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Microvascular Residual Risk THROUGH LANDMARK STUDY

4 September 2015
A higher TG/HDL-C ratio increases the incidence and progression of chronic kidney disease

A higher ratio of triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) was associated with greater decline in kidney function, as assessed by estimated glomerular filtration rate (eGFR) and urinary protein excretion, especially in individuals with diabetes.

Tsuruya K, Yoshida H, Nagata M et al. Impact of the Triglycerides to High-Density Lipoprotein Cholesterol Ratio on the incidence and progression of CKD: A longitudinal study in a large Japanese population. Am J Kidney Dis 2015 Epub ahead of print.
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate the impact of baseline TG/HDL-C ratio on changes in eGFR and the incidence and progression of chronic kidney disease (CKD) in a Japanese population
Study design: Longitudinal cohort study with a 2-year follow-up
Study population: 124,700 subjects (aged 39 to 74 years) in the Japanese Specific Health Check and Guidance System. This cohort included 50,392 men and 74,308 women. In total, 102,900 subjects did not have CKD at baseline, and 21,800 had CKD.
Efficacity measures
Primary:
Ratio of TG/HDL-C
Secondary:
  • eGFR (mL/min/1.73 m2), calculated as 194 x serum creatinine (mg/dL)-1.094  x age (years)-0.287 x 0.739 (for women). Low eGFR was defined as <60 mL/min/1.73 m2
  • Proteinuria, as assessed by dipstick testing, and defined as ≥1+
  • CKD, defined as eGFR <60 mL/min/1.73 m2 and/or the presence of proteinuria
Methods:

The decline in eGFR was assessed according to the following criteria:

  • ≥25% decrease from baseline in eGFR category (³90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2)
  • rapid decline in eGFR was defined as sustained decline in eGFR >5 mL/min/1.73 m2 per year
  • >30% decrease in eGFR from baseline
    Univariable and multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for incident CKD, low eGFR, and proteinuria, as well as progression of CKD, were determined using a logistic regression model adjusted for potential confounding covariates. These included age, sex, waist circumference, hypertension, obesity, diabetes mellitus, smoking, daily alcohol consumption, frequency of exercise, history of stroke and heart disease, and medication for dyslipidaemia. Data were analysed for all subjects, subjects without CKD at baseline and those with pre-existing CKD
Main results:
  • A higher TG/HDL-C ratio at baseline was associated with significantly greater decline in eGFR, even after adjustment for confounding factors (Table 1). The impact of higher TG/HDL-C ratio was greater in individuals with diabetes than in those without (p for interaction 0.002).

 

Table 1. Impact of baseline TG/HDL-C ratio on change in eGFR and urinary protein, all subjects

Variable

Baseline TG/HDL-C quartile

 

1

M <1.26

F <0.97

2

M 1.26-1.96

F 0.97-1.45

3

M 1.97-3.14

F 1.46-2.24

4

M >3.14

F >2.24

Change in eGFR

Multivariable adjusted LSM (SE)

-0.52 (0.12)

-0.72 (0.12)

-1.02 (0.12)

-1.25 (0.12)

Increase in urinary protein, %

8.4

9.1

10.2

11.4

Multivariable-adjusted OR (95% CI)

Reference

1.02               (0.97-1.08)

1.10                 (1.04-1.16)

1.18                 (1.12-1.25)

LSM least square mean; SE standard error

 

In subjects without CKD at baseline, a higher TG/HDL-C ratio was associated with a higher risk of incident CKD, especially in those with diabetes (p for interaction 0.05) (Table 2).

 

Table 2. Impact of baseline TG/HDL-C ratio on risk for incident CKD, subjects without CKD at baseline

Variable

Baseline TG/HDL-C quartile

 

1

M <1.22

F <0.96

2

M 1.22-1.89

F 0.96-1.43

 

3

M 1.89-3.02

F 1.43-2.20

4

M >3.02

F >2.20

Incident CKD, %

7.6

9.0

9.8

11.4

Multivariable-adjusted OR (95% CI)

Reference

1.07                 (1.00-1.14)

1.10                 (1.03-1.17)

1.25                 (1.18-1.34)

 

A higher TG/HDL-C ratio was associated with higher risk of rapid decline in eGFR and increase in urinary protein excretion in subjects with CKD (Table 3).

 

Table 3. Impact of baseline TG/HDL-C ratio on rapid decline in eGFR and urinary protein excretion, subjects with CKD at baseline

Variable

Baseline TG/HDL-C quartile

 

1

M <1.42

F <1.08

2

M 1.43-2.21

F 1.08-1.62

 

3

M 2.21-3.50

F 1.62-2.54

4

M >3.50

F >2.54

Rapid decline in eGFR, %

5.8

6.3

7.3

7.4

Multivariable-adjusted OR (95% CI)

Reference

1.18               (0.99-1.40)

1.39               (1.17-1.65)

1.23*               (1.03-1.46)

>30% decline in eGFR %

0.8

1.1

1.4

1.8

Multivariable-adjusted OR (95% CI)

Reference

1.35               (0.91-2.01)

1.53               (1.04-2.26)

1.73**               (1.19-2.54)

 

 

 

 

 

Increase in urinary protein, %

8.5

9.8

11.5

12.7

Multivariable-adjusted OR (95% CI)

 

1.05               (0.92-1.21)

1.19               (1.04-1.35)

1.28***                 (1.12-1.46)

p for trend, *p=0.01; **p=0.004; ***p<0.001

Authors’ conclusion: A higher TG/HDL-C ratio affects the decline in eGFR and incidence and progression of CKD in the Japanese population

COMMENT

Abnormalities of lipid metabolism have been previously linked with progression of CKD, although the underlying mechanism(s) has yet to be fully elucidated. Early studies have implicated both elevated TG and low plasma HDL-C plasma concentration with the residual risk of diabetic kidney disease.1 More recently, the REALIST Micro study showed that the risk of diabetic kidney disease increased by 23% per 0.5 mmol/L (22 mg/dL) increase in TG and decreased by 14% per 0.2 mmol/L (7.7 mg/dL) increase in HDL-C, components of atherogenic dyslipidaemia.2

An alternative marker of atherogenic dyslipidaemia is the ratio of TG/HDL-C; this continuous variable is also considered a useful index for insulin resistance.3,4 In a previous report, the TG/HDL-C ratio was associated with CKD in large Japanese cohort, although the cross-sectional design did not permit conclusions regarding causality.5

The current study involving a 2-year follow-up of a large Japanese cohort has extended these previous findings. The study showed that a higher TG/HDL-C ratio is an independent risk factor for the incidence and progression of CKD in a general population but especially in individuals with diabetes. This association remained significant even after adjustment for multiple confounding factors, including both modifiable and modifiable risk factors for cardiovascular and kidney disease. Moreover, a higher TG/HDL-C ratio was also linked with incident CKD in individuals without CKD at baseline; in the highest quartile for TG/HDL-C, the risk of incident CKD was increased by 25% over 2 years compared with the lowest TG/HDL-C quartile. Additionally, in individuals with CKD at baseline, those in the highest TG/HDL quartile had 73% increase for risk of >30% decline in eGFR over 2 years compared with the lowest quartile for TG/HDL-C. The study findings are strengthened by the large cohort size and longitudinal study design, which rules out a reverse causation bias of CKD on atherogenic dyslipidaemia.

In conclusion, this study reinforces the importance of atherogenic dyslipidaemia in the development and progression of CKD, especially in individuals with diabetes. These findings clearly support the case for management of atherogenic dyslipidaemia, not only to reduce the lipid-related residual risk of cardiovascular disease, but also to reduce the residual risk for CKD.

References

1. Fioretto P, Dodson PM, Ziegler D, Rosenson RS. Residual microvascular risk in diabetes: unmet needs and future directions.  Nat Rev Endocrinol 2010;6:19-25.

2. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation 2014;129:999-1008.

3. Giannini C, Santoro N, Caprio S et al. The triglyceride-to-HDL cholesterol ratio: association with insulin resistance in obese youths of different ethnic backgrounds. Diabetes Care 2011;34:1869-74.

4. Gasevic D, Frohlich J, Mancini GB, Lear SA. The association between triglyceride to high-density-lipoprotein cholesterol ratio and insulin resistance in a multiethnic primary prevention cohort. Metabolism 2012;61:583-9.

5. Tsuruya K, Yoshida H, Nagata M et al. Association of the triglycerides to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: analysis in a large Japanese population. Atherosclerosis. 2014;233:260-7

Key words Chronic kidney disease (CKD); glomerular filtration rate; proteinuria; kidney disease progression; dyslipidaemia; triglycerides to high-density lipoprotein cholesterol ratio; diabetes; Japanese population