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Cystatin C: The Answer or a Call for Better Kidney Biomarkers in Cirrhosis?

Rosenblatt, Russell MD, MS1; Verna, Elizabeth C. MD, MS2

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doi: 10.1097/TP.0000000000003223
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Kidney function is a powerful predictor of mortality in patients with cirrhosis. Acute kidney injury (AKI) is the most common extrahepatic organ failure in patients with acute-on-chronic liver failure (ACLF),1 and, when present in the form of hepatorenal syndrome (HRS) type 1, it is essentially universally fatal without liver transplantation.

While the serum creatinine level (SCr) is a potent variable in the model for end-stage liver disease (MELD) score and our most commonly used measure of kidney function, it has serious limitations with important clinical implications in cirrhosis. SCr is dependent on muscle mass and catabolism and is therefore intimately related to sarcopenia. SCr has been consistently demonstrated to underestimate kidney dysfunction in cirrhosis, especially among women and patients with high MELD.2 This directly impacts important clinical decisions, including early treatment of HRS as well as fair liver transplant allocation in the MELD-based system. In addition, even though AKI in cirrhosis was recently redefined in a consensus conference3 acknowledging the need for increased awareness of early kidney dysfunction, it is clear that we continue to underdiagnose AKI in these high-risk patients. AKI in this setting often occurs with a SCr within “normal” range, yet should not be reassuring as this has still been shown to be associated with increased mortality,4 underscoring that “normal” SCr is not so normal in a population with a very high prevalence of sarcopenia.

It is in this environment that alternative measurements of kidney function have become increasingly important. Cystatin C (CysC) is a low molecular weight protein that is almost entirely dependent upon glomerular filtration for elimination. Equally important, it is not impacted by age, gender, or muscle mass—minimizing some of the biases seen with SCr. Although it has generally not been thought to be significantly more accurate an estimator of estimated glomerular filtration rate (eGFR) than SCr, CysC has been demonstrated in previous studies to be effective in predicting mortality in cirrhosis, especially so when combined with eGFR calculated from SCr.5

In this issue of Transplantation, Mauro et al,6 add to this important literature by analyzing the predictive role of CysC and sarcopenia in the risk of ACLF and waitlist mortality, using a single-center cohort of 186 transplant candidates. Applying a cutoff of 1.5 mg/dL, the authors demonstrated that elevated CysC was associated with a >3-fold increase in the development of ACLF and 6-fold increase in waitlist mortality in multivariate analysis. However, the ability of CysC to predict ACLF was again not significantly better than SCr. Furthermore, this difference was not significant even among patients with radiographically defined sarcopenia—a frustrating finding given SCr is dependent on muscle mass and therefore would be assumed to be inaccurate in this cohort.

The findings of this study represent both the hope and frustration with our current search for adequate biomarkers of kidney function. On the one hand, it confirms a previous European study showing that CysC predicts development of AKI, ACLF, and mortality.7 On the other hand, if CysC is truly no more accurate at predicting eGFR than SCr, is its worthwhile integrating into clinical practice? SCr continues to be the standard measurement owing to both its use in the MELD score as well as ease of access and relatively modest cost—not due to its perceived accuracy in patients with cirrhosis.

What the hepatology community truly requires is a better kidney function biomarker that: (1) accurately measures GFR across the spectrum of disease severity and patient demographics; (2) is abnormal early in the AKI process; (3) distinguishes AKI from chronic kidney disease (CKD); and (4) is associated with clinical outcomes including ACLF and mortality (Figure 1). Given the morbidity and mortality associated with AKI in patients with cirrhosis, early recognition is crucial. In patients with established AKI, an ideal biomarker would also be able to identify the etiology of the injury (as differentiating between prerenal azotemia, acute tubular necrosis, and HRS can be incredibly challenging in patients with cirrhosis) and prognosticate recovery in both the short and long terms.

Characteristics of a desired biomarker for kidney function in cirrhosis. ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MELD, model for end-stage liver disease; SCr, serum creatinine.

In addition, in parallel with the general population, the prevalence of metabolic syndrome and diabetes has dramatically increased in patients with cirrhosis, as has the risk of CKD (nearly 1 of 3 of waitlist liver transplant candidates in the United States). This is best exemplified in the dramatic rise of nonalcoholic fatty liver disease, but it is also occurring in all other liver diseases. This change is at least partially responsible for the decreasing accuracy of MELD at predicting waitlist mortality as it is likely that AKI drives most of the associated waitlist mortality compared with those with stable CKD, although these groups are treated equally in the current system.8 Adjusting for patterns of kidney injury likely improves the prediction of waitlist mortality.

Finally, while ACLF is variably defined, in all classifications it is driven by organ failures—most prominently AKI. Recent data demonstrate that patients with ACLF with 3 or more organ failures have a higher short-term mortality than those listed as status 1a.9 Therefore, the identification of precipitants and those who are at risk of ACLF are important targets to reverse organ failures and improve waitlist outcomes.10 In this paper by Mauro et al,6 patients who are sarcopenic are at an increased risk of ACLF, while those who are both sarcopenic and have an elevated CysC are at an additional increased risk of ACLF. These are the fragile patients who have less functional reserve and have a higher short-term mortality, yet may not achieve appropriate MELD-related priority if SCr is not reflective of their true eGFR due to sarcopenia.

While CysC and sarcopenia were examined in this current study and demonstrated to predict poor outcomes in waitlist patients, further investigation is needed to find better biomarkers and objective findings to identify our patients at the highest risk. It is possible that combining biomarkers (such as Scr and CysC) and further refinement of estimates of GFR specifically in patients with decompensated cirrhosis will lead to a significant improvement over current practices. However, until we can advance past SCr, we cannot improve our predictive scores, ensure fairness in organ allocation, and address the current disparities.


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6. Mauro E, Crespo G, Martinez-Garmendia A, et al. Cystatin C and sarcopenia predict acute on chronic liver failure development and mortality in patients on the liver transplant waiting list. Transplantation. [Epub ahead of print. March 6, 2020]. doi: 10.1097/TP.0000000000003222
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10. Cullaro G, Sharma R, Trebicka J, et al. Precipitants of acute-on-chronic liver failure: an opportunity for preventative measures to improve outcomes. Liver Transpl. 2020; 26:283–293
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