shaping systemic immune responses, DENV non-structural proteins also contribute to immune evasion by interfering with intracellular antiviral signaling pathways. NS4B inhibits type I interferon signaling [35]. NS5 mediates STAT2 binding and degradation, thereby impairing antiviral interferon responses [36]. Moreover, DENV also targets mitochondria-linked innate immune defenses: NS3 can antagonize Retinoic acid-Inducible Gene I (RIG-I) translocation to mitochondria-associated Mitochondrial Antiviral Signaling protein (MAVS) [43], and NS2B promotes cyclic GMP–AMP synthase (cGAS) degradation, thereby impairing mitochondrial Deoxyribonucleic Acid (DNA) sensing during infection [44].

4. Pathophysiology

4.1. Hemodynamic Mechanisms

Plasma leakage is a central event in severe dengue and underlies renal hemodynamic compromise [28,45]. In experimental models, the dengue NS1 protein has been shown to induce vascular leakage on its own, with increased vascular permeability and inflammatory cytokine production [46]. Furthermore, NS1 has been shown to alter the endothelial glycocalyx, leading to loss of vascular barrier integrity [47]. Additionally, experimental studies have identified that mast cell-derived tryptase also contributes to the disruption of endothelial junctions and plasma leakage [48]. Together, these mechanisms promote effective hypovolemia and, in the most severe cases, shock, leading to prerenal AKI and potentially initiating the transition to established tubular damage. See Figure 1.

4.2. Tubular and Vascular Damage

When renal hypoperfusion persists in the critical phase, AKI can progress to acute tubular necrosis [49]. Edema and hemorrhage, as well as tubular injury with cell detachment and necrosis, have been described in autopsies of fatal cases, findings consistent with established ischemic damage [8]. These same studies also observed thrombi in the glomerular capillaries and intratubular blood material, suggesting that, in addition to the hemodynamic component, a microangiopathic component may coexist in some patients [8,50]. This possibility has also been supported by renal biopsy cases showing glomerular microthrombi consistent with dengue-associated thrombotic microangiopathy [51,52]. Taken together, these findings indicate that AKI in dengue should not be understood solely as a consequence of hypovolemia, but rather as the result of an interaction between tubular ischemia, endothelial injury, and microvascular damage [8,52]. See Figure 2A,B.

These observations also suggest that, in selected severe cases, a microangiopathic component may contribute to greater clinical severity, potentially favoring more pronounced renal dysfunction and the need for renal replacement therapy. However, direct clinical correlations with outcomes such as RRT requirement or mortality remain insufficiently characterized in the available literature.

4.3. Rhabdomyolysis and Myoglobinuria

Rhabdomyolysis constitutes an additional and potentially treatable mechanism of dengue-associated AKI [53,54]. The most direct evidence comes from renal biopsy reports documenting acute tubular necrosis (ATN) with tubular myoglobin deposition, consistent with pigment nephropathy secondary to muscle damage [55]. Other original cases described myoglobinuria, marked elevation of creatine kinase, and the need for dialysis in the context of severe dengue [54,56]. In parallel, experimental studies demonstrated that the virus can infect human muscle satellite cells, while human studies documented an increase in TNF during acute infection [57,58]. Taken together, these findings support the idea that muscle damage may result from both direct viral injury and a myotoxic inflammatory response [57,58]. See Figure 2C.

4.4. Direct Inflammatory and Viral Involvement of the Kidney

Renal involvement in dengue appears to extend beyond hemodynamic alteration [8,59]. A tissue study of fatal dengue cases detected NS1 antigen in the kidney, although the authors noted that these findings did not allow a definitive distinction between antigen within the renal parenchyma and antigen present in residual intravascular blood [60]. In line with this, a subsequent histopathological study documented severe renal damage in human autopsies but did not consistently demonstrate active viral replication in the kidney [8]. More recent studies in fatal DENV-4 infection and in children with fatal dengue identified NS3 in renal tissue, together with mononuclear infiltrates, edema, vascular congestion, and increased expression of inflammatory and endothelial-related mediators, including TNF-α, IFN-γ, MMP-9, VCAM-1, VEGFR-2, and RANTES [59,61]. Taken together, these findings suggest that renal involvement in severe dengue may span a spectrum ranging from secondary systemic inflammatory injury to possible local viral participation. However, this interpretation should remain cautious, as the available studies are limited and do not yet conclusively establish active viral replication within the renal parenchyma [8,59,60,61].

5. Clinical Manifestations

Patients infected with dengue may be asymptomatic or present symptoms ranging from moderate to severe, possibly resulting in fatal outcomes [12]. Clinically, dengue infection progresses through three phases: febrile, critical, and recovery [4]. The febrile phase lasts approximately one week and is distinguished by high fever, severe headache, myalgia and arthralgia, retro-orbital pain, fatigue, nausea, vomiting, anorexia, and minor bleeding [62]. The critical phase is characterized by increased vascular permeability with plasma leakage and may also be accompanied by significant bleeding [4]. The critical phase usually develops as viremia declines and is driven mainly by host inflammatory and vascular responses rather than by viral replication alone [14,63]. The disease can progress during the critical or recovery phase, with severe plasma loss, hemorrhage, or multiple organ failure, which can lead to death [64]. The recovery phase is characterized by progressive reabsorption of extravascular fluid, accompanied by clinical improvement, return of appetite, and hemodynamic stabilization [65].

In the context of severe dengue, AKI affects approximately 35% of patients in a recent multicenter cohort [66]. This complication increases the need for dialysis, prolongs hospital stay, and is associated with higher mortality [15,67]. The main renal manifestations include proteinuria and oliguria, which are frequently reported [53,68]. Among the prognostic pathological findings are ATN [55,69], rhabdomyolysis with myoglobinuria [55], and glomerular patterns, including glomerulonephritis in selected reports and series [68,70]. Laboratory abnormalities in dengue-associated renal involvement are diverse and involve both urinary and serum markers. Urinalysis often finds hematuria in 59.3% and microalbuminuria in 65.9% of patients [71,72]. Elevated serum CrS is a common finding in patients with dengue-associated kidney involvement [53]. Electrolyte problems are also common. In studies from Latin America and Asia, hyponatremia rates vary widely, from 21% to 62%, with an average of 45.3% [73,74,75]. Hypocalcemia is more common in moderate to severe cases, especially in children [76,77]. Such variability is probably related to differences in case mix, disease severity, timing of assessment, and study methodology.

6. Diagnosis

Dengue should be diagnosed based on clinical suspicion, especially in patients with a compatible epidemiological context [15]. Etiological confirmation can be performed using direct and indirect methods. Direct methods include detection of the viral genome by RT-PCR, particularly useful in the early phase of the disease, and NS1 antigen detection, which can be performed from the first days of clinical presentation [78]. Among indirect methods, IgM and IgG serological tests are useful both for diagnostic confirmation and for differentiating primary from secondary infection [79]. In this context, IgM becomes more useful from the fifth day of symptoms onward [78], while the combination of NS1 with IgM/IgG increases diagnostic sensitivity and widens the detection window [80].

Among the systemic complications of dengue, AKI is particularly significant due to its association with worse clinical outcomes [15]. In a clinical cohort, Hussain et al. documented AKI in 14% of the patients evaluated [74]. Within this group, KDIGO stage 1 predominated, followed by KDIGO 2 and KDIGO 3 [74]. These findings reinforce the need for early recognition of renal involvement during the course of infection [71].

The diagnostic evaluation of AKI is based primarily on serum CrS, blood urea nitrogen, urine output, and estimated glomerular filtration rate [81]. However, these parameters have limitations, as they are frequently altered once kidney injury is established [82]. Even so, they remain the basis for clinical management and severity stratification [81]. In this regard, the KDIGO criteria classify AKI based on increased serum CrS and decreased urine output [81].

In addition to traditional markers useful in AKI [81], biomarkers with the potential to identify kidney injury at earlier stages have been evaluated. Among these, serum cystatin C has shown better performance than CrS in detecting early AKI [83], while markers of tubular injury such as NGAL, KIM-1, IL-18, and L-FABP have demonstrated utility in recognizing intrinsic kidney damage before the evident rise in CrS [84]. More recently, the urinary combination [TIMP-2]×[IGFBP7] has emerged as a marker of tubular stress and early AKI risk in critically ill patients [85,86]. However, in dengue, evidence supporting the clinical utility of these biomarkers remains limited; therefore, they should currently be considered complementary to conventional clinical and laboratory evaluation [87]. In resource-limited settings, early recognition of dengue-associated AKI still relies primarily on clinical assessment, urine output monitoring, serial serum CrS measurement, and timely identification of hypovolemia or shock. In this context, advanced biomarkers may be unavailable or of limited practical applicability.

7. Management Strategy

Prevention of dengue-associated AKI is one of the most important pillars of management [87]. Treatment at the onset of the critical phase of the disease consists of monitoring in the intensive care unit, including vital signs, hematocrit, platelet count, urine output, hemorrhagic manifestations, and level of consciousness [49]. Although there is no targeted management strategy for AKI prevention, the priority is to restore circulating volume through the administration of crystalloid solutions [88]. The clinical management algorithm formulated by the PAHO emphasizes fluid resuscitation as a treatment priority, according to the risk group, and the use of intensive intravenous regimens in patients with severe dengue [89]. According to these risk groups, in the critical phase and in categories B2 and C, capillary leak, hypovolemia, and renal hypoperfusion occur, leading to elevated renal biomarkers. Therefore, timely and appropriate volume replacement plays a central role [89,90]. If AKI worsens, RRT via hemodialysis is indicated, as is routinely used [49]. Although the critical phase is strongly influenced by host inflammatory and vascular responses, routine corticosteroid or immunomodulatory therapy has not shown an established clinical benefit in severe dengue and is not part of standard supportive care [91,92].

8. Prognosis

Recovery of renal function after dengue-associated AKI is a significant factor in morbidity, as failure to recover can have long-term consequences [87]. Short-term improvement in renal function at hospital discharge has been reported in some patients with dengue-associated AKI [17]. However, other studies have shown unsatisfactory recovery of renal function [74], and persistent kidney injury has been reported in up to 45-48% of cases [17]. Long-term renal sequelae remain poorly characterized in Latin America and represent an important area for future prospective research.

9. Overview of Acute Kidney Injury Associated with Dengue Virus in Latin America

Dengue is a serious public health problem in Latin America, exacerbated by climatic phenomena in tropical and subtropical regions [1]. According to PAHO estimates, more than 10 million cases were reported annually in 2024, reaching record highs in 2023 [2]. Despite this, to date, information on AKI secondary to dengue is limited in Latin America, making it difficult to determine the current burden of the disease.

To address this gap, we performed a focused structured search in PubMed, ScienceDirect, the Cochrane Library, LILACS, and Web of Science to identify studies reporting epidemiology, RRT requirements, and mortality associated with dengue-related AKI in Latin America. The search encompassed studies published from the inception of each database until December 2025. Search terms comprised a combination of keywords and MeSH terms related to AKI and dengue, including “Dengue,” “Acute Kidney Injury,” and “Latin America.” The detailed search strategy is provided in Supplementary Table 1. Articles were limited to English and Spanish. Duplicate records and articles without available abstracts were excluded. Table 2 summarizes the studies that met the search criteria.

9.1. Overall Findings

Only four eligible studies on dengue-associated AKI in Latin America were identified, all conducted in Brazil. The available evidence was limited to small case reports, case series, and post-mortem series, with heterogeneous and incomplete reporting of renal outcomes, including limited use of uniform KDIGO staging, incomplete reporting of baseline CrS and urine output, sparse information on renal replacement therapy, and minimal follow-up regarding renal recovery after discharge. This scarcity of studies should not be interpreted as evidence of low clinical relevance, but may instead reflect underreporting of renal outcomes, limited follow-up of kidney function, and restricted visibility of locally published literature not indexed in major databases. The frequency of acute kidney injury varied among studies and was not reported in some cases. Mortality was high in series including fatal cases, whereas the need for RRT was explicitly documented in two of the available studies. Overall, these findings reflect a limited evidence base, with a predominance of severe cases and a high risk of selection bias.

These findings also highlight the need for more standardized reporting of renal outcomes in dengue cohorts from Latin America, particularly in settings where differences in diagnostic and therapeutic resources may further limit comparability across studies, including AKI definition and staging, baseline CrS or the method used for its estimation, urine output, need for renal replacement therapy, and renal recovery at discharge.

10. Conclusions

Acute kidney injury is a relevant complication of severe dengue and has been associated with worse clinical outcomes, including the requirement for renal replacement therapy and death. Current evidence indicates that renal injury in dengue is likely multifactorial, involving hemodynamic disturbances, endothelial dysfunction, tubular damage, rhabdomyolysis, thrombotic microangiopathy, and inflammatory mechanisms. In Latin America, however, the available evidence remains limited, with few published studies and inconsistent reporting of renal outcomes. As a result, the true regional burden of dengue-associated acute kidney injury is still uncertain. Further multicenter studies with standardized definitions and outcome reporting are needed to better characterize this complication and support earlier recognition and management in clinical practice.