Global emergence of the chikungunya epidemic: A narrative review of the virus-kidney relationship in Pakistan and beyond

Abstract

Chikungunya, a vector-borne viral disease, has become a critical global health issue due to its capacity for widespread outbreaks, especially in tropical and subtropical regions, and its recent global expansion. The resurgence of Chikungunya virus (CHIKV) in Karachi, Pakistan, has amplified public health challenges, driven by factors such as urbanization, climate change, and socioeconomic vulnerabilities, including limited healthcare infrastructure. Clinically, the disease primarily manifests with fever, rash, and debilitating joint pain, which often leads to prolonged discomfort and decreased quality of life. However, emerging evidence points to atypical and severe complications affecting the neurological, cardiac, and kidney systems, increasing the risk of morbidity and mortality. Kidney involvement in Chikungunya is of particular concern, with acute kidney injury being identified as a critical complication. Timely diagnosis of the infection and early identification of individuals at heightened risk of progressing to severe kidney dysfunction is crucial to improving patient outcomes. Such individuals often include those with pre-existing kidney conditions or other underlying comorbidities, making them more susceptible to complications. This narrative review aims to synthesize and expand upon the current understanding of the mechanisms underlying CHIKV-induced kidney injury. These mechanisms encompass direct viral invasion of kidney tissue, immune-mediated inflammatory responses that inadvertently damage the kidneys, and the aggravation of pre-existing kidney pathologies. Furthermore, the complex interplay between the virus and the host's immune system may exacerbate kidney complications, highlighting the multifaceted nature of CHIKV pathophysiology.

Key Words: Chikungunya virus; Acute kidney injury; Chronic kidney disease; Morbidity; Karachi; Public health

Core Tip: Chikungunya virus (CHIKV) has re-emerged as a significant health threat globally, notably in Karachi, Pakistan, exacerbated by urbanization, climate change, and healthcare limitations. While typically presenting with fever, rash, and severe joint pain, CHIKV increasingly shows severe, atypical complications, notably acute kidney injury. Kidney involvement arises from direct viral invasion, immune-mediated inflammation, and exacerbation of pre-existing kidney diseases. Identifying individuals at high risk, especially those with underlying comorbidities, is critical. Understanding CHIKV-induced kidney pathophysiology, including virus-host immune interactions, is essential for timely diagnosis and targeted intervention, ultimately aiming to reduce morbidity, mortality, and improve patient outcomes.

INTRODUCTION

Karachi, Pakistan's largest metropolitan city, is currently facing an alarming surge in chikungunya cases, a viral disease transmitted by Aedes mosquitoes. This outbreak poses significant public health challenges, further straining the already overburdened healthcare infrastructure in the city[1]. Chikungunya's global prevalence continues to escalate, with the European Centre for Disease Prevention and Control (ECDC) reporting approximately 460000 cases worldwide in 2024, with countries like Brazil and India enduring the highest burdens of the disease[2].

The term "chikungunya" originates from the Makonde language of Tanganyika, now part of modern-day Tanzania, and translates to "that which bends up", a poignant description of the stooped posture resulting from the disease's severe rheumatological symptoms. While chikungunya is typically a self-limiting illness characterized by fever, excruciating joint pain, joint swelling, muscle aches, headaches, fatigue, nausea, and skin rashes, some cases exhibit atypical manifestations. These may involve cardiac and kidney systems, exacerbating the disease's impact. Chronic arthritis is one of the most persistent and debilitating complications, often prolonging the suffering of affected individuals for months or even years[3].

Kidney complications, particularly chikungunya nephropathy, although uncommon, represent a critical area of concern that remains significantly under-researched[4]. Hospital-based studies indicate that acute kidney injury (AKI) occurs in 21% to 45% of chikungunya cases, especially among those presenting with severe or atypical symptoms[5,6]. While AKI is generally not linked to viremia, its association with increased mortality rates underscores its clinical importance[7]. Current research suggests that the chikungunya virus (CHIKV) does not directly replicate within kidney tissues; however, it may provoke kidney damage through immune-mediated mechanisms, including glomerular lesions in certain cases[8]. The long-term consequences of chikungunya-related kidney damage, particularly during subacute and chronic stages of the disease, remain poorly understood, with only limited studies available to date[8]. Preexisting conditions such as chronic kidney disease (CKD)[9] significantly elevate the risk of severe outcomes in affected patients, necessitating heightened vigilance in such populations[10-12].

This review aims to consolidate and analyze the available evidence regarding the clinical and histopathological characteristics, risk factors, and impact of chikungunya-related kidney injury. By enhancing our understanding of the interplay between the CHIKV and kidney health, the findings may inform future research and guide better clinical management of this emerging health concern.

An extensive literature search was undertaken utilizing electronic databases, including PubMed, MEDLINE, Scopus, and Web of Science. The search encompassed articles published between January 2000 and February 2025 to ensure the inclusion of foundational and recent studies. A comprehensive set of keywords and MeSH terms were employed to identify relevant research, including "chikungunya", "chikungunya virus", "chikungunya fever", "European Centre for Disease Prevention and Control", "kidney injury", "acute kidney injury", "Emerging forms", "Clinical Characteristics", "Clinical features", "Chronic Kidney Disease", "Kidney replacement therapy", "Organ failures", "Severe sepsis", and "Kidney Transplantation". Boolean operators (AND, OR) were strategically applied to refine and optimize the search results.

HISTORY AND EPIDEMIOLOGY

CHIKV was first identified in 1952[13] in the United Republic of Tanzania and later reported in other regions across Africa and Asia[14]. Urban outbreaks were documented in Thailand in 1967 and India during the 1970s[15]. In 2004, the virus re-emerged in Kenya and subsequently spread to the Indian Ocean islands, leading to a severe epidemic[16].

Since 2004, CHIKV outbreaks have become increasingly frequent and widespread, a phenomenon partly attributed to viral adaptations that enhance its transmissibility[17,18]. To date, the virus has been detected in over 110 countries spanning Asia, Africa, Europe, and the Americas[19]. In certain islands, transmission has been curtailed due to a significant proportion of the population acquiring immunity following widespread infections. However, in countries where large segments of the population remain uninfected, transmission persists, posing ongoing challenges to public health systems.

CHIKUNGUNYA WORLDWIDE OVERVIEW

According to estimates from the ECDC, approximately 320000 CHIKV cases and over 120 associated deaths were reported globally between June 2023 and June 2024. In the early months of 2025, specifically as of 25 February, over 30000 chikungunya disease cases and 14 related deaths have been recorded across 14 countries or territories spanning the Americas (11), Africa (1), Asia (1), and Europe (1). The Americas have reported the highest number of CHIKV cases worldwide in 2025. By February of this year, Brazil accounted for the majority, with 31484 cases, followed by Argentina with 512 cases, Bolivia with 33, and Paraguay with 23. Outside the Americas, Pakistan has reported 201 cases, representing the sole contributor in Asia. In Africa, Senegal has documented just two cases so far this year[20].

CHIKUNGUNYA IN PAKISTAN

The presence of CHIKV in Pakistan was first documented in 1983, initially detected in rodents, with a few human cases also reported[21]. After a hiatus of nearly three decades, cases re-emerged, primarily in Sindh Province and the Federal Capital. In November 2016, Karachi, Pakistan’s largest city, experienced a significant outbreak, infecting over 30000 individuals, of whom more than 4000 were confirmed through qualitative reverse transcription-polymerase chain reaction (RT-PCR) testing[22]. Since this outbreak, the virus has gradually spread to various cities, predominantly in regions with poor mosquito control measures.

Karachi, in particular, has faced a sharp increase in CHIKV infections, with a notable rise in cases since May 2024. Major government hospitals across the city have reported between 500 and 750 suspected cases daily, exerting considerable pressure on the already overburdened healthcare system. According to government records cited by Al Jazeera, 172 individuals in Karachi tested positive for PCR tests from May to September 2024[23].

In response to this escalating crisis, the Ministry of National Health Services has issued advisories nationwide, emphasizing the importance of preventive and control measures to curb CHIKV infections. This includes targeted interventions to enhance vector control, public health awareness, and systematic disease surveillance across the affected regions[24].

THE VIRUS

CHIKV is an enveloped, single-stranded, positive-sense RNA virus belonging to the alphavirus genus of the Togaviridae family, which also includes the Ross River virus, Semliki Forest virus, and Sindbis virus[25]. Alphaviruses are characterized by their spherical, enveloped structure with an icosahedral capsid.

The CHIKV genome comprises approximately 12000 nucleotides of positive-sense RNA, encoding five structural proteins and four non-structural proteins (nsP1–nsP4), which are crucial for the virus's replication. The structural proteins include glycoproteins E1, E2, E3, the 6K protein, and the capsid (C) protein. These elements collectively play a pivotal role in the virus's infectivity, replication, and survival within its host[26].

NATURAL HISTORY AND TRANSMISSION

CHIKV is transmitted to humans primarily through the bite of infected female Aedes mosquitoes, particularly Aedes aegypti and Aedes albopictus[27], which are also vectors for dengue and Zika viruses. These mosquitoes are most active during daylight hours. Upon biting a human host, the virus infects epithelial cells and dermal fibroblasts, where it replicates for approximately 12 days[28,29]. During this stage, CHIKV can be detected in blood monocytes, facilitating its systemic spread. Viral antigens have been found in muscles, joints, hepatic and cerebral endothelial cells, the spleen, and lymph nodes[28].

In chronic forms of infection, potential reservoirs of the virus include lymphoid organs, liver, muscles, and joints[30,31]. Following the acute phase, macrophages become the principal cellular reservoirs of CHIKV. This can lead to chronic viremia and sustained immune activation, contributing to the prolonged symptoms characteristic of chikungunya fever[30,31].

The transmission cycle is perpetuated when an uninfected mosquito feeds on a human with CHIKV circulating in its bloodstream. The mosquito ingests the virus, which then replicates within its body over several days, eventually reaching its salivary glands. Upon biting another individual, the mosquito transmits the virus into a new human host, where the replication process begins anew, resulting in high viral concentrations in the blood and further potential for transmission.

Although vertical transmission of CHIKV has been documented, particularly during the second trimester of pregnancy, the role of the placenta in virus transmission and its effects on the maternal-fetal interface remain poorly understood. If a pregnant woman is infected near the time of delivery, intrapartum transmission may occur, often leading to severe disease in the newborn[32]. However, there is no evidence of CHIKV being present in breast milk, and no cases of transmission through breastfeeding have been reported to date[33].

Clinical manifestations

Chikungunya is a systemic illness that presents a wide range of symptoms, spanning from asymptomatic cases to mild clinical signs, and even severe manifestations (Table 1). Following an incubation period of 3 to 7 days (with a range of 1 to 14 days), the disease progresses through three distinct phases: Febrile, critical, and recovery[25]. Symptoms generally onset abruptly, marked by fever and general malaise. Arthralgia often precedes the onset of fever and is the initial symptom in approximately 70% of patients[34]. The acute phase of the illness typically lasts between 7 to 10 days, although overlapping clinical presentations have been frequently observed.

Table 1 Clinical manifestations in Chikungunya virus infection.

Organ/system	Typical	Atypical
Systemic	Fever	Lymphadenopathy
Musculoskeletal	Arthralgia, arthritis, myalgia, joint edema, tenosynovitis, backache, persistent or relapsing remitting polyarthralgias	Chronic inflammatory rheumatism, articular destruction
Dermatological	Macular or maculopapular rash, erythema	Bullous skin lesions, scaling, macular erythema, intertrigo, hypermelanosis, xerosis, excoriated papules, urticaria, and petechial spots
Neurological	Headache	Meningoencephalitis, acute flaccid paralysis, Guillain-Barré syndrome, myelitis, seizures, cranial nerve palsies, encephalopathy, sensorineural abnormalities, palsies, neuropathy
Hematological	Lymphopenia, thrombocytopenia	Hemorrhage
Ocular	Red eyes, iridocyclitis, retinitis, episcleritis, macular choroiditis, uveitis, retro-orbital pain, photosensitivity	Optic neuritis, retinitis, uveitis
Gastrointestinal		Nausea, vomiting, abdominal pain, anorexia, diarrhea
Cardiovascular		Myocarditis, pericarditis, heart failure, arrhythmias, cardiomyopathy
Hepatic		Fulminant hepatitis
Pulmonary		Respiratory failure, pneumonia
Renal		Nephritis, acute kidney injury

Despite the complexity of the disease, effective management is feasible if an early diagnosis is achieved and appropriate interventions are undertaken, addressing the complications specific to each phase. In severe cases, chikungunya fever can affect multiple organs to varying degrees. Critical complications include respiratory failure, cardiovascular instability, myocarditis, acute hepatitis, hemorrhage, neurological conditions such as encephalitis or Guillain-Barré syndrome, and AKI, which is considered an atypical manifestation of the disease (Table 1)[35].

KIDNEY INVOLVEMENT

Kidney complications in chikungunya encompass a diverse spectrum, ranging from AKI to glomerular lesions manifesting as nephritic syndrome, hemolytic uremic syndrome, and CKD[36,37]. The reported incidence of kidney involvement during the acute phase of chikungunya infection varies significantly, estimated at 21% to 45%[5,6]. This variability stems primarily from the focus on hospitalized patients, with or without severe or atypical manifestations[4]. Furthermore, earlier studies often lacked standardized definitions of kidney injury or failure, while more recent research has employed criteria such as the Kidney Disease Improving Global Outcomes guidelines or the AKI Network standards[5,6]. Although AKI is not typically associated with viremia, it has been linked to higher mortality rates[8]. Encouragingly, the majority of cases present without symptoms and generally result in full recovery.

MECHANISMS AND MANIFESTATIONS OF KIDNEY DAMAGE IN CHIKV INFECTION

The kidney damage associated with CHIKV infection is the result of a complex interplay of mechanisms, with no single pathway predominating. In many cases, multiple processes converge, amplifying the likelihood of acute or chronic kidney complications. The mechanisms underlying this damage and the resulting manifestations are outlined below:

Mechanisms of kidney damage

Hemodynamic changes: One significant factor contributing to kidney injury in CHIKV infection is the hemodynamic instability induced by the inflammatory response. The viral infection triggers an intense inflammatory process, often referred to as a "cytokine storm", during which the body releases large quantities of cytokines. This cascade of events activates the complement system and platelets, resulting in endothelial damage, increased vascular permeability, and fluid loss. The ensuing hemodynamic instability can lead to impaired kidney perfusion and, in severe cases, shock. These conditions contribute to ischemia of the kidney tubules, ultimately resulting in AKI.

Rhabdomyolysis: Rhabdomyolysis, a known complication of chikungunya infection, also plays a critical role in kidney damage. This condition involves the rapid breakdown of muscle tissue, releasing toxic substances such as myoglobin into the bloodstream. Elevated intracellular calcium levels, caused by the disruption of the transcellular calcium gradient, initiate a series of events leading to cellular death. These changes result in capillary damage, local edema, and increased compartmental pressure. Furthermore, the migration of activated leukocytes to injured muscle tissue and the release of proteolytic enzymes exacerbate the inflammatory process.

In the kidneys, this inflammation contributes to kidney vasoconstriction, ischemia, and obstruction of the distal convoluted tubules by cast formations. The cytotoxic effects of myoglobin on proximal tubular cells, compounded by the depletion of ATP, lead to tubular necrosis. Myoglobin accumulation within the tubular lumen further exacerbates the obstruction, reducing kidney blood flow and impairing glomerular filtration. Collectively, these events culminate in AKI.

Direct viral effects: While CHIKV is not typically found in kidney tissues, it may still contribute to kidney damage through indirect mechanisms. The virus appears to induce kidney injury via cytopathic effects, wherein viral proteins interact with glomerular and tubular structures. Additionally, an immune-mediated mechanism may be involved. Viral antigens may bind to glomerular tissues, triggering local damage, while immune complexes formed between viral antigens and antiviral antibodies lead to the release of inflammatory mediators. Although the kidney does not serve as a site for active viral replication, these indirect effects can nonetheless have significant consequences.

Manifestations of CHIKV-associated kidney damage

AKI: AKI is a potentially grave complication of chikungunya infection, marked by an abrupt and often unpredictable decline in kidney function. While relatively rare, its occurrence seems associated with atypical and severe manifestations of the disease[4]. This condition may arise from a range of mechanisms, including damage induced by rhabdomyolysis, though it can also emerge in the absence of such processes[38,39]. Furthermore, AKI may present with hematuria and proteinuria, indicative of acute glomerulopathy[36]. In a study by Arroyo-Ávila et al[37], proteinuria was observed in 18.6% of patients and hematuria in 2.6% during the acute phase of chikungunya. These kidney disturbances can manifest not only during the acute stage of the illness but may also persist in its aftermath, significantly exacerbating the difficulties faced by those affected.

AKI has been observed even in individuals maintaining hemodynamic stability[40]. In cases involving severe sepsis or septic shock resulting from CHIKV, kidney impairment may stem from the direct action of the virus on kidney tissues[41]. Another noteworthy cause of AKI in chikungunya cases is thrombotic thrombocytopenic purpura, a condition characterized by hemolytic anemia and a significant reduction in platelet count[42,43].

Several risk factors have been identified that elevate the likelihood of developing AKI in patients with chikungunya[12]. Older adults, individuals with pre-existing conditions such as diabetes mellitus or CKD, and those experiencing gastrointestinal symptoms like diarrhea and vomiting are particularly vulnerable. The use of certain medications, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and nonsteroidal anti-inflammatory drugs, further increases the risk.

Despite the wealth of data on AKI in general populations, there remains a significant gap in understanding its impact on pregnant women with CHIKV infection. Research in this domain continues to shed light on the frequency and severity of kidney complications associated with chikungunya. For instance, a study conducted by Escobar et al[44] involving 60 pregnant women in Colombia, reported that approximately 5% of pregnant females experienced kidney dysfunction as a consequence of the infection. This condition, characterized by oliguria unresponsive to fluid or diuretic therapy. The need for ongoing investigations and comprehensive management strategies remains critical to addressing the multifaceted challenges posed by chikungunya-induced AKI.

HISTOPATHOLOGICAL ALTERATIONS IN KIDNEY IN CHIKUNGUNYA DISEASE

Histopathological studies have identified a range of glomerular abnormalities in CHIKV patients (Figure 1). Histopathological data obtained from kidney biopsies in the context of chikungunya infection remain exceedingly limited. The scarcity of such studies makes it challenging to fully elucidate the kidney implications of the virus. Research focusing on the acute phase of CHIKV infection, involving a small cohort of patients, has primarily documented acute interstitial nephritis accompanied by mononuclear infiltrates. Other findings include glomerular congestion, nephrosclerosis, and pigment cast nephropathy, often occurring in the context of severe rhabdomyolysis. These observations highlight the significant impact of the virus on kidney function during its acute phase[45-47].

Figure 1 Morphological patterns in kidney biopsies from patients with chikungunya fever. A: Kidney biopsy showing acute tubular injury and interstitial inflammation in a case diagnosed as acute tubulointerstitial nephritis [hematoxylin and eosin (HE), × 200]; B: High-power view of the same biopsy shown in A with severe acute tubular injury and focal interstitial infiltrates. The glomeruli are normal (PAS, × 400); C: Low-power photomicrograph showing acute tubular injury. The glomeruli are unremarkable (HE, × 100); D: Another kidney biopsy showing acute tubular injury. Two tubular lumina contain pigment cases (HE, × 200).

In addition to the aforementioned morphological abnormalities, studies like those conducted by Aurore et al[48] have unveiled novel insights into the histopathological changes associated with acute-phase CHIKV infection. Among five patients with CHIK-related kidney injury, the researchers reported the presence of non-necrotizing epithelioid cells, giant cell granulomas, and a unique case of focal segmental glomerulosclerosis. These findings expand the understanding of the diverse kidney pathologies that can arise in acute infections and underscore the need for further detailed analysis.

Moving beyond the acute phase, research on the subacute and chronic phases of CHIKV infection is even more limited. To date, only a single study involving 15 patients has provided histopathological insights into these later stages. Kidney samples were obtained from individuals with established kidney damage between 15 days and 24 months following the initial infection. Glomerular lesions were the predominant finding. Among the cases, FSGS and lupus nephritis were identified in three patients each. Collapsing glomerulopathy, membranous nephropathy, crescentic glomerulonephritis, and thrombotic microangiopathy were documented in two cases each, while one patient exhibited evidence of pauci-immune vasculitis. Importantly, despite these significant findings, viral material from CHIKV was not detected in the kidney tissues examined. This lack of direct viral evidence has led researchers to hypothesize that CHIKV may act as a trigger, initiating kidney lesions in genetically predisposed individuals[8].

The remaining histopathological observations available for CHIKV-associated kidney damage have largely been derived from autopsy reports. Notably, Sharp et al[49] made a groundbreaking discovery by identifying the presence of CHIKV antigens in the kidney tissues of 11 individuals who succumbed to the infection. Using immunohistochemistry techniques, CHIKV antigens were detected in various kidney compartments, including glomeruli, blood vessels, interstitial connective tissues, inflammatory infiltrates, and renal tubular epithelial cells. This was the first study to establish a direct association between CHIKV antigens and kidney tissues, offering critical evidence of the virus's involvement in kidney pathology.

ROLE OF AKI IN THE PROGRESSION OF CHIKUNGUNYA FEVER

Organ dysfunctions, such as encephalopathy, respiratory failure, and liver, heart, or kidney failure, are typically associated with significant complications in CHIKV infections. Several studies have investigated the influence of kidney failure on the progression of the disease. Interestingly, two studies concluded that kidney failure was not correlated with higher mortality rates in CHIK patients[50,51].

Contrary to these findings, other researchers have reported differing results. Gupta et al[52], in a comparison of survivors and non-survivors among CHIK patients, admitted to the intensive care unit, identified a substantially higher incidence of kidney failure and an increased need for kidney replacement therapy in non-survivors (68.2% vs 2.6%; P < 0.0001). Similarly, Godaert et al[53] found kidney failure in 30.4% of 385 patients over the age of 65 years, noting it as an independent risk factor for mortality in this demographic [hazard ratio = 3.5 (1.7–7.1), P = 0.0007].

More recently, Mesquita et al[54] observed a markedly elevated prevalence of AKI in non-surviving CHIK patients compared to survivors (84.2% vs 25%, P < 0.001). This study identified AKI as an independent risk factor for increased mortality. These findings underscore the profound impact of kidney complications on the disease's severity and patient outcomes.

PROGRESSION OF CHIKUNGUNYA FEVER IN PATIENTS WITH PREEXISTING CKD

The influence of pre-existing conditions on the outcomes of chikungunya infection remains a topic of debate. CKD has been recognized as a potential risk factor for severe or atypical manifestations of the disease[9], though studies present conflicting conclusions. For example, Bonifay et al[5] and Crosby et al[55] did not identify CKD as a risk factor for severe outcomes such as neurological complications, including Guillain-Barré syndrome, encephalitis, cerebral ischemia, and severe sepsis or septic shock.

Conversely, other research indicates that pre-existing CKD may lead to poorer outcomes following CHIK infection. In a study by Perti et al[12], involving 148 patients with CHIK in the United States, the presence of CKD was found to be associated with a 1.5-fold increase in hospitalization risk, even after adjusting for age. Furthermore, two additional studies identified CKD as an independent risk factor, increasing the risk of hospitalization by over four times[10,11]. Moreover, erythropoietin is primarily produced in the kidneys. When kidney function is impaired, its production decreases. This reduction can lead to anemia, as erythropoietin is crucial for stimulating red blood cell production in the bone marrow.

Beyond hospitalization, CKD also appears to elevate mortality risk in CHIK patients. When comparing CHIK outcomes in patients with and without CKD, those with CKD exhibited a 15-fold increase in mortality rates (3% vs 0.2%; P < 0.0001)[10]. Similarly, Simião et al[56] reported a markedly higher mortality rate among CKD patients, with a prevalence ratio of 13.9 (95%CI: 7.86–24.76; P < 0.001) among 245 deceased individuals.

Chikungunya infection and its implications for kidney transplantation

CHIKV can pose unique challenges for kidney transplant recipients and donors.

Transplant recipients: The effects of CHIKV on kidney transplant recipients remain inadequately documented, with most available data stemming from case reports. The clinical course of CHIKV infection in transplant recipients can differ from that in immunocompetent individuals. Symptoms may include fever, arthralgia, and rash, but the severity can vary. Overall, the prognosis for kidney transplant patients with CHIKV infection appears favorable, with most experiencing complete recovery of symptoms, despite some cases showing temporary kidney function decline and requiring hospitalization[57,58]. Interestingly, kidney transplantation has been deemed safe in cases where a living donor exhibited persistently positive IgM antibodies for up to 101 days but had negative nucleic acid tests (NAT)[59]. In a retrospective study of 32 kidney transplant patients from northeastern Brazil, 22% developed AKI during the acute phase of CHIK infection[60]. Notably, factors such as prednisone use, chronic arthralgia, male gender, pre-existing CKD, and age above 60 years were not identified as risk factors for AKI in these patients. However, the presence of AKI was associated with increased rates of hospitalization, likely linked to dehydration and diarrhea[60].

Transplant donors: There have been cases of successful kidney transplantation from donors who had recently recovered from chikungunya. Comprehensive testing for arboviruses is crucial to assess the risk of virus transmission. In one reported case, a healthy donor sibling who developed chikungunya symptoms just before the transplantation procedure underwent thorough testing, leading to a successful operation[61].

Diagnosis: The diagnosis of CHIKV remains a challenge because its clinical manifestations are not specific and difficult to differentiate from other infections occurring in similar geographic regions, including malaria, typhoid, and dengue; which share common symptoms with CHIKV infection[62]. For this purpose samples collected early i.e. within a week after the infection are helpful for virus detection and isolation due to high levels of viremia[63].

Early diagnosis (acute phase)

NAT: During the acute phase (first 8 days of illness), CHIKV RNA can be detected in serum using RT-PCR and real-time loop-mediated isothermal amplification[63-65].

Viral isolation: In some cases, the virus can be isolated from blood samples collected within the first few days of illness. Viral culture requires a laboratory with biosafety level 3 facilities, yet it remains the gold standard test for diagnosing Chikungunya fever. Virus isolation allows identification of the viral strain and can be important for epidemiologic and research purposes.

Later diagnosis (after the first week)

Serologic testing: After the first week of illness, serological tests for the detection of specific anti-CHIKV IgM and IgG are more frequently used: (1) IgM antibodies: Anti-CHIKV IgM is detectable after 3-5 days of infection and remains elevated for 3-6 months; and (2) IgG antibodies: Anti-CHIKV IgG is detectable after 14 days of infection and may persist in the blood for years.

The viral antigen detection is achieved by using an enzyme-linked immunosorbent assay, an immunofluorescence assay, a rapid diagnostic test, and immunoblotting methods. However, these serological techniques detecting specific anti-CHIKV IgG and IgM may be non-specific with possibilities of cross-reactivity between the CHIKV antibody and other alphaviruses. These methods then require a confirmation using the gold standard assay, which requires the detection of neutralizing antibodies by the plate reduction neutralization test or microneutralization assays, which require a sophisticated high biosafety laboratory setting and well-trained personnel[66].

The current gold standard method for CHIKV detection is RT-PCR but this method remains expensive for developing countries. For this reason, serological diagnostics are mostly used in developing countries because they are cost-effective[67].

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of Chikungunya fever can be particularly challenging, especially in Western countries where it is often misclassified as a rare disease and may even be unfamiliar to specialists. The condition's clinical presentation varies depending on the phase of the disease, complicating its distinction from other ailments[68]. During the febrile phase, it can closely resemble several common viral infections such as influenza, adenovirus, measles, rubella, and enteroviruses, as well as bacterial infections including rickettsial diseases, typhoid fever, and leptospirosis. Additionally, it may mimic emerging illnesses such as COVID-19. Beyond infectious causes, the disease can present similarly to autoimmune disorders like Still's disease or systemic lupus erythematosus, or even acute leukemias (Table 2).

Table 2 Differential diagnosis of chikungunya fever.

Infectious and immune-related causes
Other viral fevers
Dengue fever	Zika virus
Ross River virus	Enterovirus
Adenovirus	Other Alphaviruses
Rubella	Parvovirus B19
Ebola fever	Hanta virus infection
West Nile fever	Crimean-Congo fever
Bussuquara fever	Mayaro fever
Kyasanur forest disease	Lassa fever
Hepatitis B	Hepatitis C
Mumps	Herpesviruses
Parasitic infections
Falciparum malaria
Bacterial infections
Leptospirosis	Rickettsiae
Typhoid
Others
Still's disease or systemic lupus erythematosus	Acute leukemias

A detailed medical history is indispensable for an accurate differential diagnosis. This includes a thorough exploration of the patient's geographic origin, recent travel to endemic areas, and careful evaluation of symptom progression, as these factors provide vital clues for differentiation.

Vaccine

Currently, there is one chikungunya vaccine available in the United States, called IXCHIQ2. It is a live attenuated vaccine and was approved by the Food and Drug Administration in November 2023. The vaccine is given as a single intramuscular dose of 0.5 mL. It is licensed for use in adults aged 18 years and older. The vaccine is recommended for travelers to areas with a risk of chikungunya, particularly those at higher risk of severe disease, such as older adults and individuals with underlying medical conditions.

Therapy

There is currently no treatment available to prevent chikungunya disease or its potential complications, such as kidney involvement. However, early and accurate diagnosis remains crucial. It is essential to avoid the use of acetylsalicylic acid (aspirin) and ibuprofen, as these medications can increase the risk of hemorrhagic manifestations. To alleviate symptoms like fever and joint pain, paracetamol is a safer alternative. The role of steroids, immunoglobulins, and N-acetylcysteine in treatment remains a topic of debate, and there is no evidence supporting the use of steroids to prevent AKI.

For patients experiencing kidney complications, hemodialysis may be required for hemodynamically stable individuals, whereas continuous dialysis may be necessary for those who are hemodynamically unstable. Early identification of patients with severe chikungunya is of paramount importance. Comprehensive medical evaluation, including assessing blood volume, monitoring serum creatine phosphokinase levels, and ensuring electrolyte balance, plays a critical role in preventing AKI. The administration of nephrotoxic drugs should be strictly avoided, and close monitoring of clinical and laboratory parameters is essential to detect and mitigate AKI at its earliest stages. Post-discharge care is equally vital, with close follow-up recommended for patients who experienced AKI during the course of chikungunya. It is worth noting that individuals who develop AKI during chikungunya infection are at risk of progressing to CKD, even if they had normal kidney function previously. Moreover, patients with preexisting chronic kidney failure who contract chikungunya and develop AKI are likely to advance more rapidly to severe stages of CKD[10-12].

Routine use of antibiotics is not indicated for chikungunya. Nevertheless, bacterial sepsis may complicate the disease, particularly in cases of severe leukopenia and immunosuppression, leading to septic shock. In such scenarios, timely administration of appropriate antibiotics becomes critical.

Platelet transfusion is warranted in patients with severe thrombocytopenia and hemorrhage or those requiring emergency surgical intervention. However, blood transfusion in cases complicated by severe bleeding should be approached cautiously, as it may result in liver complications or refractory acidosis.

The long-term consequences of Chikungunya disease remain insufficiently documented. Ongoing rheumatic symptoms significantly impair functional capacity, influencing various dimensions of daily activities and overall quality of life, exceeding what standard tools typically measure[69]. Based on these findings, incorporating physical exercise regimens such as manual therapy, aerobic activities, resistance training, and stretching routines along with the use of orthopedic footwear as part of a multidisciplinary, patient-focused strategy could enhance physical functionality and, in turn, boost general well-being.

Chikungunya research faces several limitations. Firstly, data remains fragmented in under-researched regions, hindering global insights. Secondly, studies often emphasize acute symptoms rather than long-term effects like persistent rheumatic pain, cognitive issues, and diminished quality of life. Thirdly, the relationship between Chikungunya and pre-existing conditions (e.g., diabetes, hypertension) is underexplored, limiting the understanding of risk factors. Fourth, while men appear to face higher risks, comprehensive research on hormonal, genetic, and physiological factors is lacking. Lastly, although the roles of climate change, urbanization, and socioeconomic factors in disease spread are acknowledged, they remain insufficiently analyzed.

Recommendations

In Pakistan, preventing Chikungunya requires a focus on vector control and public awareness. Community education, elimination of mosquito breeding sites, insecticide spraying, and robust vector surveillance are critical. Public health authorities must collaborate with communities to implement integrated vector management strategies. Improved hygiene, timely interventions, and proactive measures are key to minimizing disease transmission.

CONCLUSION

Chikungunya has become a notable public health concern, with kidney complications, including AKI, often underestimated despite their prevalence. These kidney manifestations stem from a multifaceted interplay of hemodynamic instability, rhabdomyolysis, and immune-mediated damage. While significant strides have been made in unraveling these mechanisms, substantial gaps persist, particularly in understanding the long-term repercussions of CHIKV on kidney health. Advancing research in this area is vital to deepen our knowledge of these complex processes and refine strategies for the effective management of chikungunya-associated kidney injury. This highlights the pressing need for heightened awareness, prompt diagnosis, and proactive intervention to mitigate the impact of this debilitating infection.