In this large single-center study, we investigated the clinical associations between sex-specific creatinine-cystatin C ratio and long-term outcomes after KT. We found that a low creatinine-cystatin C ratio was significantly associated with an increased risk of DWFG in KT recipients. Compared with the highest creatinine-cystatin C ratio group, the lowest creatinine-cystatin C ratio group had a 2.6-fold higher risk of DWFG, even after adjusting for potential confounding factors, including age, sex, diabetes mellitus, eGFR, and serum albumin. Infection was the most common cause of death in the lowest creatinine-cystatin C ratio group.
DWFG presents as distinctly different clinical phenotypes when compared with death-censored graft failure (the focus of most previous research and a condition caused by many different pathogenic processes)8,16. However, relatively few studies have examined risk factors for DWFG, despite DWFG accounting for approximately half of overall graft losses9,17. Infection, cardiovascular disease, and malignancy are common causes of DWFG. Recipient age, diabetes mellitus, and pre-transplantation duration of dialysis are known risk factors for DWFG, but these factors are not modifiable18. Little is known about post-transplantation factors predictive of DWFG. Only a limited number of studies have investigated the relationship between post-KT eGFR and DWFG, and the relationship remains unclear8,18. Therefore, clinical parameters that reliably identify patients at higher risk for DWFG are urgently required.
Significant graded associations between reduced eGFR and adverse outcomes, including cardiovascular events, hospitalization, and mortality, have been well established19. Although creatinine is the most frequently used biomarker for eGFR, creatinine-based eGFR has an “inverted J-shape” association with all-cause mortality20,21. By contrast, cystatin C has a strong and linear association with all-cause mortality12. Accumulating recent evidence suggests that the creatinine-cystatin C ratio may have utility as a surrogate marker for mortality beyond renal function14,15. Previous studies reported that a low creatinine-cystatin C ratio is associated with an increased risk of mortality in various conditions, such as diabetes mellitus22, chronic kidney disease23,24, malignancy15, and chronic obstructive pulmonary disease25. Our data demonstrated that a low sex-specific creatinine-cystatin C ratio was an independent risk factor for all-cause mortality in KT recipients. To our knowledge, this is the first study to evaluate clinical outcomes according to creatinine-cystatin C ratio in a large population of KT recipients.
One plausible explanation for the relationship between creatinine-cystatin C ratio and DWFG observed in the present study is that the ratio might reflect muscle mass. Since creatinine is an end-product of muscle catabolism, serum creatinine is affected by muscle mass26,27. In contrast, cystatin C is produced by all nucleated cells28. Therefore, a low creatinine-cystatin C ratio might be a marker of low muscle mass. In addition, the risk factors for low creatinine-cystatin C ratio found in our study were older age, longer dialysis duration, and re-transplant, which are all known risk factors for low muscle mass. Low muscle mass has emerged as a strong predictor of mortality in various populations. Several investigators, including our group, have reported an association between low muscle mass and poor transplant outcomes after KT29,30.
Another possible explanation for our findings is that cystatin C might reflect inflammatory status. Several studies have suggested that cystatin C is directly linked to adverse outcomes beyond renal function11,13, and previous studies reported that cystatin C is associated with inflammatory markers31,32,33. A low creatinine-cystatin C ratio, resulting from an elevated cystatin C level, may indicate an inflammatory state rather than a decline in renal function.
In addition, previous various studies have reported that patients with low muscle mass have increased vulnerability to infection and an increased risk of infection-related mortality34,35,36. Taking into account that the lowest tertile group might be associated with low muscle mass, this is consistent with our finding that infection is the most common cause of death in the lowest creatinine-cystatin C ratio group.
Our findings have potentially important clinical implications. Creatinine-based eGFR may overestimate GFR in patients with a low muscle mass, whereas cystatin C is less affected by muscle mass. Accordingly, the National Kidney Foundation (NKF) and the American Society of Nephrology have recommended the use of cystatin C to estimate GFR37. In situations where cystatin C and creatinine are measured concurrently, the creatinine-cystatin C ratio could be used as a potential clinical parameter for predicting DWFG, an outcome that is otherwise difficult to predict.
This study has several limitations. First, it was a retrospectively designed single-institution study, and the results of the study were not validated in an independent cohort. Therefore, further external validation of these study results is necessary. However, since it was conducted at a single center, the study has the advantages of consistent use of immunosuppressive drugs, standardized patient management protocols, and more complete and reliable data regarding mortality (including causes). Second, this study investigated cystatin C data measured at least 6 months after KT. It is therefore unknown whether the creatinine-cystatin C ratio has similar significance in predicting early mortality after KT. Third, because of the late introduction of cystatin C measurements, creatinine-cystatin C ratios were not obtained on the same day after KT across patients. In 2015, the NKF published guidelines recommending the use of cystatin C to evaluate kidney function post-KT, and cystatin C measurements were begun relatively recently in the Republic of Korea. Nevertheless, our data on the creatinine-cystatin C ratio have the advantage of representing real-world data. Fourth, since muscle mass was not measured, we were unable to directly assess the relationship between low muscle mass and creatinine-cystatin C ratio.
In conclusion, a low creatinine-cystatin C ratio was significantly associated with an increased risk of DWFG in KT recipients.
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- Source: https://www.nature.com/articles/s41598-024-52649-5