Uraemic syndrome following acute renal failure in horses

Abstract

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:

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; investigation; writing – original draft; writing – review and editing.

None.

No conflicts of interest have been declared.

Ethical approval was not required for this clinical commentary.