Introduction
Among clinically significant foodborne liver flukes representing a global health burden and relevant to One Health are members of Opisthorchiidae, including Opisthorchis felineus (Rivolta, 1884), Opisthorchis viverrini (Poirier, 1886), and Clonorchis sinensis (Looss, 1907), as well as members of Fasciolidae, namely Fasciola hepatica (Linnaeus, 1758) and Fasciola gigantica (Cobbold, 1855) (FAO 2016). Official statistics estimate that approximately 200,000 individuals are newly infected with these trematodes each year (WHO 2021).
Members of the family Opisthorchiidae inhabit diverse habitats with a minimal geographic overlap between these species. C. sinensis is endemic to East Asia, particularly China and South Korea, with an estimated 15 million individuals infected (Xiao et al. Reference Xiao, Chai, Fang and Lai2023). O. viverrini is prevalent in Southeast Asia, notably in Thailand, the Lao People’s Democratic Republic, Cambodia, and Vietnam, where approximately 12 million individuals are infected (Sripa et al. Reference Sripa, Suwannatrai, Sayasone, Do, Khieu and Yang2021; Zhao et al. Reference Zhao, Feng, Doanh, Sayasone, Khieu and Nithikathkul2021). O. felineus has a broad geographic distribution, with isolated cases reported across Western Europe, including Italy, Spain, Portugal, and Germany (Pozio et al. Reference Pozio, Armignacco, Ferri and Gomez Morales2013), and Eastern Europe, including Russia, Ukraine, Belarus, and Kazakhstan (Chemich et al. Reference Chemich, Zakhlebaeva, Il’ina and Sholokhova2014; Kiyan et al. Reference Kiyan, Bulashev and Katokhin2018; Pakharukova and Mordvinov Reference Pakharukova and Mordvinov2022; Skripova Reference Skripova2013), with an estimated 1 million individuals infected (Pakharukova and Mordvinov Reference Pakharukova and Mordvinov2022). Nevertheless, official statistics likely underestimate the true prevalence (Fedorova et al. Reference Fedorova, Fedotova, Zvonareva, Mazeina, Kovshirina and Sokolova2018).
Fasciolidae species are of significant veterinary concern due to their substantial economic impact on cattle and sheep, particularly in endemic and developing countries (Cuervo et al. Reference Cuervo, Bargues, Artigas, Buchon, Angles and Mas-Coma2024). Humans can become accidental hosts by ingesting water or plants contaminated with metacercariae (Pavlović et al. Reference Pavlović, Dakić, Milosević, Korać, Brmbolić and Dzamić2014). Nonetheless, fascioliasis remains the most prevalent trematodiasis, with human cases diagnosed in over 81 countries worldwide (Caravedo and Cabada Reference Caravedo and Cabada2020).
The life cycle of liver flukes is complex, involving several stages: eggs, miracidia, sporocysts, rediae, cercariae, metacercariae, and an adult form known as maritae. For Opisthorchiidae species, the cycle begins when a freshwater snail, especially of the Bithynia genus, ingests the parasite’s eggs (Nguyen et al. Reference Nguyen, Van Hoang, Dinh, Dorny, Losson and Bui2021; Ponomareva et al. Reference Ponomareva, Orlova, Vlasenko, Serbina and Yurlova2024; Saijuntha et al. Reference Saijuntha, Andrews, Sithithaworn and Petney2022). Within the snail, the eggs develop into cercariae: a free-swimming form of the parasite. Cercariae then penetrate the muscle tissue of cyprinid (carp) fish and then encyst, transforming into metacercariae: the infective stage of the parasite. Definitive hosts, including various fish-eating mammals such as felines, canines, beavers, hamsters (e.g., muskrats), and humans, become infected by consuming raw or undercooked fish (Pakharukova and Mordvinov Reference Pakharukova and Mordvinov2016).
The life cycle of Fasciolidae spp. has some differences from that of Opisthorchiidae spp. Fasciolidae eggs, excreted with the feces of a definitive host, enter freshwater and develop into miracidia. These then invade Lymnaeidae snails (the intermediate host), where they undergo successive stages of development: sporocysts, rediae, and cercariae. The cercariae emerge from the snail and encyst in freshwater, thereby forming metacercariae: the infective stage. Upon ingestion by a mammalian host, the metacercariae excyst in the gastrointestinal tract under the action of gastric juice. The newly excysted juveniles penetrate the intestinal wall, enter the peritoneal cavity, and migrate to the liver. Within the liver, the flukes penetrate the liver capsule and migrate through the parenchyma for several weeks before entering the bile duct, where they mature into adults capable of producing a new generation of eggs (Fang et al. Reference Fang, Yang, Wang, Chen, Li and Liu2022).
Infection with liver flukes results in diseases known as opisthorchiasis, clonorchiasis, and fascioliasis, respectively. These diseases comprise two stages: acute and chronic. The acute stage begins soon after parasite ingestion and is characterised by a fever, weakness, right abdominal pain, and dyspeptic syndrome (Chernikova Reference Chernikova, Steinmann and Utzinger2021). The chronic stage, which gets established approximately 1 month postingestion, is marked by active egg production by adult worms. These eggs are released into water through the host’s feces, thus initiating a new cycle (Pakharukova and Mordvinov Reference Pakharukova and Mordvinov2016). Infection with liver fluke parasites induces significant pathological changes in the hepatobiliary system, including cholangitis, periductal fibrosis, obstructive jaundice, extensive bile duct damage, and cholelithiasis, observed in both humans and animal models (Bahcecioglu et al. Reference Bahcecioglu, Tawheed, Tunc, Artas, Madkour and Cicek2024; Kovner et al. Reference Kovner, Pakharukova, Maksimova and Mordvinov2019; Liu et al. Reference Liu, Zhu, Cai, Lv and Li2019; Sripa Reference Sripa2003). One of the severest complications of opisthorchiasis – in contrast to fascioliasis – is bile duct cancer (Tan and Machrumnizar Reference Tan and Machrumnizar2023). Carcinogenic potential of O. viverrini and C. sinensis is well established, with numerous research articles linking chronic infection by these liver flukes to the initiation of cholangiocarcinoma (CCA) (Pan et al. Reference Pan, He, Yin, Xu, Wu and Yi2024; Papachristou et al. Reference Papachristou, Schoedel, Ramanathan and Rabinovitz2005; Peng et al. Reference Peng, Feng, Rinaldi, Yonglitthipagon, Easley and Laha2014; Plieskatt et al. Reference Plieskatt, Rinaldi, Feng, Peng, Easley and Jia2015). CCA is an aggressive malignant tumor of the bile duct with a high lethality rate and a 5-year survival rate of 9.8% (Elgenidy et al. Reference Elgenidy, Afifi and Jalal2022). The International Agency for Research on Cancer (IARC) has classified O. viverrini and C. sinensis as Group 1 biological carcinogens (carcinogenic to humans). Although the carcinogenicity of O. felineus in humans remains to be definitively proven owing to limited studies, it has been well documented in other mammals, thereby leading to its classification as a Group 3 carcinogen (IARC 2024; Fedorova et al. Reference Fedorova, Kovshirina, Kovshirina, Hattendorf, Onishchenko and Katanakhova2023). Nevertheless, recent years have seen the accumulation of data supporting the carcinogenic potential of O. felineus in both experimental models and clinical practice (Gouveia et al. Reference Gouveia, Pakharukova, Laha, Sripa, Maksimova and Rinaldi2017; Kovshirina et al. Reference Kovshirina, Fedorova, Vtorushin, Kovshirina, Ivanov and Chizhikov2019; Maksimova et al. Reference Maksimova, Pakharukova, Kashina, Zhukova, Kovner and Lvova2017; Mordvinov et al. Reference Mordvinov, Minkova, Kovner, Ponomarev, Lvova and Zaparina2021; Pakharukova et al. Reference Pakharukova, Zaparina, Baginskaya and Mordvinov2022).
Traditionally, diseases associated with liver fluke infections have been considered pathologies of the hepatobiliary system. Diagnosis and treatment of these parasitic diseases involve a comprehensive set of approaches, including (i) ultrasonographic examination of the liver and gallbladder, (ii) duodenal intubation, (iii) stool examination for parasite eggs, (iv) liver function tests (ALT, AST, and alkaline phosphatase), and (v) administration of an anthelmintic therapy (e.g., praziquantel, triclabendazole, or tribendimidine) (Fedorova et al. Reference Fedorova, Fedotova, Zvonareva, Mazeina, Kovshirina and Sokolova2018; Mordvinov and Pakharukova Reference Mordvinov and Pakharukova2022; Pakharukova et al. Reference Pakharukova, Pakharukov and Mordvinov2018, Reference Pakharukova, Samsonov, Serbina and Mordvinov2019; Plengsuriyakarn et al. Reference Plengsuriyakarn, Eursitthichai, Labbunruang, Na-Bangchang, Tesana and Aumarm2012; Sripa et al. Reference Sripa, Mairiang, Thinkhamrop, Laha, Kaewkes and Sithithaworn2009). On the other hand, growing evidence suggests that liver flukes have a broader impact on the definitive host, by affecting more than just the hepatobiliary system. In this review, we highlight the need for a comprehensive approach to investigation into the pathogenesis of the disease, including examination of at least the urinary system in patients with chronic opisthorchiasis, clonorchiasis, or fascioliasis. The aim of this article is to compile and present all existing information on kidney injury development during infections caused by Fasciolidae spp. and three Opisthorchiidae spp.
Materials and methods
Data selection
The analysis included all available scientific data published from January 1950 to February 2025. The following English-language databases were used: PubMed (https://pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.com/), WHO (https://www.who.int/), and IARC (https://monographs.iarc.who.int/list-of-classifications). Russian databases included Rospotrebnadzor (https://rospotrebnadzor.ru/) and eLibrary (https://www.elibrary.ru/defaultx.asp).
To be included in this review, a study had to mention at least one liver fluke (Fasciola hepatica, F. gigantica, Opisthorchis felineus, O. viverrini, or Clonorchis sinensis) and terms indicating kidney injury development (‘kidney disease’, ‘kidney injury’, ‘kidney pathology’, ‘renal disease’, ‘renal injury’, ‘renal pathology’, ‘glomerular injury’, ‘glomerular lesions’, ‘interstitial fibrosis’, ‘glomerulonephritis’, ‘tubular atrophy’, ‘glomerulosclerosis’, ‘glomerulofibrosis’, ‘proximal tubule dystrophy’, ‘renal dystrophy’, ‘kidney stones’, ‘microproteinuria’, ‘macroproteinuria’, ‘proteinuria’, ‘kidney parenchyma change’, ‘kidney injury molecule-1’, ‘KIM-1’, or ‘cast’) or their analogs in the Russian language for Russian databases. The number of publications meeting these criteria was 51. All papers were included in the study. The current review includes case reports, cohort studies, studies on experimental models or cattle, and reviews. All relevant data cited in the manuscript are provided in Table 1.
Summary of all relevant studies of liver flukes associated kidney injuries
Meta-analysis
For the quality assessment of animal studies, the SYRCLE’s Risk of Bias (RoB) tool was used. Quality was presented on a numeric scale, with unclear data and high risk of bias scored as 0, and low risk scored as 1. Data with a RoB score above 5 were considered to have a moderate risk of bias and were included in the meta-analysis. For the quality assessment of human case-control studies, the Newcastle-Ottawa Scale (NOS) was used. Similar to the RoB scoring, studies with an NOS score above 5 were included in the meta-analysis (Table S1). Data extraction and quality assessment were performed by two independent researchers.
Two meta-analyses were conducted. The first meta-analysis addressed the question: ‘Does trematode infection lead to renal function insufficiency?’ For this analysis, data on biochemical markers such as creatinine concentration, tubular reabsorption, Tmax (Transport Maximum), T1/2 (half-time), and BUN (blood urea nitrogen) were used. Since these parameters indicate renal function insufficiency, their effect sizes were pooled (mean score calculated). It should be noted that many studies included pairwise tests between multiple groups; in such cases, each comparison was included in the meta-analysis separately (Table S1).
The second meta-analysis aimed to answer the question: ‘Does trematode infection lead to renal injury?’ Markers such as urine protein, eGFR (estimated Glomerular Filtration Rate), urine IgG, and CIC (Circulating Immune Complexes) were analysed. Data preparation followed the same methodology as in the first meta-analysis. Egger’s test was used to assess data bias towards negative or positive results.
The meta-analysis included all studies that met the following criteria: quantitative research methods, presence of a control group, and pairwise comparisons. Studies that did not use quantification methods (e.g., case reports or clinical descriptions) were excluded from the analysis. Thus, the first meta-analysis included 12 publications and 25 observations, while the second one included 5 publications and 11 observations.
Results
F. hepatica and kidney injuries in humans
Among Fasciolidae, data on kidney injury were available only in relation to F. hepatica. The first documented mention of fascioliasis and renal injury in international databases was made by Farag et al. Nonetheless, they reported no significant renal changes: levels of creatine phosphokinase, lactate dehydrogenase, and results of renal function tests were almost within reference ranges, despite coinfection with Fasciolidae spp. and Schistosoma mansoni (Farag et al. Reference Farag, Salem, el-Hifni and Kandil1988).
Zali et al. have published a case report about a patient with multiple organ damage associated with chronic F. hepatica infection. Unexpectedly, computed tomography (CT) scans revealed not only an increase in the number and size of hypodense lesions in the liver but also extension of the lesions into the pancreas, spleen, and both kidneys. After appropriately administered therapy, no pathological changes associated with liver fluke infection were detectable on CT scans. Those authors believe that this unusual case may be explained by the patient’s compromised immune system, resulting from the use of immunosuppressants (Zali et al. Reference Zali, Ghaziani, Shahraz, Hekmatdoost and Radmehr2004).
Llanos et al. have presented the first documented case report showing the development of systemic vasculitis in the context of chronic F. hepatica infection, with evidence of skin, renal, spleen, ophthalmic, and neurological involvement. The temporal association between the patient’s improvement and fascioliasis treatment supports a cause–effect relationship between these two health problems (Llanos et al. Reference Llanos, Soto, Sabugo, Gallegos, Valenzuela and Verdaguer2006). All included studies reporting kidney injury associated with F. hepatica infection are case reports and clinical descriptions of detected pathology without a control group.
F. hepatica–associated renal injuries in cattle and model animals
In lambs experimentally infected with F. hepatica (mean parasite count per sheep: 4,255), substantial hemosiderin deposition has been detected in proximal tubules of the renal cortex (Pullan et al. Reference Pullan, Sewell and Hammond1970). This was the earliest single histopathological observation reported in the scientific literature. Due to its high molecular weight, hemosiderin cannot pass through renal filters and accumulates in the epithelium, thus leading to tubular atrophy and interstitial fibrosis in the rat model (Zhou et al. Reference Zhou, Laszik, Wang, Silva and Vaziri2000).
Examination of a renal tissue from infected buffaloes has revealed mesangioproliferative and membranoproliferative glomerulonephritis, with deposition of immune complexes in glomeruli and positive staining for an F. hepatica antigen (Marques et al. Reference Marques, Scroferneker and Edelweiss2004). This study was focused solely on histopathological findings.
An experiment on sheep (infective dose of 200 metacercariae of F. hepatica) has shown that the lack of resistance to multiple F. hepatica infections may be associated with hepatic drug-metabolising monooxygenases. In this experiment, a significant decrease in renal microsomal cytochrome P450 levels in both kidneys was observed 10 weeks after infection initiation (hereafter: post infection) (the overall quantity of cytochrome P450 was determined spectrophotometrically by the method of Omura and Sato) (Calléja et al. Reference Calléja, Bigot, Eeckhoutte, Sibille, Boulard and Galtier2000). This finding is consistent with a similar decrease in the total quantity of P450-mediated monooxygenases in rat kidneys at 6 weeks post infection, likely because of a renal compensatory process (Biro Sauveur et al. Reference Biro Sauveur, Eeckhoutte, Baeza, Boulard and Galtier1995).
Sheep infected with 100 metacercariae of F. hepatica also exhibit hypoalbuminaemia, hyperglobulinaemia, and a lower creatinine concentration. Additionally, significantly lower blood urea nitrogen (BUN) levels as compared to uninfected sheep have been observed, indicating a need to assess protein metabolism during chronic fascioliasis (Matanović et al. Reference Matanović, Severin, Martinković, Simpraga, Janicki and Barisić2007). Similar results have been obtained with an increased parasitic load: a decrease in BUN and no significant changes in blood creatinine concentration have been registered in sheep experimentally infected with 220 F. hepatica metacercariae (Zeng et al. Reference Zeng, Wang, Qiu, Sun, Qiu and Ma2023). Furthermore, interstitial lymphoplasmacytic inflammatory infiltrates have been detected in the kidneys of rats infected with 20–25 metacercariae of F. hepatica (Saric et al. Reference Saric, Li, Utzinger, Wang, Keiser and Dirnhofer2010).
O. viverrini and kidney injuries in humans
Soukhathammavong et al. have observed an increased rate of renal pathology in endemic regions of the Lao People’s Democratic Republic. Their study, which included 431 patients infected with O. viverrini, revealed that approximately 8.5% of the patients had kidney stones, 7.5% of the patients had kidney cysts, and ~1.6% of the patients had hydronephrosis (Ayé Soukhathammavong et al. Reference Ayé Soukhathammavong, Rajpho, Phongluxa, Vonghachack, Hattendorf and Hongvanthong2015). Although this study included a large patient dataset, it lacked a control group of uninfected individuals. Notably, the results pointed to a rather strong association between kidney cysts and advanced hepatic periductal fibrosis (Ingsathit et al. Reference Ingsathit, Thakkinstian, Chaiprasert, Sangthawan, Gojaseni and Kiattisunthorn2010).
Saichua et al. have found that individuals living in endemic regions have elevated levels of anti–O. viverrini IgG in their urine. The study indicates that urine IgG levels positively correlate with advanced hepatic periductal fibrosis and CCA. Those authors propose that immune-complex–mediated renal injury may be involved (Saichua et al. Reference Saichua, Sithithaworn, Jariwala, Diemert, Sithithaworn and Sripa2013). Additionally, a study in Northeastern Thailand has established an association between obstructive jaundice and the development of acute kidney injury in patients with CCA (95% O. viverrini positive cases) (Mairiang et al. Reference Mairiang, Bhudhisawasdi, Borirakchanyavat and Sitprija1990).
Recently, Tonsawan et al. demonstrated an interconnection between O. viverrini infection and glomerulopathy. In their study, parasite antigens were detectable in endothelial cells of peritubular capillaries and glomeruli as well as in mesangial cells and cells of renal tubules (Tonsawan et al. Reference Tonsawan, Intarak, Sripa, Puapairoj, Sripa and Sithithaworn2022).
Another notable study, by Prathumkam et al., has evaluated the impact of multiple praziquantel doses intended for the treatment of O. viverrini infection in humans. Among 490,969 subjects who underwent ultrasonographic examination, 1.2% of the patients exhibited kidney parenchyma changes that correlated with the number of praziquantel doses. These changes were more prevalent in males than in females (Prathumkam et al. Reference Prathumkam, Thinkhamrop, Khuntikeo, Chamadol, Thuanman and Kelly2022). This finding indicates a potential nephrotoxic effect of praziquantel: a drug commonly used to treat Opisthorchiidae infections. It is important to note that praziquantel can be obtained without a prescription, thus enabling individuals to self-treat without medical supervision. Many people believe they can use the drug without altering their dietary habits, but this limited approach is rarely effective. Taking an insufficient dose of praziquantel may not eliminate all parasitic worms from the liver but can contribute to the development of renal injury as a nonparasitic factor. This issue underscores the limitations of the evaluation of renal injury development by means of population studies alone. Such factors as prescription drugs, dietary habits, smoking, and alcohol consumption can influence renal tissue. To isolate and analyse specific effects of a parasite, experiments on animal models are conducted.
O. viverrini and kidney injuries in model animals
Boonpucknavig et al. have reported damage to the glomerular basement membrane, accompanied by the accumulation of immune complexes, in a Syrian hamster model. Their study revealed immune complexes and amyloid deposition in renal glomeruli at 1.5 months post infection with 100 O. viverrini metacercariae. Additionally, they noted progressive glomerular deterioration, tubular atrophy, interstitial inflammation, and fibrosis, which were associated with significant proteinuria and a decline in renal function (Boonpucknavig et al. Reference Boonpucknavig, Boonpucknavig, Tanvanich, Doungchawee and Thamavit1992). This is the earliest reported mention of kidney injury in the context of chronic experimental O. viverrini infection.
Sriraj et al. have performed kidney function tests in Syrian hamsters by measuring BUN and creatinine levels. At 1 month post infection with 50 O. viverrini metacercariae, no changes were observed (Sriraj et al. Reference Sriraj, Boonmars, Aukkanimart, Songsri, Sripan and Ratanasuwan2016). This outcome could be due to a minimal impact on the kidneys during the acute stage and early chronic stage of the infection, or it could be attributed to high variation of levels of kidney injury markers in serum (Aukkanimart et al. Reference Aukkanimart, Boonmars, Sriraj, Songsri, Laummaunwai and Waraasawapati2015).
By contrast, Haonon et al. have detected some elevated levels of markers of kidney injury in Syrian hamsters infected with 50 O. viverrini metacercariae. During the acute phase of the infection, BUN and creatinine concentrations were found to be increased, subsequently declining in the chronic stage. Nevertheless, histological examination revealed distal tubular dilatation, inflammation, and renal fibrosis, all of which were more pronounced in the chronic stage (Haonon et al. Reference Haonon, Liu, Dangtakot, Intuyod, Pinlaor and Puapairoj2021).
Elsewhere, a decrease in BUN and serum creatinine levels was observed in the chronic stage, at 3 months post infection, in Syrian hamsters infected with 50 O. viverrini metacercariae. In contrast, the microalbumin/creatinine ratio, which is commonly associated with glomerular basement membrane malfunction, was significantly higher in the infected animals. Histopathological examination revealed tubular dilatation, vacuoles in glomeruli, renal fibrosis, and kidney injury molecule 1 (KIM1)-positive areas (Tunbenjasiri et al. Reference Tunbenjasiri, Pongking, Sitthirach, Kongsintaweesuk, Roytrakul and Charoenlappanit2024). Tunbenjasiri et al. have also assessed the combined effects of O. viverrini infection and high-fat/high-fructose diets. They reported a decline of renal function in both the diet+infection group and the group infected with O. viverrini alone, as indicated by lower BUN and serum creatinine levels. The diet+infection group exhibited a higher albumin-to-creatinine ratio. Histological analysis revealed significantly larger areas positive for kidney fibrosis and KIM1 in both infected groups. Furthermore, Tunbenjasiri et al. identified alterations of the gut microbiota, with increased abundance levels of various families, including Lachnospiraceae and Ruminococcaceae, in the group subjected to O. viverrini infection alone (Tunbenjasiri et al. Reference Tunbenjasiri, Pongking, Sitthirach, Kongsintaweesuk, Roytrakul and Charoenlappanit2024). It is important to note that imbalances of the gut microbiota in chronic kidney diseases include changes of both abundance and composition, resulting in elevated cell numbers of Lachnospiraceae, Enterobacteriaceae, and Ruminococcaceae (Sampaio-Maia et al. Reference Sampaio-Maia, Simões-Silva, Pestana, Araujo and Soares-Silva2016).
Haonon et al. have investigated the combined effects of O. viverrini infection and a high-fat/high-fructose diet. Eight months post infection, both O. viverrini–infected animals and those with the combined infection and diet exhibited pronounced tubular abnormalities, including tubular dilation, cell flattening and atrophy, cast formation, interstitial fibrosis, and inflammatory responses. Upregulation of high mobility group box-1 protein (HMGB1) was observed in both groups. Notably, monocyte chemoattractant protein 1 (MCP1) and KIM1 were upregulated only in the diet+infection group (Haonon et al. Reference Haonon, Liu, Dangtakot, Pinlaor, Puapairoj and Cha’on2022). Additionally, upregulation of protein-bound uremic toxins in serum was found, which could also serve as a marker of chronic kidney disease (Haonon et al. Reference Haonon, Liu, Dangtakot, Pinlaor, Puapairoj and Cha’on2022; Gryp et al. Reference Gryp, De Paepe, Vanholder, Kerckhof, Van Biesen and Van de Wiele2020).
In a murine model, it has been demonstrated that O. viverrini infection induces a more pronounced glomerular inflammatory response in the kidneys of Mta1 +/+ mice compared to Mta1 -/- mice (Nair et al. Reference Nair, Bommana, Pakala, Ohshiro, Lyon and Suttiprapa2011). Although the suitability of mice for modelling opisthorchiasis has been debated (Boonmars et al. Reference Boonmars, Boonjaraspinyo and Kaewsamut2009), these findings suggest that metastasis-associated protein 1 (MTA1) may act as a key mediator of inflammatory damage in both the liver and kidneys of O. viverrini–infected animals (Nair et al. Reference Nair, Bommana, Pakala, Ohshiro, Lyon and Suttiprapa2011).
Thus, several studies on animal models provide evidence that chronic O. viverrini infection is associated with kidney injury. The observations include proteinuria, metabolic disturbances, renal fibrosis, cast formation, tubular-cell abnormalities, and a chronic inflammatory response. Additionally, obesity induced by a high-fat/high-fructose diet can exacerbate parasite-mediated kidney disease.
C. sinensis and kidney injuries in humans
Only one population study has focused on renal pathology during C. sinensis infection. Namely, Xie et al. investigated the influence of this parasitic disease in combination with Helicobacter pylori infection in 4122 human subjects, of whom 33.8% were infected by C. sinensis alone and 5% were coinfected by both pathogens. Both the C. sinensis monoinfection and coinfection groups exhibited altered creatinine levels and serum β2-microglobulin concentration, but no increase in BUN levels was observed. The estimated glomerular filtration rate (eGFR) proved to be reduced in the coinfected group, albeit only in females (Xie et al. Reference Xie, Deng, Chen, Wu, Li and Yang2020). Although the correlation between biochemical markers and infection severity may be controversial, large-sample-size population studies can detect even minimal changes in a parameter as statistically significant. Nevertheless, that study suggests that coinfection with C. sinensis and H. pylori may contribute to the development of renal pathology. Previous articles have shown that O. viverrini and O. felineus can serve as reservoirs of H. pylori (Pakharukova et al. Reference Pakharukova, Zaparina, Hong, Sripa and Mordvinov2021; Suyapoh et al. Reference Suyapoh, Tirnitz-Parker, Suttiprapa and Sripa2021), thus leading to microbiota alterations.
C. sinensis and kidney injuries in model animals
Similarly to population studies, only one study has addressed the development of kidney injury in an animal model of C. sinensis infection (Chen et al. Reference Chen, Nong, Wu, Liu, Wei and Chen2023). In that study, New Zealand rabbits were infected with C. sinensis and monitored for 28 weeks. To assess kidney function, levels of BUN and serum creatinine were measured. The results were in agreement with previous population study data, showing elevated creatinine levels at 4 and 8 weeks post infection, and these levels remained significantly higher than those in the control group throughout the study period. Nonetheless, BUN levels did not change significantly in the course of the infection. Chen et al. proposed that C. sinensis infection may affect metabolic pathways in the kidneys (Chen et al. Reference Chen, Nong, Wu, Liu, Wei and Chen2023).
O. felineus and kidney injuries in humans
All population studies dealing with kidney injury development during O. felineus infection have been conducted exclusively within the Russian Federation, with no studies (that we could find) from other former-Soviet-Union countries. Consequently, the data presented here on this topic are sourced mainly from the Russian literature.
The first documented clinical case of kidney injury development during opisthorchiasis (by E.A. Pastor) dates back to 1898; Pastor was a physician at a Saint Petersburg clinic. Patients with O. felineus infection exhibited pronounced profibrotic changes in liver tissue, along with amyloidosis of the spleen and kidneys (Avdeeva Reference Avdeeva1958). Subsequently, in the early 1970s, clinical reports of renal failure during chronic opisthorchiasis began to emerge, with patients presenting with elevated levels of urine protein, increased leukocyte counts, and microhaematuria during O. felineus infection (Rychkova et al. Reference Rychkova, Kozina and Sazonova1970; Shultsev et al. Reference Shultsev, Tsalenchuk and Olkhin1973).
Isolated clinical cases of Goodpasture’s syndrome, characterised by recurrent pulmonary haemorrhage and kidney injury, have been documented in individuals with chronic O. felineus infection in endemic areas (Girs et al. Reference Girs, Pyankin and Bychkov1971; Solovyeva Reference Solovyeva2010). Several cases of systemic kidney injury were reported in the 1980s (Pavlov and Shemetov Reference Pavlov and Shemetov1986). In 1990, Lapteva described the development of both pyelonephritis and nephritis during O. felineus infection, with associated renal dyskinesia and interstitial abnormalities as part of the pathological process (Lapteva Reference Lapteva1990).
In 1999, Alperovich and Abushakhmanov published a report describing cases of O. felineus infection in patients from Tomsk city between 1970 and 1997. Among 2939 patients with chronic infection, 798 required a surgical intervention. Of these, 24% got a diagnosis of both acute liver failure and acute kidney failure (Alperovich and Abushakhmanov Reference Alperovich and Abushakhmanov1999).
Merzlikin has also reported evidence of kidney injury, with elevated serum levels of urea and creatinine in 129 individuals with chronic opisthorchiasis and obstructive jaundice. Besides, proteinuria, haematuria, and urinary casts were observed. These clinical markers correlated with the severity of the clinical presentation and duration of jaundice (Merzlikin Reference Merzlikin2023).
In the endemic city of Nizhnevartovsk, Pikov and Postnikov have examined 78 young individuals aged 15 to 18 years infected with O. felineus. In that article, ultrasonography of the kidneys revealed no specific changes. Nonetheless, 7.7% of the patients exhibited nephroptosis, 11.5% of the patients showed diffuse increased echogenicity of renal parenchyma, and 16.7% of the patients presented with various structural aberrations. Furthermore, 32.1% of the patients showed changes in the vasorenal index and a decrease in the resistance index of interlobular and arcuate arteries, while the pulse index in segmental arteries was found to be increased (Pykov and Postnikov Reference Pykov and Postnikov2006).
Several studies by Beloborodova and Kalyuzhina have focused on kidney injury development in individuals infected with O. felineus. Their data, collected over several decades, suggest that chronic opisthorchiasis can lead to chronic glomerulonephritis (Beloborodova et al. Reference Beloborodova, Zibnitskaya and Kalyuzhina2005; Kalyuzhina et al. Reference Kalyuzhina, Beloborodova and Zibnitskaya2006, Reference Kalyuzhina, Sibireva, Kalyuzhina and Livshits2009; Kalyuzhina and Kalyuzhin Reference Kalyuzhina and Kalyuzhin2004; Kolosovskaya et al. Reference Kolosovskaya, Khardikova, Kalyuzhina, Surkova, Smyshevskaya and Varlacheva2009; Sibireva et al. Reference Sibireva, Surkova, Livshits, Grankina, Kalyuzhin and Kalyuzhina2009). Some of their studies were case reports, while others were population-based data and were included in the meta-analyses (Figure 1). One study of interest analysed 100 individuals with chronic O. felineus infection and pre-existing glomerulonephritis. Among these patients, 81% had mesangial proliferative glomerulonephritis, 5% had membranoproliferative glomerulonephritis, and 11% had mesangial capillary glomerulonephritis. The study revealed that patients with chronic O. felineus infection feature more pronounced impairments of glomerular filtration and of tubular reabsorption. Glomerulonephritis in these patients was linked with elevated creatinine levels, a decreased eGFR, and reduced reabsorption (Kalyuzhina and Kalyuzhin Reference Kalyuzhina and Kalyuzhin2004).
Analysis of the potential effects of Opisthorchiidae spp. infection on kidney function and injury. A. The first meta-analysis represents dependency between trematode infection and renal function insufficiency. B. The second meta-analysis represents dependency between trematode infection and renal injury development. In both forest plots, each row corresponds to a single estimation, with the effect size represented by a dot and 95% confidence interval by horizontal lines. Dots are colour-coded by study type: blue – animal studies, orange – clinical trials. The red dashed line indicates the pooled effect. The black dashed line represents no effect. SMD – standardised mean difference. In both panels, funnel plots with Egger’s test were used to assess publication bias. Precision in a funnel plot is calculated as 1/SE (standard error). Each point represents an individual study, and the red dashed line indicates 95% confidence interval.
Another study by Kolosovskaya et al. included 360 patients with chronic opisthorchiasis, with an infection duration of at least 5 years. The study showed the development of chronic kidney disease, as evidenced by elevated creatinine levels and a decreased eGFR. Ultrasonographic examination revealed heterogeneous echo signals in 28% of the patients. Among 72 renal biopsy samples, 12 exhibited mesangial proliferative glomerulonephritis, and 10 showed vascular changes with mild-to-moderate productive arteriolar and capillary vasculitis accompanied by local perivascular sclerosis (Kolosovskaya et al. Reference Kolosovskaya, Khardikova, Kalyuzhina, Surkova, Smyshevskaya and Varlacheva2009).
Differences have been identified in the immune profiles of patients with chronic glomerulonephritis, with or without underlying chronic O. felineus infection. Those with glomerulonephritis and chronic O. felineus infection manifested lower numbers of leukocytes and CD2+, CD3+, and CD4+ cells, along with elevated levels of IgM, IgG, and IgE. Additionally, diminished levels of IL-4 and higher levels of IL-6 were observed in serum (Kalyuzhina and Kalyuzhin Reference Kalyuzhina and Kalyuzhin2004; Kalyuzhina et al. Reference Kalyuzhina, Sibireva, Kalyuzhina and Livshits2009; Kolosovskaya et al. Reference Kolosovskaya, Khardikova, Kalyuzhina, Surkova, Smyshevskaya and Varlacheva2009). These findings have guided the design of treatments of chronic glomerulonephritis in the context of O. felineus infection, e.g., the use of chophytol (a choleretic) combined with ticlopidine (an anticoagulant) for managing renal pathology (Sibireva et al. Reference Sibireva, Surkova, Livshits, Grankina, Kalyuzhin and Kalyuzhina2009). Nevertheless, these studies have limitations because all patients were sourced from a nephrology department and had pre-existing renal pathology, making it challenging to determine – by means of clinical data alone – whether O. felineus induces kidney injury or merely exacerbates the disease course.
On the other hand, one mechanism underlying the development of glomerulonephritis in the context of O. felineus infection has been proposed. The accumulation of circulating immune complexes in the kidneys is the most likely candidate for an inducer of renal injury (Zibnitskaya Reference Zibnitskaya2002). This pathogenesis is widely discussed in the Russian literature and may be associated with the formation of toxic allergic reactions (Rybka Reference Rybka2016), although the latter statement is controversial. Several authors have demonstrated that O. felineus infection is an important factor that reduces the risk of atopic bronchial asthma in endemic regions (Fedorova et al. Reference Fedorova, Janse, Ogorodova, Fedotova, Achterberg and Verweij2017; Saltykova et al. Reference Saltykova, Ogorodova, Bragina, Puzyrev and Freidin2014).
The accumulation of immune complexes in the kidneys in this context is supported by another retrospective study. An autopsy analysis in the endemic region of Khanty-Mansiysk (Russia) uncovered IgA accumulation in glomeruli of individuals infected with O. felineus. Renal injuries were more pronounced in patients with hypertension, although glomerular IgA accumulation was detectable even in normotensive patients. Additionally, O. felineus total antigen accumulation was identified in the kidneys of both hypertensive patients and normotensive patients. Isolated casts, crescents, and focal glomerulosclerosis were also observed in the group with O. felineus infection and hypertension. These findings support the potential role of O. felineus in the pathogenesis of glomerular disease (Kovner et al. Reference Kovner, Kapushchak, Hadieva, Persidskij and Pakharukova2025).
O. felineus and kidney injuries in model animals
Studies focusing on kidney injury development during experimental O. felineus infection are scarce. Saydasheva and Biktimirov have noted Bowman’s capsule expansion and glomerular hypercellularity in Syrian hamsters, along with numerous sites of haemorrhage in the kidney parenchyma (Saidasheva and Biktimirov Reference Saidasheva and Biktimirov2017). In another study, white rabbits were infected with 50 O. felineus metacercariae and monitored for 18 months. The researchers demonstrated a decrease in serum potassium levels in the experimental animals (Sidelnikova Reference Sidelnikova2019): a phenomenon that may be attributed to renal dysfunctions, such as nephropathy, uremia, and chronic kidney failure, as reported previously (Tonsawan et al. Reference Tonsawan, Intarak, Sripa, Puapairoj, Sripa and Sithithaworn2022).
Kapushchak et al. have demonstrated elevated levels of urine protein, urine creatinine, and urine KIM1 at 1 to 13 months post infection in a Syrian hamster infected with 75 O. felineus metacercariae. Histological examination pointed to the development of glomerulonephritis with isolated casts in renal tubules, both in the cortex and medulla. Mesangial-matrix expansion was also detectable after periodic acid-Schiff methenamine (PASM) silver staining (Kapushchak et al. Reference Kapushchak, Zaparina, Mordvinov and Pakharukova2022). Furthermore, markers of lipid peroxidation, such as 4-hydroxy-2-nonenal (HNE), were detectable (Kapushchak and Tumashev Reference Kapushchak and Tumashev2020). Previous studies have shown increased amounts of reactive oxygen species (ROS) during opisthorchiasis in liver tissue (Zaparina et al. Reference Zaparina, Rakhmetova, Kolosova, Cheng, Mordvinov and Pakharukova2021), which may also contribute to kidney injury and glomerulonephritis.
Summarising the data from experimental studies and clinical trials, it is evident that chronic O. felineus infection is associated with the development of kidney injury. Chronic glomerulonephritis – characterised by elevated urine protein and creatinine levels as well as glomerular changes such as mesangial-matrix expansion, Bowman’s capsule expansion, and hypercellularity – is the predominant form of kidney injury in this context. The data obtained from Syrian hamsters are in agreement with the aforementioned clinical data, further confirming that the Syrian hamster is an appropriate animal model for studying O. felineus infection.
A comparison of the three Opisthorchiidae spp
To evaluate differences in renal pathology development among the three above-mentioned liver fluke infections, a comparative study was conducted at 1 and 3 months post infection. Metacercariae of O. felineus (from the Ob River, Russian Federation), O. viverrini (from Thailand), and C. sinensis (from South Korea) were used to infect experimental animals synchronously at a specific pathogen-free (SPF) facility (Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024). Biochemical examination revealed elevated creatinine levels in blood serum after the first month in only O. viverrini–infected animals and O. felineus–infected animals. By the third month, serum creatinine levels were found to be elevated in all three infected groups. Urine creatinine levels proved to be increased only in O. felineus–infected animals and C. sinensis–infected animals. Histological examination of renal tissue uncovered interstitial fibrosis at 1 month post infection in C. sinensis–infected animals and at 3 months post infection in both the O. felineus–infected group and C. sinensis–infected group. No interstitial fibrosis was found during O. viverrini infection. PASM staining visualised mesangial-matrix expansion but only at 3 months post infection in the O. felineus–infected group and O. viverrini–infected group. As mentioned above, one of the mechanisms of kidney injury development may be the accumulation of circulating immune complexes in glomeruli. Prominent IgA deposition was found only at 3 months post infection in Syrian hamsters infected with O. felineus and those infected with C. sinensis (Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024). In contrast, only minimal IgA deposition was observed in animals infected with O. viverrini. It was hypothesised that animals infected with O. viverrini form a less pronounced immune response as compared to those infected with the other two Opisthorchiidae species. This supposition is supported by a smaller extent of immune-cell infiltration and a higher rate of hyperplasia observed in O. viverrini–infected animals (Salao et al. Reference Salao, Watakulsin, Mairiang, Suttiprapa, Tangkawattana and Edwards2019). It is also known that O. viverrini has the potential to modulate a host’s immune response (Jittimanee et al. Reference Jittimanee, Wongratanacheewin, Kaewraemruaen and Jittimanee2021; Salao et al. Reference Salao, Watakulsin, Mairiang, Suttiprapa, Tangkawattana and Edwards2019; Srisai et al. Reference Srisai, Chaiyadet, Jumnainsong, Suttiprapa, Leelayuwat and Saichua2024) and may affect the kidneys through other pathological factors, which require further investigation.
Meta-analysis of kidney injury markers in liver fluke infections
The pooled effect from the first meta-analysis was 0.734 (Z = 5.638, P < 0.001), indicating a moderate-to-large effect of trematode infection on renal function. Substantial heterogeneity was observed among effect sizes (I 2 = 63.7%, τ 2 = 0.182; Figure 1A), suggesting that the degree of renal impairment may vary depending on factors such as infection duration or study subject (human vs. animal model).
The pooled effect from the second meta-analysis was 0.583 (Z = 3.544, P < 0.001), representing a moderate effect of trematode infection on glomerular barrier impairment based on biochemical data. A high level of heterogeneity was observed across studies (I 2 = 72.63%, τ 2 = 0.152; Figure 1B). This suggests that while trematode infection can lead to glomerular basement membrane injury, the severity of this effect varies considerably. Unfortunately, histological examination of renal tissue could not be included due to the limited number of available studies.
For both meta-analyses, significant publication bias was detected via Egger’s test (P < 0.001; Figure 1), likely reflecting the underreporting of studies showing no effect of trematode infection on renal parameters - i.e., a tendency to publish only positive findings.
In summary, the analysed data indicate a strong association between trematode infection and kidney injury, with effects that can be substantial. However, the considerable variability in effect sizes across studies precludes a definitive conclusion regarding the extent of renal involvement in the pathological process. Further studies are needed to clarify the impact of trematode infection on renal health.
Discussion
Summarising the presented data, we can highlight potential pathological manifestations of kidney injury development during liver fluke infection. This review emphasises two aspects: (1) the importance of comprehensive examination of patients with chronic parasitic infections, including those caused by liver flukes; and (2) the necessity of research into the impact of chronic inflammation associated with a parasitic burden on extrahepatic organs, including the kidneys, in animal models. We also discuss possible pathological processes involved in chronic trematode infections. Several factors that may influence kidney function are examined below (Table 2).
The most common biochemical and morphological changes observed in the kidneys of humans and animals with chronic liver fluke infection
CT: computed-tomography scanning, uACR: urine microalbumin/creatinine ratio, BUN: blood urea nitrogen, eGFR: estimated glomerular filtration rate, HNE: 4-hydroxy-2-nonenal, GBM: glomerular basement membrane, ↑: upregulation, ↓: downregulation, ||: no change
Despite the fact that not all studies could be assessed using the Newcastle-Ottawa Scale or SYRCLE’s RoB Tool, several key kidney injuries potentially associated with liver fluke infection can be highlighted: (1) glomerulonephritis (mesangioproliferative, immune complex-mediated); (2) tubular injury; (3) interstitial fibrosis; (4) proteinuria; (5) reduced estimated glomerular filtration rate (eGFR); and (6) IgA deposition in the glomeruli. Below, we explore the potential link between the development of kidney injury in the context of chronic liver damage, gut microbiome alterations, and the host immune response.
Kidney impairment often manifests itself as higher urine protein levels, a reduced eGFR (Tonsawan et al. Reference Tonsawan, Intarak, Sripa, Puapairoj, Sripa and Sithithaworn2022), and altered creatinine levels in both urine and serum. Changes in BUN levels have been ambiguous and have not shown a strong association with trematode infections. Histological examination may reveal interstitial fibrosis, mesangial-matrix expansion, and tubular epithelium dystrophy.
One possible factor contributing to kidney injury development is the accumulation of ROS. Lipid peroxidation has been observed in liver tissue during liver fluke infections (Bian et al. Reference Bian, Xu, Xu, Li, Wang and Sheng2016; Da Silva et al. Reference Da Silva, Baldissera, Bottari, Gabriel, Rhoden and Piva2017; Pakharukova et al. Reference Pakharukova, Zaparina, Kapushchak, Baginskaya and Mordvinov2019; Salao et al. Reference Salao, Thapphan, Thai, Faksri, Suttiprapa and Tangkawattana2023; Zaparina et al. Reference Zaparina, Rakhmetova, Kolosova, Cheng, Mordvinov and Pakharukova2021, Reference Zaparina, Kapushchak, Lishai, Hong, Sripa and Pakharukova2024). Both the parasite and the host’s immune response contribute to the production of ROS (Mordvinov et al. Reference Mordvinov, Ponomarev, Pakharukov and Pakharukova2021), which can potentially affect the kidneys. Upregulation of 8-oxo-2′-deoxyguanosine has been found in the urine of experimental animals and may be partly connected to the peroxidation of kidney tissue (Zaparina et al. Reference Zaparina, Rakhmetova, Kolosova, Cheng, Mordvinov and Pakharukova2021).
Another factor is amyloid deposition. During O. felineus infection, amyloid deposits have been found in liver tissue (Kovner et al. Reference Kovner, Kapushchak, Zaparina, Mordvinov and Pakharukova2024; Ponomarev et al. Reference Ponomarev, Lishai, Kovner, Kharkova, Zaparina and Kapuschak2023). Amyloidosis is likely associated with AA amyloid, which has an immune origin and has also been found in goats with mixed gastrointestinal infections by nematodes and Fasciola spp. (Ulutaş et al. Reference Ulutaş, Voyvoda, Ulutaş and Aypak2008). Amyloidosis of the kidneys in both humans and Syrian hamsters chronically infected with O. felineus or O. viverrini has been reported and may contribute to kidney injury development (Boonpucknavig et al. Reference Boonpucknavig, Boonpucknavig, Tanvanich, Doungchawee and Thamavit1992; Kovner et al. Reference Kovner, Kapushchak, Hadieva, Persidskij and Pakharukova2025; Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024). Parasitosis-induced amyloidosis has also been described during infections with Leishmania donovani and O. viverrini (van Velthuysen and Florquin Reference van Velthuysen and Florquin2000).
Obstructive jaundice is a common complication of liver fluke infections (Remacha et al. Reference Remacha, Goñi and Espinel2019) and leads to elevated serum levels of bilirubin and other bile acids. These biomolecules exert toxic effects on the renal tubule epithelium, thereby possibly resulting in dystrophy and necrosis (Fickert and Rosenkranz Reference Fickert and Rosenkranz2020; Tinti et al. Reference Tinti, Umbro, D’Alessandro, Lai, Merli and Noce2021).
Some studies have detected a correlation between microbiome alterations and renal pathology (Amini Khiabani et al. Reference Amini Khiabani, Asgharzadeh and Samadi Kafil2023; Ramezani and Raj Reference Ramezani and Raj2014; Sampaio-Maia et al. Reference Sampaio-Maia, Simões-Silva, Pestana, Araujo and Soares-Silva2016; Sumida et al. Reference Sumida, Pierre, Yuzefpolskaya, Colombo, Demmer and Kovesdy2023). It has been proposed that indoxyl sulfate and p-cresyl sulfate, produced by a pathogenic gut microbiota, can be absorbed into the bloodstream and contribute to the development of proximal tubule dystrophy as uremic toxins. Numerous authors have documented alterations in the gut microbiota during liver fluke infections (Gryp et al. Reference Gryp, De Paepe, Vanholder, Kerckhof, Van Biesen and Van de Wiele2020; Haonon et al. Reference Haonon, Liu, Dangtakot, Intuyod, Pinlaor and Puapairoj2021; Mutapi Reference Mutapi2015).
During O. viverrini infection, the family Ruminococcaceae (genus Ruminococcus) is upregulated (Haonon et al. Reference Haonon, Liu, Dangtakot, Intuyod, Pinlaor and Puapairoj2021), suggesting that pathologic microflora may participate in the synthesis of glucorhamnan, which causes dendritic cells to produce TNF. Additionally, an analysis of the host fecal proteome registered upregulation of MAP3K7-binding protein 2 (Tab2). Overexpression of Tab2 may be linked to the translocation of uremic toxins such as p-cresyl and indoxyl, thereby promoting kidney injury.
It is also noteworthy that in the study on the microbiome associated with three species of Opisthorchiidae (O. felineus, O. viverrini, and C. sinensis), the most prevalent bacterial taxon was also Enterobacteriaceae. Pakharukova et al. conducted a comparative analysis of gut and bile microbiota disturbances during infections with one of the three liver flukes (Pakharukova et al. Reference Pakharukova, Lishai, Zaparina, Baginskaya, Hong and Sripa2023). During C. sinensis infection, opportunistic pathogens such as Acinetobacter, Pseudomonas, and Streptococcus were identified. Earlier research articles had shown that the number of Acinetobacter cells increases in experimental uremia (Wang et al. Reference Wang, Zhang, Jiang and Cheng2012), and the overall number of aerobic bacterial cells (including Pseudomonas and Streptococcus) increases in individuals with chronic kidney diseases (Hida et al. Reference Hida, Aiba, Sawamura, Suzuki, Satoh and Koga1996; Ramezani and Raj Reference Ramezani and Raj2014). These bacteria can contribute to the synthesis of uremic toxins (particularly indoxyl sulfate and p-cresol sulfate), which are absorbed into the blood and are typically excreted by the kidneys (Ramezani and Raj Reference Ramezani and Raj2014). Elevated serum concentrations of indoxyl sulfate and p-cresyl sulfate have been found to negatively correlate with kidney function levels in humans, thus contributing to oxidative stress and inflammation in kidney tissues (levels of indoxyl sulfate have correlated with elevated levels of IL-1β and TNF among individuals with chronic kidney disease). Uremic toxins can accumulate and ultimately induce uremic syndrome, which reduces the eGFR, as evidenced by a statistically significant correlation between concentrations of uremic toxins and elevated creatinine and urea levels. These findings have also been confirmed in laboratory animal studies indicating that uremic toxins can damage renal tubular cells (Asgharian et al. Reference Asgharian, Gholizadeh, Samadi Kafil, Ghojazadeh, Samadi and Soleymani2022; Lin et al. Reference Lin, Chen, Pan, Chuang, Wang and Sun2011; Ramezani and Raj Reference Ramezani and Raj2014; Satoh et al. Reference Satoh, Hayashi, Watanabe, Ueda, Yamato and Yoshioka2003; Tsuji et al. Reference Tsuji, Uchida, Nakanoh, Fukushima, Haraguchi and Kitamura2024). Additionally, increased abundance of Enterobacteriaceae has been observed during each of the three Opisthorchiidae spp. infections. Dysbiosis (an aberrant gut microbiota), particularly the one affecting Lactobacillaceae and Bifidobacteriaceae, is commonly associated with chronic kidney disease in both humans and uremic animals (Amini Khiabani et al. Reference Amini Khiabani, Asgharzadeh and Samadi Kafil2023; Hanifi et al. Reference Hanifi, Kafil, Khosroshahi, Shapouri and Asgharzadeh2020; Ramezani and Raj Reference Ramezani and Raj2014). It has been shown that Lactobacillaceae and Bifidobacteriaceae influence BUN levels, and the use of probiotics improves the well-being of patients with chronic kidney disease (Hanifi et al. Reference Hanifi, Kafil, Khosroshahi, Shapouri and Asgharzadeh2020; Ranganathan et al. Reference Ranganathan, Ranganathan, Friedman, Joseph, Delano and Goldfarb2010).
Although there are no data on the effect of an altered gut microbiota on the kidneys during F. hepatica infection, evidence suggests that the excretory–secretory product of this parasite contributes to the elevated abundance of Deferribacteraceae bacteria (Gong et al. Reference Gong, Huang, Pan, Jin, Fan and Shi2025). Furthermore, these bacteria have been associated with chronic kidney damage (Sumida et al. Reference Sumida, Pierre, Yuzefpolskaya, Colombo, Demmer and Kovesdy2023). Therefore, further research is needed to investigate disturbances of the intestinal microbiota in the context of chronic infection by Fasciola species and associated kidney injury. Thus, the state of the gut microbiota influences not only systemic inflammatory processes but potentially also kidney health during chronic liver fluke infections, thereby contributing to the accumulation of uremic toxins in renal tissues and to associated inflammation and oxidative stress.
Factors contributing to kidney injury development have been investigated only superficially. Nevertheless, one factor has been researched in detail: the accumulation of immune complexes during liver fluke infection appears to be a key factor in kidney disease development (Boonpucknavig et al. Reference Boonpucknavig, Boonpucknavig, Tanvanich, Doungchawee and Thamavit1992; Kapushchak and Tumashev Reference Kapushchak and Tumashev2020; Kolosovskaya et al. Reference Kolosovskaya, Khardikova, Kalyuzhina, Surkova, Smyshevskaya and Varlacheva2009; Kovner et al. Reference Kovner, Kapushchak, Hadieva, Persidskij and Pakharukova2025; Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024). Immune-complex–mediated injury to the glomerular barrier explains the upregulation of urine protein and a decrease in the eGFR, along with the expansion of the mesangial matrix (Nangaku et al. Reference Nangaku, Shankland and Couser2005; Yu et al. Reference Yu, Ding, An, Yang, Zhang and Li2023). Although the concept of immune-complex–mediated kidney injury has been hypothesised earlier, strong evidence emerged only recently (Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024).
Three recent studies revealed IgA accumulation in the mesangium, both in human material and in an experimental model (Boonpucknavig et al. Reference Boonpucknavig, Boonpucknavig, Tanvanich, Doungchawee and Thamavit1992; Kovner et al. Reference Kovner, Kapushchak, Hadieva, Persidskij and Pakharukova2025; Zaparina et al. Reference Zaparina, Kovner, Petrova, Kolosova, Mordvinov and Pakharukova2024). Immunoglobulins are components of circulating immune complexes, and their presence in the glomerular basement membrane confirms their involvement in kidney injury development. Notably, for another trematode genus – Schistosoma spp. (three major species: S. mansoni, S. haematobium, and S. japonicum) – it has been well documented that renal impairment occurs in 10% to 15% of the patients with the hepatosplenic form of the infection, and that nephrotic syndrome is the most common clinical presentation. Renal biopsies from patients with S. mansoni infection have revealed mesangioproliferative glomerulonephritis (the predominant type of injury), focal segmental glomerulosclerosis, mesangiocapillary glomerulonephritis, and focal segmental glomerular hyalinosis (Barsoum Reference Barsoum1987, Reference Barsoum2013; el-Sherif and Befus Reference el-Sherif and Befus1988; Gonçalves et al. Reference Gonçalves, Fontes and Canuto2017; Rodrigues et al. Reference Rodrigues, Otoni, Voieta, Antunes and Lambertucci2010; Sobh et al. Reference Sobh, Moustafa, Sally, Deelder and Ghoniem1988). Schistosoma-associated kidney injury has also been found to be mediated by immune complexes. IgA deposits in glomeruli, as seen in patients with hypertension due to the hepatosplenic form of schistosomiasis, may contribute to the progression of kidney disease. This phenomenon is attributed to impaired clearance of immunoglobulins by Kupffer cells (Alamartine et al. Reference Alamartine, Sauron, Laurent, Sury, Seffert and Mariat2011). In chronic intestinal schistosomiasis, elevated urinary levels of MCP1 indicate subclinical glomerular damage in patients infected with S. mansoni. MCP1 is one of the most widely studied biomarkers of glomerulopathies and correlates with glomerular inflammation and interstitial nephritis (Kim and Tam Reference Kim and Tam2011; Sousa et al. Reference Sousa, Meneses, Dam, Corstjens, Galvão and Pinheiro2023). Recent data suggest that patients infected with S. mansoni but without a kidney disease exhibit significantly higher urinary levels of vascular endothelial growth factor (VEGF) as compared to uninfected individuals (Sousa et al. Reference Sousa, Meneses, Dam, Corstjens, Galvão and Pinheiro2023). In renal tissue of male Swiss albino mice infected with S. mansoni, there is significant upregulation of mRNA expression of KIM1, neutrophil gelatinase-associated lipocalin (NGAL), MCP1, and transforming growth factor beta (TGF-β). That study also suggests that schistosomiasis significantly increases levels of both nitrites/nitrates and malondialdehyde (MDA) in renal tissues (Galvão et al. Reference Galvão, Meneses, Pinheiro, Martins, Daher and Bezerra2022). This pathological process appears relevant to the infections caused by the Opisthorchiidae species as well.
It should be noted that some differences in the manifestations of kidney injury may be related to the host immune response. Despite differences in the acute immune response, the chronic immune response associated with O. viverrini, C. sinensis, and F. hepatica infections is characterised by a Th2-dominated immune response pattern (Quinteros et al. Reference Quinteros, O’Brien and Donnelly2022). Notably, chronic F. hepatica primo infection in both cattle and animal models is associated with a similar pattern of Th1 immune response suppression (e.g., decreased IL1β and TNF α) with stimulation of Th2/Treg response (e.g., increased IL4, IL10, and TGFβ) (Chen et al. Reference Chen, Daugschies, Wang and Mao2000; Flynn et al. Reference Flynn, Irwin, Olivier, Sekiya, Dalton and Mulcahy2007; Gironès et al. Reference Gironès, Valero, García-Bodelón, Chico-Calero, Punzón and Fresno2007; Musah-Eroje and Flynn Reference Musah-Eroje and Flynn2018; Naranjo-Lucena et al., Reference Naranjo-Lucena, Correia, Molina-Hernández, Martínez-Moreno, Browne and Pérez2021; Ruiz-Campillo et al. Reference Ruiz-Campillo, Barrero-Torres, Abril, Pérez, Zafra and Buffoni2023; Zhang et al. Reference Zhang, Moreau, Peigné, Huang and Chauvin2005). Additionally, increased IL10 concentrations have been observed in the mesenteric and hepatic lymph nodes of rats (Wesołowska et al. Reference Wesołowska, Zawistowska-Deniziak, Norbury, Wilkowski, Pyziel and Zygner2018), while elevated Il4 gene expression has been detected in the hepatic lymph nodes of sheep during chronic F. hepatica infection (Ruiz-Campillo et al. Reference Ruiz-Campillo, Pacheco, Abril, Bautista, Martínez-Moreno and Martínez-Moreno2024).
The Th2 immune response pattern has also been observed in chronic O. viverrini and O. felineus infections in Syrian hamster models (Pakharukova et al. Reference Pakharukova, Zaparina, Kovner and Mordvinov2019; Quinteros et al. Reference Quinteros, O’Brien and Donnelly2022). For instance, chronic O. viverrini infection in this model has been shown to upregulate Tgfb1 and Il10 gene expression in the spleen and mesenteric lymph nodes (Jittimanee et al. Reference Jittimanee, Sermswan, Puapairoj, Maleewong and Wongratanacheewin2007). Importantly, the Th2 immune response has been linked to immune complex deposition in the kidneys and podocyte injury (Lv et al. Reference Lv, Wang, Zhang, Shao, Lin and Liu2022).
Characterising the immune response in humans, particularly in the late stages of infection, remains challenging due to the high prevalence of comorbid conditions and diseases. Current population-based studies indicate the following immune alterations: (1) the immune response suppression in chronic C. sinensis infection (Kan et al. Reference Kan, Li, Li, Yao, Du and Wu2022); (2) elevated IL-6 levels in cases of chronic O. viverrini infection and advanced periductal fibrosis (Surapaitoon et al. Reference Surapaitoon, Suttiprapa, Mairiang, Khuntikeo, Pairojkul and Bethony2017); eosinophilia in children with chronic F. hepatica infection (Aron-Said et al. Reference Aron-Said, Montes, White and Cabada2021); reduced lymphocyte counts (CD2, CD3, CD4, and CD8) in chronic O. felineus infection (Grigorieva et al. Reference Grigorieva, Stepanova, Stepanova, Kalgina and Kurlaeva2023; Kalyuzhina et al. Reference Kalyuzhina, Sibireva, Kalyuzhina and Livshits2009; Kalyuzhina and Kalyuzhin Reference Kalyuzhina and Kalyuzhin2004; Kolosovskaya et al. Reference Kolosovskaya, Khardikova, Kalyuzhina, Surkova, Smyshevskaya and Varlacheva2009). Thus, humans, experimental animal models, and cattle exhibit comparable immune response patterns to chronic liver fluke infection: either a Th2 response or immunosuppression. A summary of the comparison between immune responses and detected kidney injury is presented in Table 3.
Comparison of the immune response of different hosts to liver fluke infection and the detected kidney injury
To sum up the presented data, they are compelling evidence of kidney injury development during foodborne-trematode infections of the liver (Figure 2), with the accumulation of circulating immune complexes being one of the key contributing factors. Other factors, such as ROS accumulation, gut microbiome alterations, or amyloidosis, may also promote the development of renal pathology, but they require further research.
A possible cascade of renal injury during chronic liver fluke infections. (The figure was prepared using GIMP 2.10, https://www.gimp.org/.) The schematic illustrates a general model of the involvement of kidney injury in chronic liver fluke infection. In chronic liver fluke infection, in the liver, an obstructed bile duct can be clearly visualised and lead to the accumulation of bile acids and bilirubin. This obstruction and persistent secretion of excretory–secretory product result in chronic inflammation, chronic ROS production, cholangio- and periductal fibrosis, cholestasis, and amyloidosis. The intestinal-barrier disruption associated with chronic liver fluke infection and secretion of excretory–secretory product cause the translocation of bacterial products, such as lipopolysaccharides (LPSs) from Enterobacter, Acinetobacter, Pseudomonas, Staphylococcus, etc., thus enhancing systemic inflammation. Blood vessels carry circulating immune complexes, antibodies, bilirubin, and bile acids, which contribute to systemic inflammation and oxidative stress. Accumulation of uremic toxins in the bloodstream exacerbates systemic inflammation and organ dysfunction. All these factors and pathological conditions culminate in kidney injury. The glomerulus undergoes various pathological changes, including immune-complex deposition, mesangial-matrix expansion, interstitial fibrosis, and expansion of Bowman’s capsule, thus inducing cast formation. The glomerular filtration barrier is compromised, with podocyte injury and endothelial-cell damage contributing to proteinuria and a reduced eGFR. Renal tubules are affected by the accumulation of bile acids, bilirubin, and ROS, resulting in tubular-cell injury and dysfunction. Elevated levels of KIM1 and creatinine indicate tubular damage and impaired renal function.
This study has certain limitations. The review incorporates all available data on kidney injury potentially associated with liver fluke infections that were accessible at the time of the study. Some reviewed data were presented as case reports or clinical descriptions of detected pathology without a control group, precluding formal quality assessment. Data published more than 50 years ago provided only average values, and it is also not possible to request additional information for quality assessment analysis. Currently, it cannot be definitively concluded that liver fluke infection initiates or exacerbates kidney injury. Because the available data are scattered (including experimental, population-based, clinical, and pathological observations), we cannot draw a definitive conclusion about specific kidney injuries caused by particular liver fluke infections.
Conclusion
In this review, we summarise the current understanding of the potential effects of liver fluke infection on kidney health. Glomeruli and filtration tubules of the kidneys are especially affected. Common markers of kidney injury associated with liver fluke infection include an increased eGFR, elevated KIM1 serum and tissue levels, and the presence of IgA nephropathy. Further investigation is needed to elucidate key mechanisms of liver fluke–associated kidney injury, in particular to identify proteins involved in the pathogenesis of this condition. Accumulating evidence suggests that liver fluke infection may be linked to biopsy-proven glomerular diseases. The review aims to highlight the importance of evaluating the condition of extrahepatobiliary organs in liver fluke-infected humans and animals, particularly within the One Health framework.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/S0022149X26101187.
Author contribution
A.K. and Ya.K.: Conceptualisation, data curation, formal analysis, investigation, visualisation, and writing – original draft. M.P.: Funding acquisition, project administration, and writing – review and editing.
Acknowledgements
We are thankful to the Multi-Access Center for Microscopy of Biological Objects (Microscopy Center) of the ICG SB RAS (FWNR-2022–0021) for their valuable help. We are thankful to Nikolai Shevchuk (http://shevchukediting.com) for the English-language editing of this manuscript.
Financial support
This research was funded by the Russian Science Foundation, grant number 24-44-00048.
Compting interests
The authors declare that they have no conflicts of interest.
