In this matched case-control study, higher TFF3 was strongly associated with incident CKD over a median follow-up of 8.6 years. Baseline TFF3 levels were higher among Blacks, females, individuals with diabetes and those using antihypertensive medications. Higher TFF3 remained significantly associated with incident CKD after adjustment for these factors, as well as for other CKD risk factors, including urinary albumin excretion.
TFF3 is a member of the trefoil factor family (TFF; consisting of TFF 1, TFF 2 and TFF 3), peptides which are secretory products of a variety of mucin-producing epithelial cells, including the gastrointestinal tract [22
]. These peptides play a crucial role in the defense and repair of the mucosa through numerous mechanisms, including formation of mucous barriers, rapid repair by cell migration (‘restitution’), antiapoptopic effects, and modulation of differentiation and immune response and inflammatory processes [23
]. Pathologic expression of TFF peptides has been observed during a variety of chronic inflammatory diseases and certain tumors [24
]. TFF3 has been accepted by the FDA and the EMEA as a biomarker of drug-induced acute kidney tubular alterations in rat studies used to support clinical trials [13
]. This decision was based on changes in urine TFF3 levels in rats with 2 weeks of drug-induced nephrotoxicity.
Recent experiments in humans have found TFFs synthesized throughout the urinary tract, with TFF3 being the predominate TFF in cells of the proximal and distal tubules and collecting duct [26
]. Synthesis of TFF3 was found primarily in the basal and intermediate layers. The authors hypothesized that TFF3 may be partly responsible for the regenerative capacity of the kidney, possibly through restitution, which is initiated very quickly after injury [27
], and/or effects on differentiation, which takes place over a longer time period [30
]. Others have hypothesized similar roles for TFF3 in the gastric antrum [32
The role of TFF3 in CKD is unknown. We speculate that TFF3 is involved in the repair of injury, presumably to the tubular epithelium, and that the higher levels observed in the urine are indicative of ongoing repair, which, in turn, is indicative of damage or ongoing inflammatory processes. If this hypothesis is correct, TFF3 may be useful as a marker of CKD risk. Levels of TFF3 were much higher in participants with diabetes and in participants using antihypertensive medications than in their counterparts. The reasons for these differences are unknown. Diabetes and hypertension are potent risk factors for CKD [18
], and these differences may provide additional evidence that TFF3 levels are associated with ongoing kidney damage. The lack of an association between TFF3 and urinary ACR argues against this hypothesis, but the restricted range of ACR values in these studies limits our ability to fully explore this potential association. The reasons for higher levels among Blacks compared to Whites and women compared to men are unknown.
This study has several limitations, including the use of a case-control design, which excludes individuals that died or were lost to follow-up or were ineligible for the follow-up examination. Any systematic bias, however, would likely attenuate the observed association. The relatively small sample size provided limited power for investigating associations within various subgroups, such as by diabetes status. The relative small sample size does not preclude statistical chance as an explanation for this difference. The definition of incident CKD (i.e., follow- up eGFR <60 ml/min/1.73 m2
and a ≥25% decrease in eGFR) was based on a single serum creatinine measurement at each visit, which can be imprecise. The case definition, therefore, may not detect significant changes in kidney function, or may detect clinically insignificant decreases [18
]. Again, any imprecision would likely result in observing attenuated associations. This is a pilot study, and the observed associations should be explored in larger studies.
In conclusion, we found that higher urinary levels of TFF3 were associated with incident CKD. If confirmed in additional studies, TFF3 may be useful as a marker of future risk of CKD.