Higher abdominal fat area associates with lower donor kidney function before and after living kidney donation
We had hypothesized that higher levels of CT-determined abdominal fat are associated with lower kidney function. In this study, we found a significant association between CT-determined abdominal fat area and kidney function prior to and (in analyses with BSA-standardized mGFR) after donation, with a higher fat area associated with lower kidney function. The results of this study aid in elucidating the effects of body composition (measures) on kidney function.
Prior to donation, all abdominal fat compartments showed a significant association with kidney function, with higher CT-derived abdominal fat area values resulting in lower mGFR values. In studies among healthy individuals, visceral obesity was independently associated with kidney function impairment in all ages and both sexes, except for males < 45 years old18. VAT, SAT, and IMAT have been associated with kidney function decline and/or chronic kidney disease in the general population19, and VAT area independently affected estimated GFR (eGFR) levels in a study among healthy women20. Furthermore, baseline visceral fat area was associated with proteinuria in healthy individuals21. Interestingly, especially donors in the lowest fat index quartiles had higher mGFR levels compared to donors with higher levels of fat indexes in the present study.
After donation, at 3 months follow-up, the tomographic measured abdominal fat areas continued to be strongly associated with lower (BSA-standardized) mGFR levels. In addition, donors with higher pre-donation tomographic abdominal adipose tissue index levels experienced a significantly higher decrease in kidney function between screening for donation and 3 months after donation. A study among Japanese living kidney donors showed that kidney function 12 months after donor nephrectomy was significantly lower in donors with higher VAT area than in donors with lower VAT area22. Retroperitoneal adipose tissue measurement was also significantly correlated with a decrease in eGFR at the first and sixth month after donation in comparison with eGFR before donation23. Thus, it seems that donors with higher levels of abdominal fat areas have a lower kidney function level at which they start their post-donation kidney function trajectory. It is of interest to know how this association between pre-donation abdominal fat levels and post-donation kidney function develops long-term after donation. In the present study, 57% of the study population had available kidney function data 5 years after donation. Although analyses with these long-term kidney function data suggest a trend indicating that higher levels of tomographic abdominal fat areas are associated with lower kidney function at 5 years post-donation, further studies on long-term outcomes of living kidney donation are essential to completely elucidate this association.
The negative association between IMAT and kidney function was an interesting finding. IMAT is an indicator of myosteatosis, fat infiltration into skeletal muscle, and a predictor of a deviant course in numerous patient populations24,25,26,27. Most studies use skeletal muscle radiation attenuation or muscle density measured in HU as a surrogate marker for myosteatosis. The measurement of adipose tissue area in skeletal muscle on CT scans is a novel technique for assessing myosteatosis and may be a promising method in myosteatosis research. To the best of our knowledge, this is the first study to demonstrate a relationship between myosteatosis and kidney function in healthy living kidney donors. Further research that includes long-term clinical outcomes, such as the development of kidney disease, is needed to establish cut-off values for intramuscular adipose tissue and myosteatosis.
The association between abdominal fat area and kidney function before and after donor nephrectomy was most apparent when using mGFR standardized for BSA. In the secondary analyses with unstandardized mGFR, the association between abdominal fat area and mGFR was uncovered when weight was added to the regression model. Weight was added to account for body size, which is known to influence kidney function17. Standardizing GFR for BSA removes the effects of body size and although it is a known methodological practice, it is currently under discussion for its substantial consequences in populations with extreme body sizes28. Due to the screening guidelines for living kidney donation in our center (e.g., advice to lose weight if BMI > 30 kg/m2 and exclusion if BMI ≥ 35 kg/m2), the study population of the present study consisted of individuals with relatively ‘normal’ body sizes. BSA standardization has little consequences on GFR levels in individuals with such ‘normal’ body sizes and may enable more specific assessment of the relationship between abdominal fat area and kidney function in those individuals, independent of overall body size29.
The possible mechanisms underlying the negative association between abdominal adipose tissue and kidney function include direct and indirect effects. The direct interaction between adipose tissue and the kidney is referred to as the ‘adipo-renal axis’ and plays an important role in maintaining normal kidney function. Adipose tissue secretes a large number of factors which play an active role in the endocrine system30,31. Normal levels of these adipose tissue factors are important in preserving kidney function31. Excess caloric intake results in hypertrophy or hyperplasia of adipocytes, leading to several processes resulting in high levels of adipose-derived molecules and dysregulated metabolites, leading to oxidative stress, (chronic) inflammation, and kidney fibrosis, eventually causing kidney injury31.
There is also an indirect effect: an increased amount of visceral adipose tissue is associated with conditions including metabolic syndrome and diabetes32,33,34, which are risk factors for developing CKD35,36,37. Other possible underlying mechanisms could be related to mechanical stress on the kidney due to, for example, pressure exerted by perirenal adipose tissue. An increase in perirenal adipose tissue can cause kidney damage by a direct obstruction of the parenchyma and vessels, followed by an increase in sodium reabsorption and subsequently the development of high blood pressure38,39. Additionally, the compression of kidney parenchyma leads to an increase in interstitial hydrostatic pressure, resulting in reduced kidney blood flow and possible kidney disease progression37,38,39.
Much remains unknown about the possible mechanisms underlying the relationship between abdominal adipose tissue and kidney function, and future research, potentially incorporating investigations of (pathological) parameters such as interstitial fibrosis, tubular atrophy, and perirenal adipose tissue in protocol biopsies, is needed to further elucidate these connections.
Strengths of this study include its relatively large cohort size, kidney function measurements (as opposed to estimates), and limited missing data (< 5%). Limitations are the lack of severely obese donors, limited generalizability due to the majority of participants being of European descent, single institution and retrospective design of the study. The earliest time point after donation at which mGFR was measured was 3 months post-donation. This impaired analysis of change in single-kidney mGFR of the remaining kidney during the first months following donation.
This study found that higher levels of abdominal fat, as measured by CT analysis, were associated with lower pre- and post-donation kidney function. Although the magnitude of the impact of pre-donation abdominal fat area on short-term post-donation kidney function may seem small in comparison with factors such as age and pre-donation mGFR, body composition is one of the few factors that may be optimized prior to donation. This study also raises questions about the use of BMI as a gold standard measure3,4,5 for screening donors, as it does not provide information on abdominal fat areas. BMI did not show an association with mGFR prior to donation, where the tomographic fat indexes did. CT analysis, which is routinely performed in most centers as part of screening for donation, may be a more effective way to assess body composition and associated health risks. Further research is needed to translate this knowledge to clinical practice, determine the effectiveness of CT-derived body composition measurements in donor screening guidelines, and investigate the potential benefits of abdominal fat reduction in living kidney donors.
This study shows that a higher abdominal fat area, measured by CT analysis, is associated with lower kidney function at the time of screening and after living kidney donation. The results of this study aid in elucidating the effect of body composition on kidney function in living kidney donors. Further investigations are imperative to explore the association between adipose tissue measured via CT and kidney function in various (living kidney donor) populations, particularly those affected by obesity. Additionally, radiological assessment of for example perirenal adipose tissue and its influence on kidney function may be of considerable interest in expanding our understanding of living kidney donation and kidney outcomes.
link
