Introduction
Patients with chronic kidney disease (CKD) often have some adverse clinical symptoms such as fatigue, anorexia, nausea, itching, paresthesias, and pain, which are collectively referred to as uremia symptoms. Previously, these symptoms were thought to be associated with the accumulation of uremic toxins. Because these symptoms tend to occur in patients with advanced CKD and improve after dialysis, they will largely disappear if the patient receives a kidney transplant. However, there are many types of uremic toxins, and it is unclear which uremic toxins cause specific adverse clinical symptoms. If humanity can unmask these "killers", new targeted therapies can be developed to improve the quality of life of patients and reduce the risk of death.
On January 22, 2024, AJKD published a post-hoc analysis of the CRIC study, which showed that 26 uremic toxins were strongly associated with adverse clinical symptoms, and that in addition, in a multivariately corrected Cox regression model, the levels of some uremic toxins were associated with estimated glomerular filtration rate (eGFR) levels and the risk of developing renal failure or death.
Study design
The CRIC study is a prospective, multicenter observational study of adult patients with CKD in the United States. During 2003~2008, a total of 3939 non-dialysis CKD patients aged 21~74 years old with an eGFR of 20~70ml/min/1.73㎡ were included. In some of these patients, uremic toxin levels and uremia symptoms were included in the data. Only patients with CKD with intact uremic toxin levels and complete follow-up information (including symptom reporting data) were included in this analysis.
The primary endpoint of the study is uremia symptoms, including pain, anorexia, nausea, fatigue, and pruritus. Secondary endpoints were renal failure and death.
The researchers used three methods to verify the association between uremic toxins and uremia symptoms, including linear regression, Lasso, and random forest. Finally, the researchers also used the Benjamini-Hochberg correction method to control the false discovery rate (FDR) to less than 5%.
Findings:
A total of 1761 patients with CKD who participated in the CRIC study were included in this analysis. The mean age (±SD) of patients was 59±11 years, 44% were female, and 41% were of African descent. The average eGFR was 43±17ml/min/1.73㎡, and the median urine protein-to-creatinine ratio (UPCR) was 133 (IQR: 53~674) mg/g. There was no significant difference in baseline characteristics of patients in this analysis compared to other patients with CKD who were not included in this analysis.
The analysis found that the most common uremia symptoms in CRIC studies were pain (55%), fatigue (53%), itching (45%), paresthesias (45%), while nausea (28%) and anorexia (22%) were reported less frequently. Only 16% of participants reported no uremia symptoms at baseline. Patients with CKD at baseline eGFR were more likely to report uremia symptoms of higher severity or comorbid symptoms (P<0.001).
01
Uremic toxins associated with uremia symptoms
A total of 26 uremic toxins were analysed to be associated with specific uremic symptoms, as detailed in Table 1.
Table 1 Relationship between uremic toxins and symptoms
02
The relationship between uremic toxins and kidney failure and death
After a mean follow-up of 11±4 years, 26 uremic toxins were found to be significantly associated with renal failure and death, of which 3 were positively correlated and 3 were negatively correlated with renal failure, and 8 were positively correlated with the risk of all-cause mortality and 6 were negatively correlated, as shown in Table 2.
Table 2 Relationship between levels of 26 uremic toxins and renal failure and death
Research Discussion
Available evidence suggests that the burden of fatigue, anorexia, nausea, pruritus, paresthesias, and pain is high in non-dialysis patients, and very few patients do not have this burden. Previously, it was thought that these adverse clinical symptoms were closely related to the accumulation of uremic toxins, but it was not possible to closely link uremic toxins with the corresponding adverse clinical symptoms. As a result, scientists have not been able to develop targeted treatment options for symptoms such as fatigue, anorexia, nausea, itching, and pain in CKD. Existing management options are symptomatic, such as analgesics.
The MDRD study also discussed the relationship between non-dialysis CKD patients and uremic toxins, and found that tryptophan was associated with nausea and anorexia, and uridine and fatigue and carbohydrates were associated with loss of appetite. However, MDRD uses different uremic toxin measurement protocols and different symptom assessment tools, so there may be some differences from some of the results in this analysis. However, the sample size of this analysis is larger and multiple statistical methods are used, so confidence may be higher.
However, haemodialysis patients were not included in this study, so the results of this study may not be applicable to haemodialysis patients. Previous studies have found significant differences in circulating uremic toxin components in hemodialysis patients and non-dialysis CKD patients.
In conclusion, this analysis reveals the uremic toxins associated with uremic symptoms and provides the possibility of causative treatment of uremia symptoms. In the future, there may be patients with CKD who will benefit from this.
Bibliography:
1. Wulczyn KE, Shafi T, Anderson A, et al. Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study, American Journal of Kidney Diseases, Jan 22, 2024.
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