LDL-C/apoB and HDL-C/apoA-1 ratios predict incident chronic kidney disease in a large apparently healthy cohort

doi:10.1016/j.atherosclerosis.2016.06.029

Atherosclerosis

Volume 251, August 2016, Pages 170-176

https://doi.org/10.1016/j.atherosclerosis.2016.06.029 Get rights and content

Highlights

•
Baseline TG, HDL-C levels and TG/HDL-C ratio predicted subsequent development of CKD.
•
A significant longitudinal association was found between incident CKD and the baseline LDL- C/apoB and HDL-C/apoA-1 ratios.
•
The risk for incident CKD was not associated with baseline LDL-C, non-HDL-C, apoB, apoA-I, or the apoB/apoA-I ratio.
•
Particle size of HDLs and LDLs may contribute to the development of CKD.

Abstract

Background and aims

The objective of this study was to evaluate the ability of lipid variables to predict the development of chronic kidney disease (CKD). We investigated the longitudinal association between lipid profiles and incident CKD in a large apparently healthy cohort.

Methods

A retrospective longitudinal analysis of 10,288 subjects who had participated in comprehensive health check-ups at least four times over a 7-year period was conducted. The risk of incident CKD associated with lipid variables was analyzed using adjusted hazard ratio (HR) for CKD per 1 standard deviation (SD) increase in lipid level. The development of CKD was defined as estimated glomerular filtration rate <60 ml/min/1.73 m².

Results

Over a mean follow-up of 56.5 ± 14.3 months, 356 (3.5%) subjects developed CKD. The multivariate adjusted HRs for incident CKD per 1 SD increase in baseline lipid level were 1.29 (95% confidence interval [CI], 1.17–1.41) for triglycerides (TG), 0.77 (0.68–0.88) for high-density lipoprotein cholesterol (HDL-C), 1.22 (1.12–1.32) for the TG/HDL-C ratio, 0.82 (0.73–0.92) for the low-density lipoprotein cholesterol/apolipoprotein B (LDL-C/apoB) ratio, and 0.74 (0.66–0.83) for the HDL-C/apoA-1 ratio. No longitudinal association was found between incident CKD and baseline total cholesterol, LDL-C, non-HDL-C, the LDL-C/HDL-C ratio, apoB, apoA-I, or the apoB/apoA-I ratio.

Conclusions

The LDL-C/apoB and HDL-C/apoA-1 ratios as well as TG and HDL-C concentrations independently predicted an increased risk for developing CKD. Our findings suggest that particle size of HDLs and LDLs may contribute to the development of CKD.

Introduction

Dyslipidemia may affect the kidney directly by causing deleterious renal lipid disturbances, as well as indirectly through systemic inflammation and oxidative stress, vascular injury, and other signaling molecules with renal action [1], [2]. Since the lipid nephrotoxicity hypothesis was proposed in 1982, increasing evidence has supported the hypothesis that dyslipidemia contributes to the development of renal disease, but the pathophysiology remains uncertain [2]. Feeding a hyperlipidemic diet to an animal model initiates and worsens renal dysfunction. Hypercholesterolemia and hypertriglyceridemia contribute to podocyte injury, which leads to segmental sclerosis associated with secondary damage to the tubulointerstitium [3], [4]. In addition, oxidized LDL induced renal injury in in vitro studies [4], [5], [6]. Mesangial cells express receptors for low density lipoprotein (LDL) and oxidized LDL, which induce proliferation of mesangial cells, increase mesangial matrix deposition, and enhance production of chemokines, cytokines, and growth factors. Chemokines, such as macrophage chemo-attractant protein-1, enhances recruitment of macrophages, which infiltrate the glomerulus and become foam cells [4], [5].

Clinical data also support that dyslipidemia contributes to the development of renal disease [4]. A few large sample sized longitudinal studies have shown that lipid abnormalities are associated with the development of renal disease in individuals who were free of kidney disease [7], [8], [9], [10], [11]. Several other clinical data have shown a relationship between lipid abnormalities and progression of renal disease [4]. However, the evidence is not as strong as it is in experimental studies because results are inconsistent regarding the ability of cholesterol and triglycerides (TGs) to predict the development of renal disease, and small sample sizes limited statistical power [4], [7], [8], [9], [10], [11], [12], [13]. Furthermore, these studies did not measure the full lipid profile [4], [7], [8], [9], [10], [11].

The objective of this study was to evaluate the ability of several lipid variables to predict the development of chronic kidney disease (CKD). Thus, we investigated the longitudinal association between lipid profiles and incident CKD in a large apparently healthy cohort.

Section snippets

Subjects

A large number of people undergo voluntary comprehensive health check-ups each year at Samsung Medical Center, and a considerable proportion of these individuals return for a medical check-up either annually or biennially. All anthropometric information, laboratory tests, radiology imaging results, and coded answers to self-reported questionnaires are stored electronically in medical records. Initial data were obtained from 25,170 individuals >20 years who participated in at least four

Results

Overall, the participants were not obese and had a mean BMI of 24.0 ± 2.8 kg/m². Mean age of the participants was 50 years, and 67.6% were men. Among the participants, 7.2% had diabetes at baseline. The mean follow-up period was 56.5 ± 14.3 months, during which 356 (3.5%) new cases of CKD occurred. Individuals who developed CKD later were more likely to have diabetes and use hypertensive and lipid medications at baseline (Table 1). After adjusting for age, sex, baseline eGFR, fasting glucose,

Discussion

Baseline TG and HDL-C levels predicted subsequent development of CKD over a mean follow-up of 57 months in this large longitudinal cohort study. Interestingly, a significant longitudinal association was also found between incident CKD and the baseline LDL-C/apoB and HDL-C/apoA-I ratios. In the discrimination capabilities for predicting CKD, no differences were observed between these lipid parameters. On the other hand, the risk for incident CKD was not associated with baseline TC, LDL-C,

Conflict of interest

The authors declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

Financial support

This work was supported by a grant (SMX1161861) from the Samsung Biomedical Research Institute, Republic of Korea.

Author contributions

J.C.B, and J.H.K contributed to the study design.

J.H.J and T.Y.Y acquired the data.

J.C.B, and J.M,H participated in the analysis and interpretation of data.

J.C.B wrote the manuscript which was critically reviewed and edited by S.K and M.K.L.

All authors contributed to the development and revision of the report and approved the final report for submission.

Acknowledgements

We acknowledge the efforts of the health screening group at Samsung Medical Center in Seoul, Korea. This work was supported by a grant (SMX1161861) from the Samsung Biomedical Research Institute, Republic of Korea. This funding source played no role in the study design, collection, analysis, and interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. J.H.K is the guarantor of this work and, as such, had full access to all the data in the

References (41)

A. Cases et al.
Dyslipidemia and the progression of renal disease in chronic renal failure patients
Kidney Int.
(2005 Dec)
K. Tsuruya 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. Off. J. Natl. Kidney Found.
(2015 Dec)
P. Muntner et al.
Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study
Kidney Int.
(2000 Jul)
N.C. Bhalodkar et al.
Accuracy of the ratio of triglycerides to high-density lipoprotein cholesterol for predicting low-density lipoprotein cholesterol particle sizes, phenotype B, and particle concentrations among Asian Indians
Am. J. Cardiol.
(2006 Apr 1)
J.R. Diamond et al.
Focal and segmental glomerulosclerosis: analogies to atherosclerosis
Kidney Int.
(1988 May)
N.E. Miller
Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis
Am. heart J.
(1987 Feb)
J.M. Weinberg
Lipotoxicity
Kidney Int.
(2006 Nov)
V. Ratziu et al.
Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial
Gastroenterology
(2008 Jul)
C.J. Chou et al.
WY14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha ) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice
J. Biol. Chem.
(2002 Jul 5)
C.W. Park et al.
PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice
Kidney Int.
(2006 May)

Y. Tanaka et al.

Fenofibrate, a PPARalpha agonist, has renoprotective effects in mice by enhancing renal lipolysis

Kidney Int.

(2011 Apr)

I.A. Bobulescu

Renal lipid metabolism and lipotoxicity

Curr. Opin. Nephrol. Hypertens.

(2010 Jul)

X.Z. Ruan et al.

An update on the lipid nephrotoxicity hypothesis

Nat. Rev. Nephrol.

(2009 Dec)

J.A. Joles et al.

Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. Journal of the American Society of Nephrology

JASN

(2000 Apr)

C.K. Abrass

Cellular lipid metabolism and the role of lipids in progressive renal disease

Am. J. Nephrol.

(2004 Jan-Feb)

B. Bussolati et al.

Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway

J. Am. Soc. Nephrol. JASN

(2005 Jul)

O.N. Goek et al.

Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples

Nephrol. Dial., Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc.

(2012 Jul)

E.S. Schaeffner et al.

Cholesterol and the risk of renal dysfunction in apparently healthy men

J. Am. Soc. Nephrol. JASN

(2003 Aug)

C.S. Fox et al.

Predictors of new-onset kidney disease in a community-based population

Jama

(2004 Feb 18)

N. Tolonen et al.

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes

Diabetologia

(2009 Dec)

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Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry.
We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG).
We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411–1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412–2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = −0.164, (95% CI = [−1.329 to 1.00]; p = 0.782), and TG β = −0.934 (CI = [−2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477–1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = −1.3 ([−2.533 to −0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = −0.117 (95% CI [−1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis.
In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry.
Wellcome (220740/Z/20/Z).
Association of High-Density Lipoprotein Cholesterol With GFR Decline in a General Nondiabetic Population
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All these studies used estimates of GFR, and some studies included persons with diabetes or CKD. In most studies, the populations were not representative of the general population, and in several studies they did not adjust for relevant confounders.19,43–46 Hypertriglyceridemia and abdominal obesity, in particular, correlate with lower HDL-C levels and have been linked to GFR decline and incident CKD in the general population.39
Although lower high-density lipoprotein cholesterol (HDL-C) levels are considered a risk factor for cardiovascular disease (CVD), experimental evidence suggest that aging, inflammation, and oxidative stress may remodel HDL-C, leading to dysfunctional HDL-C. Population studies on HDL-C and loss of the glomerular filtration rate (GFR) reported inconsistent results, but they used inaccurate estimates of the GFR and may have been confounded by comorbidity.
We investigated the association of HDL-C levels with risk of GFR loss in a general population cohort; the participants were aged 50–62 years and did not have diabetes, CVD, or chronic kidney disease (CKD) at baseline. The GFR was measured using iohexol-clearance at baseline (n=1627) and at the follow-up (n=1324) after a median of 5.6 years. We also investigated any possible effect modification by low-grade inflammation, physical activity, and sex.
Higher HDL-C levels were associated with steeper GFR decline rates and increased risk of rapid GFR decline (>3 ml/min per 1.73 m² per year) in multivariable adjusted linear mixed models and logistic regression (–0.64 ml/min per 1.73 m² per year [95% CI –0.99, –0.29; P < 0.001] and odds ratio 2.7 [95% CI 1.4, 5.2; P < 0.001] per doubling in HDL-C). Effect modifications indicated a stronger association between high HDL-C and GFR loss in physically inactive persons, those with low-grade inflammation, and men.
Higher HDL-C levels were independently associated with accelerated GFR loss in a general middle-aged nondiabetic population.
The LDL-C/ApoB ratio predicts major cardiovascular events in patients with established atherosclerotic cardiovascular disease
2021, Atherosclerosis
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The LDL-C/ApoB ratio in contrast had not been shown to predict cardiovascular events before. It however previously was shown to predict incident metabolic syndrome [9] and incident chronic kidney disease [27]. Our study is the first prospective investigation to demonstrate a significant role for the easily obtainable LDL-C/ApoB ratio in predicting MACE and all-cause mortality.
The low density lipoprotein cholesterol to Apolipoprotein B (LDL-C/ApoB) ratio is a validated proxy for low density lipoprotein (LDL) particle size that can be easily calculated from a standard lipid/apolipoprotein profile. Whether it is predictive of cardiovascular events in patients with established atherosclerosis is not known and is addressed in the present investigation.
We determined the LDL-C/ApoB ratio in a cohort of 1687 subjects with established atherosclerosis. Prospectively, major cardiovascular events (MACE) including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke were recorded over a period of 9.9 ± 4.6 years. The study covers >16,000 patient-years.
At baseline, the LDL-C/ApoB ratio was 1.36 ± 0.28 in our cohort. During follow up, a total of 558 first MACE were recorded. The LDL-C/ApoB ratio predicted MACE in univariate Cox proportional hazard analysis (HR 0.90 [0.82–0.98]; p = 0.014); this finding was confirmed after adjustment for age, gender, intensity of statin treatment, hypertension, history of smoking, type 2 diabetes, body mass index and ApoB (HR 0.87 [0.78–0.97]; p = 0.013).
The LDL-C/ApoB ratio is independently predictive of MACE in subjects with established atherosclerosis.
Association of blood lipid profile with incident chronic kidney disease: A Mendelian randomization study
2020, Atherosclerosis
Citation Excerpt :
Previous epidemiologic studies also observed positive relations of blood TG level [7–9,30–32], blood nonHDL-c level [9,10], TC:HDL-c ratio [8–10], and TG:HDL-c ratio [6,8,9,19] with the risk of CKD, whereas lower blood HDL-c level [6–8,10,33,34] was associated with a higher risk of CKD. Besides, most studies found no statistically significant associations of blood TC [7–10,33] and LDL-c [8,9,34,35] levels with the risk of CKD. Therefore, our results were generally consistent with the current literature.
Cohort studies found blood lipid traits were associated with the risk of chronic kidney disease (CKD). We aimed to investigate whether blood lipid traits were causally associated with the risk of CKD in the Chinese.
15,244 participants without kidney disease and cancer from the Dongfeng-Tongji cohort were recruited in 2008–2010 in Shiyan City, China. Blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels were measured. 5251 participants had genotype data and were included in the Mendelian randomization analysis. Incident CKD was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m² in 2013. Logistic regression and Mendelian randomization methods were used to estimate the observed and causal associations of blood lipid traits with incident CKD.
Various blood lipid traits were associated with CKD risk, and the odds ratios (95% confidence intervals) for incident CKD comparing the extreme quartiles were 1.45 (1.24–1.70) for TG, 1.26 (1.08–1.46) for nonHDL-c, 2.21 (1.91–2.57) for TC:HDL-c ratio, 2.14 (1.83–2.51) for TG:HDL-c ratio, and 0.47 (0.40–0.55) for HDL-c. The Mendelian randomization analysis indicated that 1 mmol/l increase in the genetic predicted blood TG level was associated with a 5% (95% confidence interval, 0–10%) higher risk of CKD.
Although blood levels of HDL-c, TG, nonHDL-c, TC:HDL-c ratio, and TG:HDL-c ratio were observed to be associated with incident CKD, the Mendelian randomization analysis provided genetic evidence to support causal relation for blood TG level only.
Large triglyceride-rich lipoproteins from fasting patients with type 2 diabetes activate platelets
2020, Diabetes and Metabolism
Citation Excerpt :
In the present study, our focus was on the interactions of large TGRL with platelets in T2D patients, as this population bears an increased risk of developing cardiovascular complications compared with non-diabetics. Indeed, in fasting healthy individuals, CM and their remnants are rapidly cleared from the circulation, and negligible concentrations of apoB48 are reported in plasma [28–30]. Thus, as these particles are unlikely to play a role in atherothrombotic events in healthy subjects [31], the relevance of studying the effect of fasting large TGRL on platelets from healthy subjects is flimsy.
Type 2 diabetes (T2D) patients present with risk factors for atherothrombosis such as fasting hypertriglyceridaemia and platelet hyperactivity. Our study objective was to determine the effect of large triglyceride-rich lipoproteins (TGRL) from fasting T2D patients on platelet aggregation and, if any, to identify the signaling pathway involved.
Large TGRL were isolated from the plasma of 25 T2D patients by ultracentrifugation (density < 1.000 g/mL). Platelets were isolated from healthy blood donors (HBD) and suspended in buffer, then preincubated in the presence or absence of TGRL and stimulated with either collagen or thrombin. Platelet aggregation and the arachidonic acid (AA) signaling pathway were studied.
Fasting T2D large TGRL were mostly of hepatic origin (apoB100/apoB48 ratio: 42 ± 7) and rich in triglycerides (TG/total apoB ratio: 4.2 ± 0.5), and able to potentiate agonist-stimulated platelet aggregation (collagen: +68%, P < 0.05; thrombin: +771%, P < 0.05). It should also be mentioned that TGRL from the plasma of HBD (n = 7) had no effect on platelet aggregation. In addition, T2D large TGRL increased thromboxane B₂ (TxB₂) concentration in platelets stimulated with either collagen (+34%, P < 0.05) or thrombin (+37%, P < 0.05) compared with platelets stimulated with either of these agonists without TGRL. Phosphorylation of p38 MAPK and cytosolic phospholipase A₂ (cPLA₂) was enhanced after incubation of platelets with T2D TGRL and thrombin (+87% and +32%, respectively, P < 0.05) compared with platelets incubated with thrombin only.
Large TGRL from fasting T2D patients may play a role in the development of atherothrombosis by increasing platelet aggregation and activating the platelet AA signaling pathway.
Intra-individual variability in high density lipoprotein cholesterol and risk of end-stage renal disease: A nationwide population-based study
2019, Atherosclerosis
Citation Excerpt :
This is because of reverse cholesterol transport, whereby HDL-C transfers cholesterol from the periphery to the liver for excretion [5]. Beyond this general property, HDL-C appears to exert an influence, not only on cardiovascular risk, but also on CKD and its progression to ESRD [1,6,15,16]. A recent, large study by Bowe et al. showed the association between HDL-C levels and renal outcomes in a general population cohort of almost 2 million.
There is a growing evidence demonstrating an association between dyslipidemia and progression of chronic kidney disease (CKD), but results on the effects of high-density lipoprotein cholesterol (HDL-C) on renal outcome have been conflicting. In this study, the relationship between HDL-C variability and the risk for progression to end-stage renal disease (ESRD) was investigated.
This study analyzed data of 4,283,318 subjects who were free of ESRD at the time of enrollment, received more than three medical examinations from 2009 to 2012, and were followed to the end of 2015, based on the Korean National Health Insurance Service database. HDL-C variability was measured using the standard deviation, coefficient of variation, average real variability and variability independent of the mean (VIM).
A total of 2,095 new cases of ESRD were observed during a median follow up of 3.38 years. There was a graded association between higher HDL-C variability and incident ESRD. In the multivariable adjusted model, hazard ratio comparing the highest and lowest quartiles of VIM of HDL-C was 1.82 (95% confidence interval, 1.58–2.09). The results were consistent when the variability of HDL-C was modeled using standard deviation, coefficient of variation and average real variability and were independent of other confounding factors, including the presence of CKD.
HDL-C variability independently predicted an increased risk for developing ESRD. Our findings suggest that identification of HDL-C variability may help improve risk stratification for the prevention of ESRD.

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LDL-C/apoB and HDL-C/apoA-1 ratios predict incident chronic kidney disease in a large apparently healthy cohort

Highlights

Abstract

Background and aims

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Conflict of interest

Financial support

Author contributions

Acknowledgements

Kidney Int.

Am. J. kidney Dis. Off. J. Natl. Kidney Found.

Kidney Int.

Am. J. Cardiol.

Kidney Int.

Am. heart J.

Kidney Int.

Gastroenterology

J. Biol. Chem.

Kidney Int.

Kidney Int.

Renal lipid metabolism and lipotoxicity

Curr. Opin. Nephrol. Hypertens.

An update on the lipid nephrotoxicity hypothesis

Nat. Rev. Nephrol.

Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. Journal of the American Society of Nephrology

JASN

Cellular lipid metabolism and the role of lipids in progressive renal disease

Am. J. Nephrol.

Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway

J. Am. Soc. Nephrol. JASN

Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples

Nephrol. Dial., Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc.

Cholesterol and the risk of renal dysfunction in apparently healthy men

J. Am. Soc. Nephrol. JASN

Predictors of new-onset kidney disease in a community-based population

Jama

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes

Diabetologia