In this study, we demonstrated that serum TNFR levels are associated with eGFR-CysC, but not eGFR-Cr, even in healthy subjects with normal kidney function, as well as in patients with type 2 diabetes and normal kidney function. The findings also showed that neither of the TNFRs was affected by age and sex in healthy subjects. Moreover, patients with type 2 diabetes had higher TNFR levels than healthy subjects.
Because the decline in eGFR with age is expected to affect TNFR excretion, resulting in lower fractional TNFR excretion with age, the population with eGFR-Cr < 60 mL/min/1.73 m2 was excluded from this study. We previously reported that TNFR levels increased with declining eGFR-CysC in patients with type 2 diabetes and normal kidney function, and that the increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline19. Building on this previous work, the present study demonstrated that the correlation between TNFR levels and eGFR-CysC was observed even in healthy subjects with normal kidney function.
Franceschi et al.20 proposed the concept of inflammaging, referring to chronic low-grade inflammation that is exacerbated with age and affects the acquired and innate immune systems. The elderly exhibit an inflammaging-like phenotype featuring increases in inflammatory markers such as inflammatory cytokines in the blood and activation of inflammatory signals in the tissues, suggesting the induction of chronic low-level inflammation21. In the present study, eGFR-CysC did not change from age 20 to 49, but decreased after age 50. Therefore, age-related elevation in TNFR levels after the age of 50 may simply reflect declining eGFR-CysC, given the finding of multivariate analysis that the relationship between TNFR2 and age disappeared after adjustment for eGFR-CysC. In other words, the increase in inflammatory markers with aging may instead reflect the effects of declining kidney function. Further research is needed to elaborate on the exact mechanisms involved in the increase of TNFRs.
A post hoc analysis of cardiovascular outcome trials involving relatively preserved kidney function in patients with type 2 diabetes treated with a sodium-glucose co-transporter protein-2 (SGLT2) inhibitor, canagliflozin, reported two major findings. Not only were baseline TNFR levels associated with the progression of kidney disease, but also a smaller difference in TNFR levels between baseline and 1 year after SGLT2 inhibitor treatment was associated with better subsequent kidney outcomes22,23. Moreover, it has been reported that TNFR levels are associated with histological findings in renal tissues, such as mesangial fractional volume and percentage of endothelial cell fenestration, in early diabetic nephropathy24. Therefore, the measurement of TNFR levels may be valuable not only for predicting kidney biopsy findings and future kidney outcomes, but also as a marker of treatment responsiveness, suggesting potential therapeutic applications. Additionally, the association between longitudinal changes in TNFR and the subsequent risk of end stage kidney disease or kidney function decline has been reported in studies such as the VA NEPHRON-D trial involving advanced DKD patients and the AASK trial targeting CKD patients with hypertension25. A report has also been published indicating that the Janus kinase inhibitor baricitinib lowers TNFR levels in patients with type 2 diabetes, while another report suggested that the renin-angiotensin-system inhibitor losartan does not have the same effect26. There is thus a need for further investigation to determine how TNFR concentrations change with different treatments.
As shown in Supplementary Table 5, the levels of TNFR in the Native American Pima tribe with type 2 diabetes appeared to be higher than those in Japanese patients with type 2 diabetes. This could be explained by the Japanese having lower kidney function but similar levels of albuminuria compared with Pima Native Americans10,24. Considering how high circulating TNFR2 level and TNFR2 mRNA level are in fat tissue in obese individuals compared with those in others, it cannot be ruled out that BMI is somewhat involved in the elevated TNFR levels observed in Pima Native Americans with type 2 diabetes27. However, in the present study, BMI was not associated with TNFR levels in either healthy subjects or patients with type 2 diabetes, suggesting that this tribe’s TNFR levels are elevated by genetic or other factors.
The impact of various factors on TNFR levels in patients with diabetes makes it difficult to definitively state that these levels independently differ between Japanese and Caucasian populations. However, the TNFR levels in Japanese patients with type 2 diabetes tend to be lower than those in their Caucasian equivalents28,29,30. Further validation is needed to determine whether there are ethnic differences in TNFR levels and what clinical factors influence TNFR levels.
Our study is associated with several limitations that warrant mentioning. We used serum cystatin C-based estimates of eGFR, which are less accurate than direct measurements. Moreover, only Japanese subjects were enrolled in this work. Therefore, the results may not apply to other ethnic groups or DKD patients with kidney function decline. Furthermore, we assembled the healthy subjects from among those who worked at Juntendo University Hospital. Therefore, many of the recruited subjects are likely to have a better understanding of disease than the general healthy population. As such, this control group may have been healthier than the general healthy population.
In conclusion, we revealed that the serum TNFR levels in healthy Japanese subjects are not affected by age or sex, but are related to eGFR even in those with normal kidney function. Further studies are needed to collect a larger number of appropriate subjects from multiple centers and to clarify reference values not only in healthy subjects from the Japanese population but also from other ethnic groups.
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- Source: https://www.nature.com/articles/s41598-024-57265-x