Our study findings show that RFR strongly predicts AKI after cardiac surgery in young adults with acyanotic CHD with normal baseline eGFR, using either a CrCl or a cystatin C eGFR method. Notably, RFR based on CrCl showed perfect predictive ability for AKI, while baseline renal function markers such as creatinine and cystatin C were poor predictors. Preoperative risk assessment for AKI is essential for optimizing patient management and potentially improving outcomes. Stratifying patients by AKI risk before surgery can aid clinical decision-making, patient education and identify high-risk patients for trial enrollment.
Prior study results have demonstrated that the risk of AKI during cardiac surgeries can be reduced by identifying high-risk patients and applying a comprehensive care bundle accordingly28. However, these studies stratified patients based on biomarker evidence of kidney stress. Patients with reduced RFR can be identified well before receiving surgery or other planned stressors and, therefore, benefit from a proactive management strategy, including minimizing nephrotoxic medications, reducing exposure to radiocontrast, adjusting fluid intake, nephrology consultation upon hospital admission, and possibly even changes to the surgical and anesthetic plans28,29. Medications like ACE inhibitors, ARBs, and sodium-glucose cotransporter 2 inhibitors have shown promise in mitigating kidney damage in conditions like diabetes and hypertension30,31,32. Furthermore, this strategy could also be combined with biomarker measurements following surgery. Future work is needed to explore if patients with reduced RFR may benefit from these medications to help reduce intraglomerular pressure and GFR decline.
Importantly, patients with CHD in our study had significantly lower RFR values, whether measured by CrCl or cystatin C eGFR, compared to those without CHD despite all participants having a similarly normal baseline eGFR. This finding suggests that a lower RFR could indicate compromised “kidney fitness” or the kidney’s ability to adapt to physiological stressors, such as cardiac surgery33. A kidney experiencing reduced fitness might be operating at or near its maximum filtration capacity, thus limiting its ability to increase filtration under stress and heightening the risk of AKI. Interestingly, although not statistically significant, baseline eGFR was higher in the AKI group when compared to those who did not experience AKI, suggesting possible hyperfiltration in which the remaining functional nephrons in the kidney increase their filtration rate to compensate for lost renal mass, potentially masking early kidney damage34.
There is a lack of methods to determine AKI risk in patients without kidney disease recognizable by serum creatinine, proteinuria, or blood pressure findings. Cooper et al. highlighted the persistent elevation of biomarkers such as IL-18 and liver-type fatty acid–binding protein seven years after cardiopulmonary bypass-induced AKI, suggesting subclinical kidney damage despite normal kidney function by conventional measures35. Volovelsky and colleagues demonstrated the predictive value of preoperative fibroblast growth factor 23 for severe AKI post-cardiac surgery36. This concept of kidney frailty or fitness emphasizes the importance of early risk stratification and intervention, particularly for vulnerable populations like those with CHD where the six-year mortality rate is five-fold higher for adults with CHD with a moderate or severe reduction in GFR when compared to patients with a normal GFR37.
Our results highlight the utility of cystatin C for estimating GFR, eliminating the need for timed urine collections required by CrCl. The cystatin C method offers a faster and more practical alternative for clinical use. Our data also indicates that creatinine-based estimates of RFR exceed those derived from cystatin C. This discrepancy is likely due to the increased tubular secretion of creatinine following a protein-rich meal, which prior studies have shown raises serum creatinine concentrations through non-steady state conditions induced by the conversion of creatine to creatinine during cooking12. Our results also provide important insights into the timing of a GFR increase following a protein load. The peak increase in CrCl and cystatin C eGFR occurred two hours after the protein load in 82% of our study participants. This is consistent with previous studies that show a peak GFR increase within three hours after a protein load in subjects with a normal baseline eGFR11,12,13. Notably, Christiadi et al. demonstrated that in patients with CKD, plasma cystatin C levels reached their lowest point approximately four hours after a protein load in more than 40% of CKD stage 3 patients and 52% of those with CKD stage 438. This delayed response suggests that individuals with reduced baseline kidney function may require a longer sampling period to fully capture the peak GFR increase compared to those with a normal baseline GFR.
The albumin-to-creatinine ratio is a well-established predictor of CKD progression, with evidence linking elevated ACR levels to worse outcomes, such as accelerated declines in GFR39. However, its use in predicting AKI is less extensively studied. We found no statistically significant difference in the preoperative albumin to creatinine ratio between patients with AKI and those without, although values were numerically greater in those with AKI.
Our study has several strengths, including its prospective design and the use of both CrCl and cystatin C-based eGFR methods to assess RFR in patient cohorts at increased risk for kidney disease progression. However, our study also has limitations, such as the small sample size and the focus on a younger, predominantly acyanotic CHD population, which may limit the generalizability of our results to older or more diverse cohorts. In larger cohorts, it is plausible that the observed perfect prediction may not hold as precisely, given the potential for increased variability. We did not have data available regarding a history of prior AKI episodes or detailed data on prior surgical history, including the number and type of previous cardiac surgeries. In patients with congenital heart disease, multiple staged surgical interventions are common and could influence the risk of kidney injury and long-term renal outcomes. In addition, we did not assess urinary retention with bladder ultrasound or urinary catheterization, which could have resulted in measurement error. Our clinical laboratory used a modified Jaffe technique for reporting serum creatinine, and the CKiD25 equation was validated using an enzymatic method. Additionally, the discrepancy between creatinine-based and cystatin C-derived estimates of renal function points to the need for more precise methods to assess RFR. An important consideration in interpreting our findings is the time-dependent nature of serum biomarker responses to acute changes in GFR. Cystatin C may require time to reach a new steady-state concentration following changes in filtration rate, potentially limiting its ability to capture rapid, transient increases in GFR fully. This may partly explain the smaller magnitude of RFR observed with cystatin C compared to creatinine clearance. Nonetheless, the statistically significant changes observed with cystatin C suggest that it remains sensitive to detecting RFR, albeit potentially with reduced sensitivity to very short-lived fluctuations. Real-time GFR monitoring using fluorescent molecules and transdermal sensors shows significant potential for accurately and efficiently assessing RFR in future investigations40.
In conclusion, our study highlights the strong predictive value of RFR for identifying AKI risk after cardiac surgery in young adults with acyanotic CHD and normal baseline eGFR. Using cystatin C as an alternative to creatinine clearance offers a faster, more practical method for quantifying RFR. Future work should determine the relationship between RFR and long-term outcomes, such as CKD progression, and explore the use of real-time monitoring technologies to improve early risk stratification and intervention.
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