Review
Clinical management of the uraemic syndrome in chronic kidney disease

https://doi.org/10.1016/S2213-8587(16)00033-4Get rights and content

Summary

The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction, which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic algorithm can be developed for this complex and multifactorial condition, with interventions targeting several modifiable factors simultaneously.

Introduction

Kidney failure is associated with deterioration of body functions. The clinical picture as a whole—the uraemic syndrome—is named after urea, the most abundant metabolite retained in kidney failure and the first uraemic retention product identified. The uraemic syndrome can be caused by chronic kidney disease or acute kidney injury, and affects almost every organ system (panel 1).1 The syndrome results from the biological effects of metabolites that are not excreted or metabolised by the kidneys and are retained within the body.2 Such metabolites are named uraemic retention products, or uraemic toxins if they exert biological or toxic effects. The deterioration of renal endocrine function (production of erythropoietin, active vitamin D, or renin), the deregulation of kidney electrolyte homoeostasis, and functional alterations resulting from chronic kidney disease and its causes (eg, diabetes, autoimmune disorders) also contribute to the syndrome. The clinical picture worsens with kidney failure, with coma and death (end-stage kidney disease; table 1) the ultimate result if the patient is left untreated. However, since the 1940s, renal replacement therapies (dialysis or transplantation) have extended the life expectancy of patients with this potentially fatal condition.

Although dialysis and transplantation extend the life expectancy of patients with uraemia, mortality remains substantially higher than in age-matched populations with normal kidney function;3, 4 general and cardiovascular mortality tend to rise even before patients need dialysis.5, 6 In this Review, we discuss several therapeutic options to treat the consequences of the uraemic syndrome in chronic kidney disease, based on the pathophysiology of the uraemic syndrome and taking into account newly detected, pathological pathways.

Although we have followed the principles of evidence-based medicine as much as possible in this Review, much of the data cited are from observation studies. Randomised controlled trials in kidney disease are scarce,7 and many studies have had negative results.8 This fact is largely attributable to the complex and multifactorial nature of the disease, which makes it difficult to recruit large patient groups with uniform pathophysiological backgrounds. Additionally, because of multi-layered pathophysiology, the effect of therapeutic options that correct one aspect of disease (eg, hypercholesterolaemia) can be masked by the effect of other factors (eg, hypertension, fluid overload) on outcome measures.

Section snippets

Traditional and non-traditional risk factors

Cardiovascular and non-cardiovascular mortality contribute equally to the high mortality seen in people with chronic kidney disease.9 Socioeconomic and geographical factors, including access to therapy, explain the variable mortality in chronic kidney disease and end-stage kidney disease populations.10 Cardiovascular disease in patients with chronic kidney disease is characterised by immunity-driven inflammatory changes that cause vessel wall stiffening, arteriopathy, and cardiomyopathy leading

Uraemic retention products

Information about uraemic retention products has increased continuously in the past few decades. At least 150 uraemic retention products have been described so far,13, 14 and with developments in metabolomics and proteomics in the past decade, each new study has the potential to add dozens of new substances to this list. The idea that removal of one single solute would be sufficient to solve the problem of uraemic toxicity has long since been abandoned. By contrast, the notion that all these

Scope of Review

Since the pathophysiology of the uraemic syndrome affects the function of almost every organ (panel 1), this Review is restricted to elements for which relevant information is available and that imply specific therapeutic approaches. Definition of which pathophysiological events are directly caused by uraemic retention products and which, as a whole or in part, are caused by other aspects of kidney dysfunction is not always easy. We will summarise which elements are linked to uraemic retention

Management

The studies, guidelines, position statements, and reviews referred to in this section are summarised in the appendix. Treatment aimed at modifying risk factors will be discussed in broad terms independently of underlying intermediate mechanisms. Of note, positive interventions in the general population, could counterintuitively cause or amplify complications in chronic kidney disease. This section on management includes 56 original studies (appendix), of which only 35 (63%) are randomised

Conclusion

Patients with chronic kidney disease have complex pathophysiology for which the underlying mechanisms intertwine (appendix). Inflammation and disturbed bone homoeostasis in particular lead to complications and high and accelerated mortality. Management (appendix) cannot always be based on high-level evidence, because of difficulties in the recruitment of patients with sufficiently homogeneous background of primary disease, metabolic features, and response to the uraemic syndrome. Specific

Search strategy and selection criteria

We searched PubMed, Embase, Web of Science, and the Cochrane Library for articles published in English up to Dec 1, 2015. Search terms related to the main topics of this Review were used—eg, “metabolic bone disease” or “inflammation” and “chronic kidney disease”, “chronic renal failure” or “chronic kidney disease” and “physiopathology”, “treatment”, “therapy”, “outcomes”, “morbidity”, or “mortality”. Randomised controlled trials or large observational studies on hard outcomes were retained by

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