Digestive Diseases and Sciences (2018) 63:665–675
Cystatin C Is a Gender‑Neutral Glomerular Filtration Rate Biomarker
in Patients with Cirrhosis
Ayse L. Mindikoglu
· Antone R. Opekun
· William E. Mitch
· Laurence S. Magder
· Robert H. Christenson
Thomas C. Dowling
· Matthew R. Weir
· Stephen L. Seliger
· Charles D. Howell
· Jean‑Pierre Raufman
· John A. Goss
· Saira A. Khaderi
· John M. Vierling
Received: 18 September 2017 / Accepted: 21 December 2017 / Published online: 1 February 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Background Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower
model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to
men with comparable hepatic dysfunction.
Aim The aim of this study was to determine the gender diﬀerences in serum Cr, cystatin C, and other endogenous glomerular
ﬁltration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates.
Methods We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender diﬀerences
in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace
protein, beta-2 microglobulin, and dimethylarginines.
Results Comparison of men and women showed signiﬁcantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl,
P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production
rate, men and women exhibited no signiﬁcant diﬀerences in the means of serum cystatin C and other GFR biomarkers,
measured GFR, GFR estimated using Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances.
After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels
(P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and
history of hypothyroidism.
Conclusions Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR
estimated by Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender
biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a
complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those
Keywords Cystatin C · Cirrhosis · Glomerular ﬁltration rate · Gender disparity · Creatinine clearance · Liver
Serum creatinine (Cr) is recognized to be an inaccurate
marker of renal function in patients with cirrhosis [1–4]. The
Cr production rate in patients with cirrhosis is about 50%
lower than that in individuals with intact hepatic function
. The liver is the principal organ in which guanidinoacetic
acid is methylated to produce methylguanidinoacetic acid
(creatine) [1, 5]. Subsequently, creatine and creatine phos-
phate are converted to Cr in skeletal muscle [1, 5]. There-
fore, optimal Cr production rate depends on both normal
hepatic function and skeletal muscle mass [1, 5]. As a con-
sequence of hepatic dysfunction and skeletal muscle mass
loss (sarcopenia), the rate of Cr production rate is reduced
in patients with cirrhosis [1–3].
Cr production is also impacted by gender diﬀerences.
The Cr production rate was reported to be about 10% lower
in healthy women compared to age- and weight-matched
* Ayse L. Mindikoglu
Extended author information available on the last page of the article