Noninvasive assessment of renal dysfunction in patients with end-stage liver disease: New solutions for old problems?

Renal dysfunction has an ominous prognostic impact in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT), being associated with a significant reduction in survival rates.1 For this reason, an accurate evaluation of renal function is crucial to assist physicians in determining therapeutic management and prognostic stratification, as well as in defining transplantation strategies (ie, LT alone vs. simultaneous liver and kidney transplantation). Due to its low cost and wide availability, serum creatine (sCr) is the most employed biomarker in noninvasive evaluation of renal function in clinical practice. However, it suffers from several limitations in patients with ESLD. Indeed, sCr-based equations tend to overestimate glomerular filtration rate (GFR), especially in patients with ascites and sarcopenia.2,3 The magnitude of this effect is even higher in female patients, leading to a more marked disadvantage in the MELD-based allocation policy.4,5 A chance to overcome these issues could arise from the use of new biomarkers in the evaluation of renal function. In their prospective multicenter study, Gonzalez et al6 focused on the diagnostic and prognostic performance of Cystatin C (Cys-C) in the assessment of kidney dysfunction in a cohort of 244 patients listed for LT. They found that Cys-C levels at the time of LT evaluation provide a more accurate assessment of renal function than sCr. More in-depth, Cys-C values showed a stronger correlation with measured GFR (mGFR) by I125-iothalamate clearance and significantly outperformed sCr in predicting key thresholds of mGFR (both mGFR ≤60 mL/min/1.73 m2 and mGFR ≤30 mL/min/1.73 m2).6 Furthermore, when compared with sCr-based equations, including the liver-specific ones (RFH-GFR and GRAIL), Cys-C–based equations (CKD-EPI-Cys-C and CKD-EPI-creatinine-Cys-C) estimated mGFR with higher precision, especially in patients with mGFR below the abovementioned key thresholds.6 In addition, overestimation of GFR, which was higher in females than in males with all the formulas, occurred less frequently with the CKD-EPI-Cys-C equation both in the whole cohort and in female patients only.6 Importantly, Cys-C but not sCr was an independent predictor of mortality as well as delisting for clinical deterioration and age.6 The effect of rising baseline Cys-C levels on mortality was also observed in a subgroup analysis of patients with ascites, age above 60 years old, body mass index <30, or non-White ethnicity.6 The study by Gonzalez and colleagues stands out as one of the few to prospectively explore Cys-C performance in candidates for LT, building on prior evidence that highlights its superiority in the assessment of kidney function in patients with cirrhosis outside the LT setting.7 Notably, a portion of the cohort (137 out of 244 patients) also underwent the gold standard measurement of GFR by I125-iothalamate clearance, adding considerable weight to the study findings.6 By providing a more accurate assessment of kidney function, the use of Cys-C could improve prognostic stratification and prediction of mortality risk in patients with ESLD. This could lead to better prioritization in the LT waitlist by overcoming disparities resulting from reliance on sCr-based equations for the estimation of GFR and MELD scores. Addressing these inequities is of utmost importance, especially for those subgroups of patients who are mostly disadvantaged by current allocation policies. Female patients, as well as those with sarcopenia and ascites, have lower MELD scores than other patients with the same GFR due to lower sCr levels. Cys-C could offer a potential solution to this issue, as it is not influenced by gender or muscle mass. It seems logical and important to explore the possibility of including novel biomarkers such as Cys-C into existing tools or developing entirely new strategies to optimize the allocation policy of patients with ESLD awaiting LT. In addition, a more reliable assessment of renal function could assist clinicians in identifying candidates for LT who may benefit from simultaneous liver and kidney transplantation. Once again, Cys-C provides a new opportunity for improving patient management. It must be mentioned that the possibility of extending this finding to the whole population of patients with ESLD awaiting LT is limited by the lack of mGFR in hospitalized patients with higher MELD in this study.6 Therefore, further studies are needed to better clarify how to best employ Cys-C across our entire waitlisted population. A first step might be routine collection of Cys-C in waitlisted patients in UNOS to derive robust real-world data. In conclusion, the use of Cys-C could have significant implications for the management of patients with ESLD awaiting LT. A more accurate estimation of renal dysfunction might help reduce disparities in liver graft allocation, while improved better prognostic stratification of patients could lead to better outcomes through timely escalation of treatment.