Divergence between serum creatine and cystatin C in estimating glomerular filtration rate of critically ill COVID-19 patients

Figures & data

Table 1. Description of the formulas used.

	Female	Male
CKD-EPI creatinine equation	sCr ≤ 62: 144*(sCr/62)^−0.329* 0.993^AgesCr > 62: 144*(sCr/62)^−1.209 * 0.993^Age	sCr ≤ 80: 141*(sCr/80)^−0.411* 0.993^AgesCr > 80: 141*(sCr/80)^−1.209 * 0.993^Age
CKD-EPI cystatin C equation	CysC ≤ 0.8: 133*(CysC/0.8)^−0.499*0.996^Age * 0.932 CysC > 0.8: 133*(CysC/0.8)^−1.328*0.996^Age * 0.932	CysC ≤ 0.8: 133*(CysC/0.8)^−0.499*0.996^Age CysC > 0.8: 133*(CysC/0.8)^−1.328*0.996^Age

The units of sCr and CysC were umol/L and mg/L, respectively.

Table 2. Demographic, clinical characteristics, and laboratory findings of critically ill and moderate patients.

	Critically ill	Moderate	p Value
Demographic
Age (years)	64.5 ± 9.3	62.9 ± 9.3	0.182
Male	49 (64.5 %)	49 (64.5 %)	1
Clinical characteristics
Death, n (%)	56 (73.7 %)	0	–
Disease course (days)	29 (21–38)	41 (32–50)	<0.001
Time of hospitalization (days)	17 (9–27)	16 (8.25–22)	0.269
Time of ICU (days)	9 (5.25–18)	–	–
Time from illness to ICU (days)	16.5 (11–25)	–	–
Comorbidity, n (%)
Hypertension	35 (46.1 %)	30 (39.5 %)	0.412
Diabetes mellitus	18 (23.7 %)	15 (19.7 %)	0.555
Coronary heart disease	16 (21.1 %)	8 (10.5 %)	0.075
Current smoker	11 (15.1 %)	7 (9.3 %)	0.286
Cerebrovascular disease	5 (6.6 %)	2 (2.6 %)	0.246
Laboratory findings
White blood cell count (×10^9/L) (3.50–9.50)	11.57 (8.04–16.46)	5.35 (4.27–6.46)	<0.001
Leukocytosis	52 (68.4 %)	3 (4.0 %)
Neutrophil count (×10^9/L) (1.80–6.30)	10.24 (7.37–15.12)	3.25 (2.54–4.16)	<0.001
Lymphocytes (×10^9/L) (1.10–3.20)	0.56(0.40–0.78)	1.15 (0.95–1.76)	<0.001
Lymphocytopenia	71 (93.4 %)	32 (42.7 %)
Hemoglobin (g/L) (115–150)	108 (123.5–138)	125 (112–137)	0.607
Anemia	36 (47.4 %)	30 (39.5 %)	0.361
Platelets (×10^9/L) (125–350)	165 (101.25–220.25)	220 (184–259)	<0.001
Thrombocytopenia	25 (32.9 %)	32 (42.7 %)
Serum albumin (g/L) (35–52)	28.5 (26.28–32.05)	38.3 (35.6–41.7)	<0.001
Hypoalbuminemia	48 (63.2 %)	3 (3.9 %)	<0.001
sCr (μmol/L) (45–84)	76.5 (53.25–104.25)	72.5 (61.25–82.25)	0.359
Elevated sCr, n (%)	19 (25 %)	5 (6.6 %)	0.002
Declined sCr, n (%)	13 (17.1 %)	3 (3.9 %)	0.008
eGFR-Cr (ml/min/1.73m^2)	85.45 (60.58–99.23)	92.04 (80.45–97.81)	0.119
Reduced eGFR-Cr	19 (25 %)	5 (6.6 %)	0.002
CysC (mg/L) (0.60–1.55)	1.17 (0.99–1.78)	0.99 (0.88–1.09)	<0.001
Elevated CysC, n (%)	24 (31.6 %)	4 (5.3 %)	<0.001
Declined CysC, n (%)	0	0
eGFR-CysC (ml/min/1.73m^2)	60.60 (34.75–79.06)	74.55 (65.58–91.19)	<0.001
Reduced eGFR-CysC	38 (50 %)	11 (14.5 %)	<0.001
IL-6 (pg/ml) (<7)	54.88 (29.76–169.35)	6.81 (3.12–16.31)	<0.001
Ferritin (mg/ml) (15–150)	1302.9 (730.45–2327.88)	357.4 (258.0–580.8)	<0.001
D-dimer (μg/ml FEU) (<0.5)
<0.5	0	0
0.5–5.0	0	28 (37.3 %)
5.0–21.0	40 (54.8 %)	15 (20 %)	<0.001
>21.0	33 (45.2 %)	32 (42.7 %)
hsCRP (mg/L) (<1)	103.05 (59.58–153.8)	3.50 (0.93–12.65)	<0.001

Figure 1. Comparison of sCr and CysC between critically ill patients and moderate patients. (a) The SCr of critically ill patients has an equivalent median with moderate patients but distributed more dispersedly; (b) The median of CysC was significantly higher in critically ill patients than in moderate patients.

Figure 2. Proportion of different definition of “renal dysfunction” including elevated sCr, elevated CysC, eGFRcr<60, eGFRcysc<60 in critically ill patients and moderate patients. In critically ill group, eGFRcysc less than 60 mL/min/1.73 m² presented in 50 % patients and eGFRcr less than 60 mL/min/1.73 m² presented in 25 % (p = 0.001). This divergence was not obvious in the moderate group (14.5 % vs 6.6 %, χ² = 2.515, p = 0.113). The proportion of elevated sCr and elevated CysC was 25 % and 31.6 % (p = 0.368)in critically ill patients. In moderate group, the proportion of elevated sCr was equal to elevated CysC (20 %).

Table 3. Demographic, clinical characteristics, and laboratory findings of nonsurvivors and survivors in critically ill patients.

	Non-survivors n = 56	Survivors n = 20	p Value
Demographic
Age (year)	65.4 ± 7.7	62.0 ± 12.7	0.274
Male, n (%)	38 (67.9 %)	11 (55 %)	0.302
Clinical characteristics
APACHEII	14 (10–20)	11 (9.25–13.0)	0.021
SOFA	6 (4–8.75)	4 (3–5)	0.002
Invasive ventilation	50 (89.3 %)	10 (50 %)	0.002
Glucocorticoids	48 (85.7 %)	15 (75 %)	0.739
Vasopressors	44 (78.6 %)	4 (20 %)	<0.001
Death, n (%)	56 (100 %)	0
Disease course	26 (20–35)	35.5 (27–49)	0.016
Time of hospitalization (days)	13.5 (9–23)	16 (8.25–22)	0.007
Time of ICU (days)	8.5 (5–13)	14 (7–27)	0.015
Comorbidity
Hypertension	19 (33.9 %)	16 (80 %)	<0.001
Diabetes mellitus	11 (19.6 %)	7 (35 %)	0.280
Coronary heart disease	11 (19.6 %)	5 (25 %)	0.853
Current smoker	8 (14.3 %)	3 (15 %)	0.992
Cerebrovascular disease	1 (1.8 %)	4 (20 %)	0.016
Laboratory findings
White blood cell count (×10^9/L)	12.11 (9.23–18.86)	9.32 (6.25–12.7)	0.017
Neutrophil count (×10^9/L)	10.94 (8.11–17.27)	8.38 (5.05–11.08)	0.017
Lymphocytes (×10^9/L)	0.53 (0.38–0.73)	0.65 (0.41–0.83)	0.243
Hemoglobin (g/L)	126 (109–140)	114 (93.75–133.25)	0.115
Platelets (×10^9/L)	157 (77–217)	181 (134.5–270.8)	0.075
Serum albumin (g/L)	27.75 (25.08–31.23)	30.40 (28.1–33.1)	0.035
Serum calcium (mmol/L) (2.15–2.50)	2.21 (.95–2.31)	2.07 (1.91–2.20)	0.115
Serum inorganic phosphorus (mmol/L) (0.81–1.45)	0.99 (0.78–1.15)	0.98 (0.86–1.37)	0.591
Serum uric acid (mmol/L) (142.8–339.2)	214.0 (134.0–302.8)	214.0 (161.3–334.8)	0.483
Urea (mmol/L) (2.6–7.5)	8.25 (5.43–11.0)	8.80 (6.05–15.15)	0.286
sCr (umol/L)	78.5 (54.75–111.25)	74.0 (45.75–90.75)	0.190
Elevated sCr, n (%)	15 (26.8 %)	4 (20 %)	0.547
Declined sCr, n (%)	6 (10.7 %)	7 (35 %)	0.033
eGFR-Cr (ml/min/1.73m^2)	85.85 (55.78–98.0)	84.85(70.85–107.85)	0.392
eGFR-Cr<60	16 (28.6 %)	5 (15 %)	0.229
CysC (mg/L)	1.21 (0.95–1.83)	1.13 (1.05–1.50)	0.972
Elevated CysC, n (%)	20 (35.7 %)	4 (20 %)	0.194
Declined CysC, n (%)	0	0
eGFR-CysC (ml/min/1.73m^2)	57.51 (30.51–81.54)	60.86 (43.55–67.96)	0.972
eGFRcr-cysc (ml/min/1.73m^2)	68.69 (41.72–91.23)	74.70 (57.66–89.63)	0.663
eGFRcr-cysc<60	24 (42.9 %)	5 (25 %)	0.158
IL-6 (pg/ml)	116.5 (37.15–220.4)	29.76 (19.16–38.38)	<0.001
IL-8 (pg/ml) (<62)	29.65 (15.30–63.85)	22.9 (9.55–31.25)	0.045
IL-10 (pg/ml) (<9.1)	13.5 (7.9–20.3)	7.8 (6.05–12.45)	0.057
TNF-α (pg/ml) (<8.1)	10.55 (7.18–19.35)	9.8 (6.95–13.8)	0.459
Ferritin (mg/ml)	1427.1 (829.15–2483.15)	867.7 (649.7–1852.5)	0.057
D-dimer (mg/ml FEU), n (%)	0	0
0.5–5.0	16 (28.6 %)	12 (60 %)
5.0–21.0	12 (21.4 %)	3 (15 %)	0.048
>21.0	27 (48.2 %)	5 (25 %)
hsCRP (mg/L)	110.20 (64.53–162.55)	60.25 (31.43–117.35)	0.009

APACHE II: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment.

Table 4. Renal function estimation using sCr and CysC showed differences in the same 76 critical ill patients.

	SCr	CysC	p Value
eGFR	85.45 (60.58–99.23)	60.6 (34.75–79.06)	<0.001
Reduced eGFR	19 (25 %)	38 (50 %)	0.001
Elevated	19 (25 %)	24 (31.6 %)	0.368
Declined	13 (17.1 %)	0	<0.001

Reduced eGFR defined as eGFR<60 mL/min/1.73 m². Elevated sCr was defined as >104 μmol/L in men and >84 μmol/L in women. Declined sCr was defined as <59 μmol/L in men and <45 μmol/L in women. Elevated CysC was defined as >1.55 mg/L. Declined CysC was defined as <0.6 mg/L.

Table 5. Differences of IL-6, TNF-α and APACHEII among three subgroups graded by the gap between eGFRcr and eGFRcysc.

Median (IQR)	Group 1	Group 2	Group 3	p Value (overall)	p Value (1 vs 2)*	p Value (1 vs 3)	p Value (2 vs 3)
IL6 (pg/ml)^b	30.21 (12.46–44.92)	56.36 (28.43–203.98)	97.72 (38.44–290.65)	0.006	0.097	0.005	1.000
TNFα (pg/ml)^c	7.6 (6.3–11.6)	11.5 (7.3–16.7)	13.1 (8.6–20.4)	0.027	0.27	0.022	0.936
APACHEII	10 (8–13)	14 (12–20)	17 (10.5–20)	0.001	0.009	0.001	1.000
SOFA	4 (1–5)	6 (4–8)	6.5 (4–8.75)	0.002	0.006	0.005	1.000
Death	11 (57.9 %)	19 (82.6 %)	16 (66.7 %)	0.205	–	–	–
Glucocorticoid	16 (84.2 %)	17 (73.9 %)	20 (83.3 %)	0.632	–	–	–

^aAll patients: n = 66, Group 1 = 19, Group 2 = 23, Group 3 = 24.

^bAll patients: n = 56, Group 1 = 17, Group 2 = 18, Group 3 = 21.

^cAll patients: n = 52, Group 1 = 15, Group 2 = 18, Group 3 = 19.

*Adjusted p-Value.

Groups I, II, and III represented patients with △eGFRcr-cysc %<25 %, 25 %–45 %, and >45 %, respectively.

△eGFRcr-cysc % was defined as △eGFRcr-cysc/mean of eGFRcr and eGFRcysc × 100 %. △eGFRcr-cysc %=$\frac{\mathrm{eGFR}\text{cr}-\mathrm{eGFR}\text{cysc}}{(\mathrm{eGFR}\text{cr}+\mathrm{eGFRcysc})/2}.$

Figure 3. The Kaplan–Meier survival curves for critically ill patients divided by reduced eGFRcr (a), reduced eGFRcysc (b), elevated sCr(c) and elevated CysC (d). Reduced eGFRcr (<60 mL/min/1.73 m²) rather than reduced eGFRcysc was associated with death after ICU admission in critically ill patients with COVID-19. Both elevated sCr and elevated CysC were associated with death after ICU admission in critically ill patients with COVID-19.

Figure 4. Patients with bigger divergence between eGFRcr and eGFRcysc had higher IL6, TNFα levels and APACHEII, SOFA scores. (Critically ill patients were grouped according to the difference ratio (△eGFRcr-cysc%) defined as △eGFRcr-cysc/mean of eGFRcr and eGFRcysc; Groups 1, 2, and 3 represented patients with △eGFRcr-cysc% 0–25%, 25%–45% and >45%, respectively).

Table 6. Different multivariate Cox proportional hazards models for risk factors of in-ICU death.

	HR	95％CI	p Value
MODEL1^a
Alb	0.955	0.899–1.015	0.137
eGFRcr<60	2.003	1.072–3.742	0.029
DD categories	1.295	0.931–1.800	0.125
MODEL2^a
Alb	0.944	0.887–1.004	0.068
eGFRcysc<60	1.173	0.684–2.012	0.561
DD categories	1.215	0.886–1.664	0.227
MODEL3^a
Alb	0.951	0.893–1.013	0.120
eGFRcr-cysc<60	1.603	0.924–2.779	0.093
DD categories	1.236	0.899–1.697	0.192
MODEL4^a
IL-6	1.000	1.000–1.001	0.356
APACHEII	1.067	1.013–1.124	0.014
DD categories	1.117	0.779–1.602	0.546
MODEL5^a
IL-6	1.000	1.000–1.001	0.008
DD categories	1.103	0.764–1.592	0.601
Vasopressors	1.772	0.887–3.540	0.105

^a About 75 patients (55 deaths) were included in this mode.