Uraemic syndrome following acute renal failure in horses

This clinical commentary accompanies the case report from Fernandes and Robin (2025) that describes an interesting case with multiple metabolic problems including acute renal failure (ARF), metabolic encephalopathy, uraemic syndrome and hyperammonaemia. The aim of this commentary is to review the definition and extrarenal effects of the uraemic syndrome in acute kidney injury (AKI) and ARF. As little data are available on horses, a descriptive comparison is made across species. Azotaemia is a pure biochemical abnormality, that is defined as the elevation or buildup of nitrogenous products and other secondary waste products within the body because of reduced renal function (Tyagi & Aeddula, 2025). When the severity of azotaemia increases, and it becomes manifested with clinical signs, this is called uraemia (Tyagi & Aeddula, 2025). Uraemia literally means ‘urine in the blood’. The increasing concentration of waste metabolites can lead to toxic levels (these are then called uraemic toxins - UTs), which can have widespread effects throughout the body because of their deleterious effects on cell metabolism and function (Schott, 2010b). Uraemic syndrome describes the combination of clinical signs that develop consequently (Schott, 2010b; Tyagi & Aeddula, 2025). Acute kidney injury (AKI) means that the kidney has sustained acute damage leading to a sudden decrease in the kidney's excretory function. AKI covers the whole spectrum ranging from mild non-azotaemic kidney injury to advanced renal failure with severe uraemia (Segev et al., 2024; van Galen et al., 2024). On a cellular level UTs cause endoplasmic reticulum and mitochondrial stress and reduced mitochondrial respiration (Andre et al., 2023). They also cause activation of the aryl hydrocarbon receptor and nuclear factor kappa B (NF-κB), reactive oxygen species production and the mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and transforming growth factor β (TGF-β) signalling pathways. These effects lead to a pro-inflammatory state, cellular dysfunction and apoptosis (Andre et al., 2023). Some 150 molecules are considered to be UTs and are believed to contribute to the uraemic syndrome when their concentrations increase following a decline in renal function (Andre et al., 2023). The most well-known UTs are blood urea nitrogen (BUN), serum creatinine, ammonia, uric acid, phenol, guanidino compounds and products of intestinal metabolism (secondary methylamines, polyamines and tryptophan breakdown products such as indole, skatole, indoleacetic acid; Lee & Downing, 1981; Schott, 2010b). Although some UTs are inversely correlated with renal function (glomerular filtration rate or serum creatinine concentrations; Ebrahimi et al., 2025), some are not (Andre et al., 2023; Veldeman et al., 2019). However, more molecular changes are occurring in the circulation. It is well-known that decreased renal function also leads to electrolyte and acid-base imbalances. Furthermore, abnormalities in trace minerals can develop such as aluminium toxicity and zinc deficiency (Schott, 2010a, 2010b). Abnormal metabolism, tissue insensitivity, clearance and production of hormones also accompany the decline in renal function, leading to hormonal problems such as secondary hyperthyroidism (hypersecretion to re-establish homeostasis) and insulin insensitivity (Schott, 2010a, 2010b). More recently, human studies and animal models have demonstrated that the damaged kidney releases a large number of inflammatory mediators and cell debris into the circulation (Faubel & Edelstein, 2016). All these molecules that are building up or released into the circulation, not just the UTs, can have effects on distant organs and contribute to the uraemic syndrome. The term uraemic syndrome is therefore used to describe the clinical signs that are associated with uraemia, however, not necessarily only caused by UTs. Azotaemia, uraemia and uraemic syndrome can develop with acute and chronic renal disease. Uraemia and uraemic syndrome typically develop with failure (the more serious end of the spectrum of acute kidney injury (AKI) or chronic kidney disease (CKD); van Galen et al., 2024) as the azotaemia needs to be severe enough for clinical signs to develop. Uraemic syndrome is well-described and commonly seen in horses with chronic renal failure (CRF) (Schott, 2010b). The chronicity of the condition causes prolonged exposure of tissues to the UTs and other above-mentioned mediators, and a multitude of clinical signs becomes gradually apparent over time as they further accumulate. Acute-on-chronic events can cause acute exacerbations of the clinical syndrome. The uraemic syndrome can also be witnessed in ARF. The syndrome is then often more difficult to recognise because classical clinical signs such as lethargy and reduced appetite are non-specific and usually also relate to the inciting or underlying disease process. There is currently limited data on uraemic syndrome in horses with ARF, however, there are some case reports such as the report from Fernandes and Robin (2025) and Bouchard et al. (1994), anecdotal evidence and strong evidence from human medicine (Andre et al., 2023; Caillard et al., 2022; Veldeman et al., 2019; Wang et al., 2019). Also, in my personal experience, the syndrome can be seen in horses with ARF. The milder and less apparent clinical signs can perhaps be explained by the fact that in people plasma concentrations of UTs mostly are lower with AKI than with CKD (Caillard et al., 2022; Chan & Liu, 2024; Veldeman et al., 2019; Wang et al., 2019), some UTs are not increasing in all patients with ARF and some increase only transiently (Andre et al., 2023; Veldeman et al., 2019; Wang et al., 2019). These kinetics are likely similar in horses. However, diet significantly affects the concentrations of UTs in people (Czaja-Stolc et al., 2025) and thus the equine diet being very different, could possibly instigate different UT patterns and therefore clinical signs. In some horses with ARF with a very steep reduction of renal function, the syndrome can become more recognisable. In my experience, this can be associated with an acute and severe onset of uraemic clinical signs, fulminant disease progression and poor outcome. This rapid onset witnessed in some horses corresponds with the findings that deleterious effects from UTs were already seen in human cells after a 30 min–1H exposure (Andre et al., 2023). In people, small animals and horses, clinical signs and complications can also be seen with non-azotaemic or mildly azotaemic AKI without uraemia (grade 1 or grade 2 AKI), albeit often very subtle or subclinical. Thus, the conclusion is that they occur over the entire spectrum of AKI from non-azotaemic to severe uraemic failure, and not only when uraemia develops. Certain UTs and other above-mentioned mediators can namely increase before serum creatinine and/or BUN concentrations are above the reference range and before one can truly speak of uraemia (Mulders et al., 2025). As clinical signs are not solely caused by UTs, but merely associated with uraemia, and clinical signs can occur because of UTs but without uraemia, the use of the term uraemic syndrome can lead to confusion and misunderstanding and its use is typically restricted to most severe situations. To avoid oversimplification and misperceptions and to cover the whole spectrum, it is suggested by the author to simply talk about clinical signs associated with renal disease. In the last 20 years, several complications involving distant organs have started to be appreciated in people with AKI, alongside the long-recognised complications such as electrolyte disturbances, fluid overload and uraemic bleeding (Faubel & Edelstein, 2016). Actually, AKI affects basically every organ in the body, with the possibility to cause multi-organ damage and dysfunction (MODS), and eventually multi-organ failure (MOF) and loss of homeostatic control over essential body functions. As a matter of fact, ARF is accompanied by extrarenal organ failure in most human patients (Mehta et al., 2004). AKI should, therefore, be considered a systemic disease. These complications are partially caused by a direct toxic effect of UTs, but also inflammatory mediators and cell debris released from the damaged kidney, and the fluid, electrolyte and acid-base disturbances cause significant deleterious effects to distant organs (Chan & Liu, 2024; Faubel & Edelstein, 2016). Furthermore, affected organs can in turn contribute to the damage to other organs. Although the pathophysiology of distant organ damage and dysfunction is currently not fully understood, it is considered multi-factorial (Caillard et al., 2022; Chan & Liu, 2024; Faubel & Edelstein, 2016). The most common organ systems that are affected by AKI are listed below: Although for a long time, there has mainly been a focus on the development of AKI following acute heart failure, cardiovascular complications can also develop secondary to AKI. This is described as cardiorenal syndrome type 3 (Caillard et al., 2022; Chan & Liu, 2024; Keller et al., 2016). In people, AKI has been associated with an elevated risk of acute heart failure, acute coronary syndrome, thromboembolism, hypertension and stroke (Chan & Liu, 2024). In uraemic small animals with AKI, arrhythmias and systemic hypertension are common (Caillard et al., 2022; Segev et al., 2024), and acute uraemia is associated with a marked reduction in coronary vascular function (Kingma Jr et al., 2006). In a study of 24 dogs with AKI, ventricular premature complexes were the most common arrhythmias observed and associated with high cardiac troponin concentrations and non-survival (Keller et al., 2016). Careful causal interpretation is crucial as patients with AKI often present with various co-morbidities that can impact cardiovascular risk and the determination of a temporal association between AKI and cardiac events can be challenging (Caillard et al., 2022; Chan & Liu, 2024). The causes for cardiac events in AKI patients are likely multi-factorial, but electrolyte and acid-base disturbances, hypoxaemia, inflammation, pain and the underlying disease process contribute (Caillard et al., 2022; Segev et al., 2024). There is also strong evidence that gut-derived protein-bound UTs, amongst which indoxyl sulphate, cause vascular dysfunction (endothelial damage) and cardiac dysfunction in people with CKD, and similar mechanisms are believed to apply in AKI (Caillard et al., 2022; Chan & Liu, 2024). Urea and guanidino compounds have myocardial depressant effects and have been associated with myocardial infarction (Chan & Liu, 2024; De Deyn et al., 2003) and phenol exhibits a dose-dependent negative inotropic effect on cardiac muscle (Chan & Liu, 2024; Lee & Downing, 1981). Uraemia-associated arrhythmias or other cardiac events are very poorly described in horses. Hypertensive cardiomyopathy with non-invasively measured MAPs of 126–222 mmHg has been described in horses with CRF (Navas de Solis et al., 2013), however, not with AKI or ARF. Respiratory compromise (acute lung injury, pulmonary oedema, aspiration or ventilation-associated pneumonia, pulmonary bleeds, thromboembolism and uraemic pneumonitis) is commonly noticed in human and small animal AKI patients (Faubel & Edelstein, 2016; Mehta et al., 2004; Segev et al., 2008, 2024), and respiratory complications are even considered a key marker of mortality risk in people with AKI (Faubel & Edelstein, 2016). The development of lung injury after AKI, typically with lung inflammation and pulmonary oedema (cardiogenic or non-cardiogenic), is complex. The following factors have been shown to play a central role: endothelial permeability and apoptosis, and inflammatory cytokines and necrotic debris released from the injured kidney. Most of these factors affect lung tissue within 2–24H (Faubel & Edelstein, 2016). Furthermore, impaired fluid, electrolyte and acid-base balance contribute to pulmonary injury (Faubel & Edelstein, 2016). A direct role of UTs is suggested but remains to be determined (Faubel & Edelstein, 2016). Respiratory compromise is rarely seen or recognised in equine AKI patients, and if occurring it is probably often, rightfully or wrongfully, believed to be caused by the underlying disease. Uraemia-induced gastrointestinal disturbances are common in small animals and in humans suffering from severe AKI and include nausea or discomfort, vomiting, diarrhoea, anorexia, gastrointestinal and oral ulcerations, with glossitis and stomatitis and halithosis (Segev et al., 2024). Gastrointestinal ulceration can lead to significant blood loss. Furthermore, recent research highlights the clinical relevance of the gut-renal axis in humans with AKI and CKD, where renal function influences the gut microbiome (causing dysbiosis) and induces gut-derived UTs production and a leaky gut, but the gut microbiome also affects the progression of renal disease and microbiome modulation can be used as a therapeutic target (Liu et al., 2024; Tsuji et al., 2024). In horses, anorexia or decreased appetite is frequently noted in horses with ARF (van Galen et al., 2024). The more severe clinical gastrointestinal expressions, including ulcerations, are more often seen in CRF (van Galen et al., 2024) but rarely in AKI or ARF. There are currently no studies available on the relationship between renal disease and the gut microbiome in horses. Neurological signs associated with renal disease are well-described in small animals (Brauer et al., 2011) and people (Baumgaertel et al., 2014). Uraemic encephalopathy is a severe neurological disorder because of the accumulation of UTs in the brain, with its severity correlating to the extent and kinetics of the accumulation of the UTs (Baumgaertel et al., 2014). Up to 20% of intensive care human patients with ARF are affected by uraemic encephalopathy (Mehta et al., 2004). Also in horses neurological signs of cerebellar dysfunction can occasionally be seen in relation to severe AKI (Bouchard et al., 1994; van Galen et al., 2024) or CRF with substantial azotemia (Frye et al., 2001). Even though rare, it is probably the most well-known extrarenal complication of AKI in horses. Witnessed signs in affected horses include obtunded mentation, lethargy, head pressing, anxiety, apparent changes in cognition, ataxia, recumbency, nystagmus, blindness and seizures (Bouchard et al., 1994; Frye et al., 2001). In an equine case series described by Frye et al. (2001), high blood ammonia concentrations were found in some but not in all of the described cases. Moreover, histopathological changes showed hyperammonaemia-induced astrocyte changes (Alzheimer type II astrocytes) and decreased glial fibrillary acidic protein (GFAP) immunohistochemistry staining (Frye et al., 2001). Frye et al. (2001) therefore suggested that hyperammonaemia could play a role in the development of neurological signs but the accumulation of guanidinosuccinic acid and other guanidino compounds was also mentioned (Frye et al., 2001). Human literature also suggests the following mechanisms to play a role: aluminium toxicity (Schott, 2010a, 2010b), cortical hyperexcitation (Baumgaertel et al., 2014) and accumulation of other UTs such as beta2 microglobulin, creatinine, uric acid, various amino acids, polypeptides, polyamines, phenols, sulphates, phosphates (Baumgaertel et al., 2014). Especially the guanidines have been identified as major neurotoxins in the development of neurological signs. They activate N-methyl-D-aspartate (NMDA) receptors and GABA receptors (Baumgaertel et al., 2014). Prognosis for horses with uraemic encephalopathy is grave (Bouchard et al., 1994; Frye et al., 2001; van Galen et al., 2024). Uraemic encephalopathy remains a diagnosis of exclusion (Frye et al., 2001). Neurological signs can also develop as a manifestation of the underlying disease, severe electrolyte derangements, systemic hypertension or side effects or overdose of used drugs (because of decreased renal excretion of drugs; Segev et al., 2024). Also, the combination of UT accumulation together with one or more of these above-mentioned mechanisms should be considered. Neurological signs that developed specifically in relation to severe hyponatraemia (serum sodium concentrations <120 mmol/L) induced by ARF have been well described in foals (Collins et al., 2016; Hardefeldt, 2014). However, with the marked azotaemia in several foals in these case reports, high concentrations of UTs could have been an overlooked major co-mechanism for the development of neurological signs. In the foals with milder azotaemia, UTs could potentially have lowered the threshold for hyponatraemic seizures through their effect on NMDA and GABA receptors. AKI small animal and human patients can be in a hypo- or a hypercoagulable state and can develop uraemia-induced thrombocytopathy, thrombocytopenia, or disseminated intravascular coagulation (DIC) (Segev et al., 2024). Anaemia can be present because of blood loss, uraemia-induced haemolysis because of erythrocyte fragility, a decrease in erythropoietin production and the negative effects on bone marrow (Segev et al., 2024). Haematological failure (defined as WBC < 1000/mm3, platelets <20,000/mm3, haematocrit <20% or requirement for platelet transfusions; Mehta et al., 2002) was demonstrated in human AKI (25%) (Mehta et al., 2004) and ARF (Mehta et al., 2002) patients. In horses, anaemia is rarely associated with AKI but is seen in CRF (van Galen et al., 2024). Haemolytic uraemic-like syndrome, with haemolysis, thrombocytopenia and thrombotic microangiopathy following ARF, has been described in horses (Dickinson et al., 2008; Morris et al., 1987). Interestingly, UTs also have a negative effect on the kidney. They play a critical role in the transition from AKI to CKD, as they establish a pro-inflammatory and pro-fibrotic environment in the kidney (Andre et al., 2023). Therefore, they are a consequence of ARF and CRF, but also a driving force for the kidneys to progress from AKI into CRF (Andre et al., 2023). AKI has an effect on outcome in people (Mehta et al., 2004), small animals (Segev et al., 2024) and horses (van Galen et al., 2024). The recent small animal consensus statement (Segev et al., 2024) and the equine consensus statement (van Galen et al., 2024) both agree on the fact that although the degree of azotaemia or serum creatinine concentration in AKI reflects the severity of injury and carries a prognostic value, it does not define the potential for reversibility. In recent years it has become more apparent that the effects on distant organs are now believed to contribute greatly to AKI mortality in people (Faubel & Edelstein, 2016; Mehta et al., 2002, 2004) and small animals (Segev et al., 2024). No data is currently available on this in horses. Some UTs have been demonstrated to have a direct impact on morbidity and mortality in people. For example, higher levels of indoxyl sulfate, a protein-bound UT, have been associated with mortality (Wang et al., 2019) and an increased risk of heart failure events (Zwaenepoel et al., 2024). In conclusion, some of the extrarenal effects of the uraemic syndrome that are well described in people, cats and dogs are also recognised in horses. Many are not or poorly described in equine literature with mainly anecdotal evidence or small case series. However, following scientific evidence from small animals and humans, they are likely to occur in horses, but remain currently underrecognised as it can be difficult to know whether they are a consequence of AKI or caused by the underlying disease that often also can cause distant organ damage with MODS or MOF. However, the equine diet differs significantly from human, canine and feline diets and could impact the production of UTs and reduce the incidence of extrarenal effects. Still, equine clinicians should look out for these signs, especially in severe AKI cases. Future research and retrospective case studies and case reports will hopefully aid in improving the description and determination of their significance in equine medicine. This case report of Fernandes and Robin (2025) is a clear example of how severe AKI with high levels of UTs (BUN, serum creatinine and ammonia) and disturbances in fluid balance, electrolyte and acid base can lead to complex pathology in multiple organs. This horse had clear evidence of gastrointestinal and neurological consequences. This case also is a good demonstration that although serum creatinine was very high (1651 micromol/L) full recovery can happen with therapeutic support. Already after the first day of treatment, there was a significant reduction of serum creatinine concentrations. As previously described in horses, if within 72 h of starting treatment, adequate urine production and decreasing creatinine are observed, the prognosis can be favourable (Groover et al., 2006; van Galen et al., 2024). However, full recovery of animals with AKI can take up to months (Segev et al., 2024; van Galen et al., 2024). G. van Galen: Conceptualization; data curation; review and by The of as of the - The of the of No of have been was not for this clinical