Remnant Cholesterol is Prospectively Associated With Cardiovascular Disease Events and All-Cause Mortality in Kidney Transplant Recipients

The FAVORIT Study

Reuben William Horace; Mary Roberts; Theresa I. Shireman; Basma Merhi; Paul Jacques; Andrew G. Bostom; Simin Liu; Charles B. Eaton

Disclosures

Nephrol Dial Transplant. 2022;37(2):382-389.

Abstract and Introduction

Abstract

Graphical Abstract

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Background: The cholesterol content of circulating triglyceride-rich lipoproteins is characterized as remnant cholesterol, although little is known about its role in the development of cardiovascular disease (CVD) outcomes, all-cause mortality or transplant failure in kidney transplant recipients (KTRs). Our primary aim was to investigate the prospective association of remnant cholesterol and the risk of CVD events in renal transplant recipients with secondary aims evaluating remnant cholesterol and renal graft failure and all-cause mortality among participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial.

Methods: Among 4110 enrolled participants, 98 were excluded for missing baseline remnant cholesterol levels and covariates. Nonfasting remnant cholesterol levels were calculated based on the lipid profiles in 3812 FAVORIT trial participants at randomization. A Wilcoxon-type test for trend was used to compare baseline characteristics across remnant cholesterol quartiles. Cox proportional hazards regression was used to evaluate the association of baseline remnant cholesterol levels with time to primary and secondary study outcomes.

Results: During a median follow-up of 4.0 years we documented 548 CVD incident events, 343 transplant failures and 452 all-cause deaths. When comparing the highest quartile (quartile 4) to quartile 1, proportional hazard modeling revealed a significant increase in CVD risk {hazard ratio [HR] 1.32 [95% confidence interval (CI) 1.04–1.67]} and all-cause mortality risk [HR 1.34 (95% CI 1.01–1.69)]. A nonsignificant increase in transplant failure was seen as well [HR 1.20 (95% CI 0.87–1.64)].

Conclusions: Remnant cholesterol is associated with CVD and all-cause mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of remnant cholesterol-lowering therapy on these outcomes may be warranted.

Additional Content: An author video to accompany this article is available at: https://academic.oup.com/ndt/pages/author_videos.

Introduction

Remnant cholesterol is the cholesterol content of triglyceride-rich lipoproteins and is composed of very-low-density lipoproteins (VLDLs)^[1] and intermediate-density lipoproteins (IDLs) in the fasting state and of VLDL, IDL and chylomicron remnants in the nonfasting state. Patients with chronic kidney disease (CKD), particularly those with renal transplantation, are at increased risk of developing cardiovascular disease (CVD).^[2] CVD in turn also enhances the rapidity of progression of CKD as is seen in the Chronic Renal Insufficiency Cohort study.^[3] Along with CKD progression, metabolic abnormalities may progress further, contributing to atherosclerotic changes and adversely affecting renal function.^[2,4] Rates of CVD death in kidney transplant recipients (KTRs) remain higher than in the general population, with the rate of CVD death 10 times higher and the annual rate of fatal or nonfatal cardiovascular events 50 times that of the general population.^[4]

Remnant cholesterol in both fasting and nonfasting states is associated with inflammation, oxidative stress, accelerated atherosclerosis and ischemic heart disease.^[1–10] Higher levels of triglycerides or non-high-density lipoprotein (HDL) cholesterol in chronic KTRs have been associated with CVD (mainly coronary heart disease) outcomes, total mortality and renal graft loss.^[1] While remnant cholesterol, elevated triglycerides and non-HDL cholesterol are correlated, remnant cholesterol remains a distinct class of lipoproteins and therefore its role in cardiovascular outcomes and all-cause mortality in KTRs is unknown.

Therefore our primary aim was to evaluate the association of remnant cholesterol in renal transplant recipients (RTRs) and the risk of CVD events, with secondary aims of evaluating the association of remnant cholesterol and renal graft failure, all-cause mortality and CVD events, using the large Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort.

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Table 1. Baseline characteristics by remnant cholesterol levels
Characterisitcs	Q1: 28.9 ± 2.4 mg/dL (n = 1070)	Q2: 33.0 ± 1.0 mg/dL (n = 909)	Q3: 36.8 ± 1.0 mg/dL (n = 895)	Q4: 41.2 ± 2.4 mg/dL (n = 938)	Overall : 34.8 ± 5.2 mg/dL (n = 3812)	P-value
Gender, n (%)						<0.001
Male	680 (62.9)	584 (63.4)	555 (61.6)	580 (61.4)	2399 (62.9)	–
Female	400 (37.1)	337 (36.6)	346 (39.4)	365 (39.6)	1413 (37.1)	–
Age (years), mean ± SD	51.3 ± 9.3	51.9 ± 9.4	51.2 ± 9.6	51.8 ± 9.3	51.9 ± 9.4	0.01
Race/ethnicity, n (%)						<0.001
Non-Hispanic White	785 (73.3)	674 (74.1)	696 (77.8)	753 (80.3)	2908 (73.3)	–
Non-Hispanic Black	220 (20.6)	182 (20)	142 (15.9)	121 (12.9)	665 (20.6)	–
Other	65 (6.1)	53 (5.9)	57 (6.3)	64 (6.8)	239 (6.1)	–
Smoking status, n (%)						0.009
No	983 (91.9)	805 (88.6)	787 (87.9)	821 (87.5)	3396 (89.1)	–
Yes	87 (8.1)	104 (11.4)	108 (12.1)	117 (12.5)	416 (10.9)	–
SBP (mmHg), mean ± SD	135.5 ± 19.6	136.2 ± 19.9	136.2 ± 19.4	136.6 ± 20.1	136.1 ± 19.8	<0.001
DBP (mmHg), mean ± SD	78.0 ± 11.8	78.3 ± 12.5	79.2 ± 12.2	78.9 ± 12.5	78.6 ± 12.2	0.01
Diabetes, n (%)						<0.001
Yes	490 (45.8)	337 (37.1)	330 (37.1)	381 (40.6)	2274 (59.6)	–
No	580 (54.2)	572 (62.9)	560 (62.9)	557 (59.4)	1538 (40.4)	–
BMI (kg/m²), mean ± SD	26.6 ± 5.79	28.6 ± 6.29	29.6 ± 6.13	30.9 ± 6.14	29.16 ± 6.02	<0.001
LDL cholesterol (mg/dL), mean ± SD	96.9 ± 28	101.3 ± 32.7	102.4 ± 34.2	102.2 ± 41.7	100.5 ± 33.9	0.01
HDL cholesterol (mg/dL), mean ± SD	52.9 ± 15.2	47.2 ± 13.3	44.3 ± 12.4	39.5 ± 10.5	46.3 ± 13.9	<0.001
Triglycerides (mg/dL), mean ± SD	89.9 ± 26.3	144.4 ± 59.9	202.5 ± 37.9	371.6 ± 289.2	198.5 ± 182.3	<0.001
TC (mg/dL), mean ± SD	167.7 ± 34.9	176.8 ± 37.9	186.2 ± 39.2	209.9 ± 51.1	167.7 ± 34.14	<0.001
eGFR (mL/min/1.73 m²), mean ± SD	51.5 ± 17.4	49.8 ± 17.6	47.8 ± 18.3	46.0 ± 16.7	46.5 ± 17.6	<0.001
Lipid-lowering medication, n (%)						<0.001
No	541 (50.6)	431 (47.4)	381 (42.6)	353 (37.7)	1707 (44.8)	–
Yes	528 (49.4)	478 (52.6)	513 (57.4)	584 (62.3)	2105 (55.2)	–
Donor type, n (%)						–
Living	451 (42.3)	334 (38.2)	372 (40.83)	416 (43.9)	1567 (42.1)	–
Cadaver	615 (57.7)	540 (61.8)	539 (59.17)	531 (56.1)	2225 (57.9)	–
Albuminuria (μg/mg), n (%)						<0.01
<10	400 (36.53)	319 (34.08)	278 (30.19)	289 (30.17)	1286 (32.89)	–
10–29	271 (24.75)	220 (23.50)	232 (25.19)	227 (23.7)	950 (24.3)	–
30–99	321 (29.32)	292 (31.2)	298 (32.36)	289 (30.17)	1200 (30.69)	–
>300	103 (9.41)	105 (11.22)	113 (12.27)	153 (15.97)	474 (12.12)	–
Asprin (mg), n (%)						–
0–325	74 (6.76)	74 (7.91)	58 (6.3)	62 (6.47)	267 (6.86)	–
325–650	636 (58.08)	533 (56.94)	549 (59.61)	563 (58.77)	2281 (58.34)	–
>650	385 (35.16)	329 (35.15)	314 (34.09)	333 (34.76)	1361 (34.81)	–

P-value comparisons across remnant cholesterol levels are based on Wilcoxon-type tests for trend for categorical variables and Jonckheere–Terpstra tests for continuous variables.

Table 2. Univariate adjusted models for CVD, transplant failure and all-cause mortality events
Characteristics	Q1: 28.9 ± 2.4 mg/dL	Q2: 33.0 ± 1.0 mg/dL	Q3: 36.8 ± 1.0 mg/dL	Q4: 41.2 ± 2.4 mg/dL	P-value trend
CVD
Age	Ref	0.97 (0.79–1.20)	1.06 (0.86–1.29)	1.27 (1.09–1.54)	0.002
BMI	Ref	1.00 (0.81–1.23)	1.16 (0.94–1.42)	1.34 (1.1–1.63)	–
Gender	Ref	0.98 (0.81–1.21)	1.13 (0.93–1.38)	1.30 (1.07–1.57)	–
Smoking status	Ref	0.98 (0.81–1.21)	1.13 (0.93–1.38)	1.30 (1.07–1.57)	0.011
Diabetes	Ref	1.07 (0.87–1.32)	1.22 (1.00–1.49)	1.37 (1.13–1.66)	0.0001
Race	Ref	0.98 (0.81–1.21)	1.12 (0.91–1.36)	1.30 (1.07–1.57)	–
Graft vintage	Ref	0.98 (0.82–1.23)	1.13 (0.93–1.38)	1.30 (1.07–1.58)	–
Avg systolic	Ref	0.98 (0.81–1.21)	1.12 (0.92–1.37)	1.19 (1.07–1.56)	0.001
Avg diastolic	Ref	0.98 (0.80–1.21)	1.14 (0.94–1.39)	1.31 (1.09–1.59)	–
Lipid lower drugs	Ref	0.98 (0.79–1.21)	1.11 (0.91–1.36)	1.27 (1.051.54)	0.009
mTOR inhibitors	Ref	0.99 (0.81–1.22)	1.13 (0.92–1.38)	1.30 (1.07–1.57)	–
Donor type	Ref	0.98 (0.81–1.23)	1.13 (0.93–1.38)	1.33 (1.09–1.61)	–
Albuminuria	Ref	0.97 (0.78–1.21)	1.11 (0.89–1.36)	1.25 (1.02–1.53)	–
Transplant failure
Age	Ref	0.99 (0.72–1.36)	1.10 (0.81–1.50)	1.19 (0.89–1.61)	–
BMI	Ref	1.00 (0.73–1.39)	1.04 (0.76–1.42)	1.18 (0.87–1.02)	–
Gender	Ref	0.98 (0.71–1.34)	1.07 (0.78–1.46	1.17 (0.87–1.59)	–
Smoking status	Ref	0.96 (0.69–1.31)	1.04 (0.77–1.42)	1.13 (1.04–1.53)	0.001
Diabetes	Ref	1.02 (0.740–1.39)	1.11 (0.82–1.51)	1.20 (0.89–1.62)	–
Race	Ref	0.99 (0.72–1.36)	1.11 (0.81–1.51)	1.22 (0.90–1.64)	–
Graft vintage	Ref	0.94 (0.68–1.29)	1.05 (0.77–1.43)	1.18 (1.05–1.59)	0.016
Avg systolic	Ref	0.97 (0.71–1.36)	1.06 (0.78–1.46)	1.15 (1.02–1.55)	0.001
Avg diastolic	Ref	0.98 (0,72–1.34)	1.07 (0.78–1.45)	1.17 (1.06–1.57)	0.023
Lipid lower drugs	Ref	0.99 (0.72–1.36)	1.09 (0.79–1.48)	1.19 (1.06–1.61)	0.001
mTOR inhibitors	Ref	0.98 (0.72–1.35)	1.07 (0.78–1.45)	1.17 (0.56–1.07)	–
Donor type	Ref	1.00 (0.731.37)	1.09 (0.81–1.49)	1.19 (0.88–1.61)	–
Albuminuria	Ref	1.01 (0.73–1.41)	1.03 (0.75–1.41)	1.02 (0.74–1.37)	–
All-cause mortality
Age	Ref	0.98 (0.75–1.29)	1.03 (0.79–1.34)	1.25 (0.98–1.60)	0.01
BMI	Ref	1.02 (0.78–1.34)	1.14 (0.88–1.49)	1.34 (1.04–1.72)	–
Gender	Ref	1.00 (0.77–1.31)	1.10 (0.85–1.43)	1.29 (1.01–1.65)	–
Smoking status	Ref	0.99 (0.75–1.29)	1.09 (0.84–1.42)	1.27 (1.00–1.62)	0.004
Diabetes	Ref	1.06 (0.821.39)	1.19 (0.92–1.54)	1.35 (1.06–1.72)	0.001
Race	Ref	1.00 (0.76–1.31)	1.11 (0.86–1.45)	1.33 (1.04–1.70)	–
Graft vintage	Ref	1.02 (0.771.33)	1.11 (0.85–1.44)	1.31 (1.02–1.67)	–
Avg systolic	Ref	0.99 (0.76–1.29)	1.11 (0.85–1.43)	1.28 (1.00–1.64)	0.001
Avg diastolic	Ref	0.98 (0.75–1.28)	1.12 (0.86–1.45	1.31 (1.02–1.67)	–
Lipid lower drugs	Ref	0.99 (0.76–1.30)	1.09 (0.84–1.42)	1.28 (0.99–1.63)	0.002
mTOR inhibitors	Ref	1.00 (0.77–1.31)	1.10 (0.85–1.43)	1.28 (1.00–1.61)	–
Donor type	Ref	0.99 (0.76–1.30)	1.10 (0.85–1.43)	1.33 (1.04–1.71)	–
Albuminuria	Ref	0.98 (0.75–1.31	1.07 (0.82–1.41)	1.26 (0.97–1.63)	–

Values are presented as HRs and 95% CIs for the univariate model.

Table 3. Multivariable-adjusted model estimates for clinical events with remnant cholesterol quartiles
Variables	Q1: 28.9 ± 2.4 mg/dL	Q2: 33.0 ± 1.0 mg/dL	Q3: 36.8 ± 1.0 mg/dL	Q4: 41.2 ± 2.4 mg/Dl	P-value trend	Total events
CVD events						548
Number at risk	201	165	187	224	–	–
Crude	Ref	0.99 (0.81–1.22)	1.13 (0.93–1.38)	1.30 (1.08–1.57)	–	–
Age adjusted	Ref	0.97 (0.79–1.19)	1.06 (0.87–1.29)	1.27 (1.05–1.54)	<0.001	–
Adjusted for all covariates	Ref	1.01 (0.79–1.29)	1.14 (0.87–1.45)	1.32 (1.04–1.67)	–	–
All-cause mortality events						452
Number at risk	120	99	110	137	–	–
Crude	Ref	1.01 (0.77–1.31)	1.11 (0.86–1.43)	1.29 (1.01–1.66)	–	–
Age adjusted	Ref	0.98 (0.75–1.29)	1.03 (0.79–1.34)	1.25 (0.98–1.60)	0.013	–
Adjusted for all covariates	Ref	0.97 (0.74–1.28)	1.12 (0.84–1.46)	1.31 (1.01–1.69)	–	–
Transplant failure events					–	343
Number at risk	96	80	86	98	–	–
Crude	Ref	0.98 (0.71–1.35)	1.07 (0.78–1.46)	1.17 (0.87–1.58)	–	–
Age adjusted	Ref	0.99 (0.72–1.36)	1.1 (0.81–1.50)	1.19 (0.89–1.61)	0.65	–
Adjusted for all covariates	Ref	0.95 (0.72–1.38)	1.10 (0.80–1.52)	1.20 (0.87–1.64)	–	–
Adjusted for all covariates without statins	Ref	0.96 (0.068–1.32)	1.11 (0.79–1.51)	1.31 (1.02–1.71)	0.045	–

Values presented as HRs and 95% CIs adjusted for age, race, gender, albuminuria, smoking, diabetes, mTOR inhibitors, treatment arm, SBP, BMI, DBP, graft vintage and lipid-lowering drugs (statins) and living versus deceased donor kidney. Each quartile has the number of participants at risk of an event.