Journal of Renal Nutrition and Metabolism

: 2021  |  Volume : 7  |  Issue : 2  |  Page : 48--50

Effect of uremic toxins on nutritional status

Anil K Bhalla 
 Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India

Correspondence Address:
Dr. Anil K Bhalla
Department of Nephrology, Sir Ganga Ram Hospital, New Delhi

How to cite this article:
Bhalla AK. Effect of uremic toxins on nutritional status.J Renal Nutr Metab 2021;7:48-50

How to cite this URL:
Bhalla AK. Effect of uremic toxins on nutritional status. J Renal Nutr Metab [serial online] 2021 [cited 2023 May 28 ];7:48-50
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The term uremia was first used by Piorry to describe the clinical condition associated with renal failure and literally means “urine in the blood.”[1] Uremia is the term that describes the syndrome of manifestations the patient experiences in the progression to and in end-stage renal failure as toxins accumulate in the plasma. Uremia can be defined as the illness that would remain if the extracellular volume and inorganic ion concentrations were kept normal and the known renal synthetic products were replaced in patients without kidneys. It is a toxic syndrome caused by severe glomerular insufficiency, associated with disturbances in tubular and endocrine functions of the kidney. The hallmark of uremic syndrome is the retention of toxic metabolites associated with changes in volume and electrolyte composition of the body fluids and excess or deficiency of various hormones.[2]

 Manifestations of the Uremic Syndrome

Uremia affects almost all organ systems causing significant morbidity. The most common manifestations include nausea, vomiting, loss of appetite, weight loss, abnormalities of the coagulation cascade, gastrointestinal bleeding, pruritus, serositis, volume overload, hypertension, soft-tissue calcification, pulmonary edema, confusion, lethargy, and death. There is evidence that uremia leads to a variety of disturbances, such as anemia, immunologic deficiency, bleeding tendency, disorders of carbohydrate and lipid metabolism, and various membrane transport disturbances.[3]

Based on their chemical and physical characteristics, uremic toxins are divided into three major groups: (i) Small, water-soluble, nonprotein-bound compounds, (ii) small, lipid-soluble, and/or protein-bound compounds, and (iii) Larger, so-called middle molecules.

EUTox (European Uremic Toxin Work Group),[4] working group of the ESAO (European Society for Artificial Organs[5] Int J Artif Organs[5]), was formed in 1999 to systematically categorize, study uremic retention molecules (general aim) experimentally, more specifically detect the “renal failure specific” factors which underlie vascular damage (genome, proteome, and secretome), design, develop, and improve extracorporeal treatment systems (industrial partners), and apply such knowledge to bioartificial reactors and regenerative medicine applications.

Metabolic and regulatory derangement in chronic kidney disease (CKD) and end-stage renal disease (ESRD) kidney dysfunction is associated with defects in acid excretion, systemic inflammation, end-organ hormone resistance, and uremic toxin accumulation. These abnormalities can further worsen kidney function, creating a vicious circle, adversely affecting patients' outcomes.

 Metabolic Acidosis

Acidemia promotes CKD progression and increases mortality. Metabolic acidosis plays an important role in accelerated protein catabolism, negative nitrogen balance, and loss of lean body mass in CKD and ESRD.[6],[7] Acidosis activates proteolysis through activating the ubiquitin–proteasome system (UPS) and caspase-3. Caspase-3 cleaves actomyosin and myofibrils, providing suitable substrates for UPS-mediated degradation. Thus, acidosis in CKD can preferentially cause muscle protein breakdown to a much greater extent than mobilizing protein from other organs. Muscle protein breakdown can have an adverse effect on the nutritional status. Acidosis also contributes to insulin resistance, growth hormone resistance, and glucocorticoid hypersecretion.[8],[9]

 Sustained Inflammation

Sustained systemic and tissue inflammation is a prominent feature of CKD and ESRD. Negative protein balance in inflammatory state in CKD and ESRD can be ascribed to the activation of multiple cytokine (tumor necrosis factor [TNF], interleukin [IL]-1, and IL-6)-mediated mechanisms. Inhibiting cytokine pathways of myostatin in CKD can mitigate inflammation-associated muscle protein degradation, improve sensitivity to insulin/insulin-like growth factor 1 (IGF-1), and reduce muscle protein breakdown, leading to increased muscle growth. Moreover, exercise upregulates follistatin and the increase is associated with increased muscle strength and mass in patients with CKD. Inflammation also induces multiple hormonal derangements including enhancing glucocorticoid-mediated effects and mitigating insulin/IGF-1 effects by inducing tissue resistance.[10]

IL-6 has also been shown to interact with serum amyloid A, leading to impairment of insulin-IGF-1 signaling through activation of suppressor of cytokine signaling 3 and downstream loss of insulin receptor substrate 1 in muscle. Moreover, IL-6-mediated signaling impairs the assimilation of endogenous amino acids for muscle protein synthesis and enhances caspase-3 activity, further compromising protein nitrogen and muscle protein balance.[11],[12] Collectively, inflammation, through a complex array of mechanisms, preferentially increases in muscle protein catabolism and suppresses muscle protein anabolism, leading to a net muscle protein loss in CKD and ESRD.[13]

 Uremia and Malnutrition – Interplay between Two Devils of Chronic Kidney Disease

Uremia is a catabolic state characterized by sustained inflammation and metabolic acidosis.[14],[15],[16] The problem of malnutrition is compounded by uremia-induced anorexia, prescribed decreased protein intake, and endocrine abnormalities such as insulin resistance, resistance to IGF-1, hyperglucagonemia, and hyperparathyroidism.[17],[18]

Malnutrition in CKD may be broadly classified into two types: Type I – protein–energy malnutrition and Type II – inflammation-related malnutrition.[19],[20] Protein–energy malnutrition is a common entity in the CKD population. Inadequate protein intake is a major contributor, although not the only cause for protein energy wasting (PEM). Causes of inadequate protein intake include anorexia and dietary restrictions.[21]

Patients undergoing hemodialysis have a high prevalence of protein–energy malnutrition and inflammation (inflammation-associated malnutrition). As these two conditions often occur concomitantly in hemodialysis patients, they have been referred together as “malnutrition-inflammation-atherosclerosis syndrome” to emphasize the important association with atherosclerotic cardiovascular disease. The three factors related to the pathophysiology in these patients are dialysis-related nutrient loss, increased protein catabolism, and hypoalbuminemia. Inflammation in CKD is the most important factor in the genesis of several complications in renal disease. Pro-inflammatory cytokines such as IL-1 and TNF-alpha play a major role in the onset of metabolic alterations in CKD patients.[22] Atherosclerosis is a very frequent complication in uremia due to the coexistence of hypertension, hyperhomocysteinemia, inflammation, malnutrition and increased oxidative stress, generation of advanced glycation end products, advanced oxidation protein products, hyperlipidemia, and altered structural and functional ability of high-density lipoprotein. Low-density lipoprotein cholesterol, apolipoprotein (A), apolipoprotein (B), and Lp (a) are also associated with atherosclerosis. Studies have now provided enormous data to enable the evaluation of the severity of malnutrition–inflammation–atherosclerosis syndrome as well as effective monitoring of these patients.[23]

 Kidney Intestinal Axis and the Gut Microbiome

There are approximately 160 different bacterial species in each of us, and a staggering 1000–1200 bacterial species shared across humanity.[24],[25],[26] These bacteria reside throughout our body, but the highest concentration is found in our gut. The fact that the microbiota weighs in at 1–2 kg, has synthetic and metabolic properties, has led some to call it another “organ.” The microbiome in patients with chronic conditions (e.g., metabolic syndrome and diabetes, atherosclerosis, and advanced CKD) is different from healthy individuals. This has led to chronic diseases being labeled as gut “dysbiosis” (as against “symbiosis” – a state of mutual harmony).

How does altered microbiota affect?

The microbiome in patients with chronic conditions (e.g., metabolic syndrome and diabetes, atherosclerosis, and advanced CKD) is different from healthy individuals. This has led to chronic diseases being labeled as gut “dysbiosis” (as against “symbiosis – a state of mutual harmony), with fewer and different bacterial species seen in rat and human CKD. This could be due to decreases in digestive capacity, slowing intestinal transit and secretion of ammonia and urea into the gut. More importantly, uremic toxins, such as indoxyl sulfate, p-cresol sulfate, and trimethylamine N-oxide, are generated by gut bacteria.[27],[28],[29] There is a breakdown of the colonic epithelial tight junctions in CKD, enabling translocation of endotoxins and other such noxious luminal contents into the intestinal wall and systemic circulation, even potentially contributing to the inflammatory state seen in CKD.[30]


The uremic state is characterized by the accumulation of a variety of molecules ranging from the water-soluble small solutes to middle molecules. Uremic milieu promotes a catabolic state characterized by sustained inflammation and metabolic acidosis, which promote protein breakdown. Anorexia, decreased intake, and endocrine abnormalities are major factors for causing a malnourished state. Malnutrition, inflammation, and atherosclerosis form a vicious cycle. Altered gut microbiome leads to increased formation and absorption of uremic toxins, which promotes progression of CKD and further nutritional and inflammatory insult.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Zemaitis MR, Foris LA, Chandra S, Bashir K. Uremia. Treasure Island, FL, USA: StatPearls; 2020.
2Cohen G. Immune dysfunction in Uremia 2020. Toxins (Basel) 2020;12:439.
3Teatini U, Romei Longhena G. Uremic Toxins: How can we improve the removal today? G Ital Nefrol 2017;34:89-101.
4Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, et al. Review on uremic toxins: Classification, concentration, and interindividual variability. Kidney Int 2003;63:1934-43.
5XII World Congress of International Society for Artificial Organs and XXVI Congress of European Society for Artificial Organs. Edinburgh, United Kingdom, 3-6 August 1999. Abstracts. Int J Artif Organs 1999;22:389-467.
6Reaich D, Channon SM, Scrimgeour CM, Goodship TH. Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans. Am J Physiol 1992;263:E735-9.
7Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ, Krapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Investig 1995;95:39-45.
8Du J, Wang X, Miereles C, Bailey JL, Debigare R, Zheng B, et al. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest 2004;113:115-23.
9Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche. Physiol Rev 2013;93:23-67.
10Roshanravan B, Gamboa J, Wilund K. Exercise and CKD: Skeletal muscle dysfunction and practical application of exercise to prevent and treat physical impairments in CKD. Am J Kidney Dis 2017;69:837-52.
11Hou YC, Lu CL, Lu KC. Mineral bone disorders in chronic kidney disease. Nephrology (Carlton) 2018;23 Suppl 4:88-94.
12Lau WL, Savoj J, Nakata MB, Vaziri ND. Altered microbiome in chronic kidney disease: Systemic effects of gut-derived uremic toxins. Clin Sci (Lond) 2018;132:509-22.
13Aroor AR, McKarns S, Demarco VG, Jia G, Sowers JR. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism 2013;62:1543-52.
14Gluba-Brzózka A, Franczyk B, Rysz vegetarian diet in chronic kidney disease – A friend or foe. J Nutr 2017;9:374.
15Cabrera VJ, Hansson J, Kliger AS, Finkelstein FO. Symptom management of the patient with CKD: The role of dialysis. Clin J Am Soc Nephrol 2017;12:687-93.
16Yamamoto S, Fukagawa M. Uremic Toxicity and Bone in CKD. J Nephrol 2017;30:623-7.
17Kovesdy CP, Kopple JD, Kalantar-Zadeh K. Management of protein-energy wasting in non-dialysis-dependent chronic kidney disease: Reconciling low protein intake with nutritional therapy. Am J Clin Nutr 2013;97:1163-77.
18Hauser AB, Stinghen AE, Kato S, Bucharles S, Aita C, Yuzawa Y, et al. Characteristics and causes of immune dysfunction related to uremia and dialysis. Perit Dial Int 2008;28 Suppl 3:S183-7.
19Zha Y, Qian Q. Protein nutrition and malnutrition in CKD and ESRD. Nutrients 2017;9:208.
20Rysz J, Franczyk B, Ciałkowska-Rysz A, Gluba-Brzózka A. The effect of diet on the survival of patients with chronic kidney disease. Nutrients 2017;9:495.
21Jiang YP, Shen Y, Liu XR. An assessment of nutritional status in children on maintenance hemodialysis due to stage 5 chronic kidney disease. Zhongguo Dang Dai Er Ke Za Zhi 2018;20:189-94.
22Amdur RL, Feldman HI, Gupta J, Yang W, Kanetsky P, Shlipak M, et al. Inflammation and progression of CKD: The CRIC study. Clin J Am Soc Nephrol 2016;11:1546-56.
23Snaedal S, Qureshi AR, Lund SH, Germanis G, Hylander B, Heimbürger O, et al. Dialysis modality and nutritional status are associated with variability of inflammatory markers. Nephrol Dial Transplant 2016;31:1320-7.
24Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635-8.
25Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol 2014;25:657-70.
26Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int 2013;83:308-15.
27Hida M, Aiba Y, Sawamura S, Suzuki N, Satoh T, Koga Y. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron 1996;74:349-55.
28Bammens B, Verbeke K, Vanrenterghem Y, Evenepoel P. Evidence for impaired assimilation of protein in chronic renal failure. Kidney Int 2003;64:2196-203.
29Vaziri ND, Yuan J, Rahimi A, Ni Z, Said H, Subramanian VS. Disintegration of colonic epithelial tight junction in uremia: A likely cause of CKD-associated inflammation. Nephrol Dial Transplant 2012;27:2686-93.
30Vaziri ND, Yuan J, Norris K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am J Nephrol 2013;37:1-6.