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1 J. Endocrinol. Invest. 36: , 2013 DOI: /8850 Lower levels of total HDL and HDL3 cholesterol are associated with albuminuria in normoalbuminuric Type 1 diabetic patients T. Bulum 1, B. Kolarić 2,3, and L. Duvnjak 1 1Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Medical School, University of Zagreb, Zagreb; 2 Medical School, University of Rijeka, Rijeka; 3 Zagreb County Institute of Public Health, Zagreb, Croatia INTRODUCTION Identification of the determinants of the onset of early diabetic nephropathy is essential for reducing the morbidity and mortality associated with diabetes, because patients with Type 1 diabetes (T1D) have a 20-50% probability of developing end-stage renal disease (1). Many studies have identified poor glycemic control, duration of diabetes, smoking and hypertension as important risk factors for microalbuminuria, marker for early diabetic kidney disease (2-6). Dyslipidemia has also been associated with the development and progression of nephropathy, and with mesangial, tubulointerstitial, and glomerular changes in the kidney (7-9). However, it was postulated that lipids predict risk of overt nephropathy in T1D only in the short term (10), and that lipids mainly act as late-stage accelerators or precipitators rather than underlying etiologic factor. Multiple lipid abnormalities are present in early stages of diabetic nephropathy in T1D patients (11), and it has been shown that lipid and lipoprotein disturbances are more closely related to albuminuria than to cardiovascular diseases in T1D (11, 12). In comparison to normoalbuminuric diabetic patients, those with microalbuminuria ABSTRACT. Background: Previous studies have suggested a positive association between dyslipidemia and chronic kidney disease, but sparse data are available on the relation of lipids and urinary albumin excretion rate (UAE) in normoalbuminuric patients with normal renal function. Aim: The aim of this study was to evaluate the associations of serum lipids, including total, LDL, HDL, HDL2, HDL3 cholesterol, and triglyceride levels with UAE in normoalbuminuric Type 1 diabetic (T1D) patients. Methods: Study included 313 normoalbuminuric T1D patients with normal renal function and before any interventions with statins, ACE inhibitors or angiotensin II receptor blockers. Subjects were classified as low-normoalbuminuric (UAE<11.0 mg/24h) or high-normoalbuminuric (UAE 11.0 mg/24h) based on median UAE of at least two 24- h urine collections. Correlations and multiple linear regressions analysis were performed to identify relationships between serum lipids and UAE in normoalbuminuric subjects. Results: Total HDL (p=0.02) and HDL3 cholesterol (p=0.01) levels were higher in low-normoalbuminuric subjects compared to high-normoalbuminuric subjects. In logistic regression analysis, after adjustment for age, sex, BMI, duration of diabetes and HbA 1c, lower total HDL and HDL3 cholesterol levels were significantly associated with risk of higher UAE in our normoalbuminuric subjects (p 0.01), with odds ratios of 0.34 to Conclusions: Elevated total HDL and HDL3 cholesterol levels are associated with lower UAE in normoalbuminuric T1D patients. However, whether the detection of elevated total HDL and HDL3 cholesterol levels in T1D patients has protective value for development of microalbuminuria needs to be assessed in further follow-up studies. (J. Endocrinol. Invest. 36: , 2013) 2013, Editrice Kurtis and macroalbuminuria have been reported to have significantly higher plasma levels of total, LDL cholesterol and triglyceride levels but lower HDL cholesterol levels, even in absence of renal insufficiency (9, 11, 13-15, 16). In a number of studies, an increase in LDL cholesterol levels has been found to be a risk factor for nephropathy and higher urinary albumin excretion rate (UAE) in T1D (2, 7, 8, 12, 14, 15). In addition, the diameter of LDL particles has been reported to be smaller in patients with microalbuminuria (17), and lower cholesterol levels predicted regression of microalbuminuria to normoalbuminuria (18). In contrast, total HDL cholesterol, as well as HDL cholesterol subclasses, has been found to be protective for coronary artery disease as well as for microand macroalbuminuria in patients with T1D (11, 19-22). However, even a mild increase in UAE in normoalbuminuric patients predicts cardiovascular risk (23). It is important to establish which lipids are most important in the pathogenesis of early changes in UAE in normoalbuminuric patients with T1D. The objective of this study, therefore, was to evaluate the associations of serum lipids, including total, LDL, HDL, HDL2, HDL3 cholesterol, and triglyceride levels with UAE in normoalbuminuric T1D patients with glomerular filtration rate >60 ml min m 2. Key-words: Albuminuria, HDL3 cholesterol, serum lipids, total HDL cholesterol, Type 1 diabetes. Correspondence: T. Bulum, MD, PhD, Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, School of Medicine, University of Zagreb, Croatia. tbulum@idb.hr Accepted January 8, First published online February 12, SUBJECTS, MATERIALS AND METHODS This study included 313 euthyroid patients with T1D. T1D was defined as an onset of diabetes before the age of 35 yr, positive autoantibodies (ICA, GAD, or IA-2) and permanent insulin treatment initiated within 1 year of diagnosis. The study included patients with following characteristics: age of yr, minimum duration of T1D of 1 year, no medical history of cardiovascular diseases or 574

2 T. Bulum, B. Kolaric, and L. Duvnjak electrocardiogram (ECG) evidence of ischemic heart disease, absence of any systemic disease, and absence of any infections in the previous month. Patients with chronic renal disease or other chronic diseases likely to affect renal function were excluded. Patients were excluded from the study if they had taken any of the following: lipid-lowering therapy, antihypertensive therapy including ACE inhibitor or angiotensin II receptor blockers, medications that might affect glucose metabolism such as glucocorticoids as well as patients taking oral glucose-lowering medication. Acute and chronic inflammation was excluded on the basis of medical history, physical examination, and routine laboratory tests, including measurement of temperature and urinalysis. All subjects were studied in the morning after an overnight fast. Basic anthropometric measurements were performed on all study subjects, including body mass index (BMI) and waist to hip ratio (WHR). Normal range for BMI was kg/m 2 and for WHR <0.85 for women and <0.9 for men. Blood pressure was measured twice in the sitting position with a mercury sphygmomanometer after a resting period of 10 min and expressed in mmhg. Those with blood pressure 130/80 mmhg were considered to have hypertension. UAE was measured from at least two 24-h urine samples and determined as the mean of 24-h urine collections. Method of 24-h urine collection included urine collection into collection bottle starting from the morning after patient emptied bladder for the first time and finishing by collecting the first urine passed the next morning, adding it to the collection bottle. Patients performed collections on two consecutive days to minimize variability. Normoalbuminuria was defined as a UAE<30 mg/24h. Those with microalbuminuria (UAE 30<300 mg/24h) and macroalbuminuria (UAE 300 mg/24h) were excluded from the study. Serum creatinine was measured in fasting blood sample. From 2010 creatinine was measured by an enzymatic method that produced values traceable to the isotope dilution mass spectrometry (IDMS) values. We calibrated creatinine results generated before 2010 to the IDMS-traceable values obtained with the enzymatic method. Data on serum creatinine levels, age, sex and race were used to calculate the estimated glomerular filtration rate (egfr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) formula, which has been shown to be accurate in determining renal function in diabetic patients with normal renal function (24). Those with impaired egfr (less than 60 ml min m 2 ) were excluded from the study. Fasting venous blood samples, taken from antecubital veins with the use of a tourniquet, were collected in the morning between 08:00 and 09:30 h after an overnight fast for the determination of glycated hemoglobin (HbA 1c ), total, LDL, HDL, HDL2, HDL3 cholesterol, triglycerides, and fasting glucose. Normal values, based on the recommendation of the American Diabetes Association, were: fasting glucose mmol/l, LDL cholesterol <2.6 mmol/l, triglycerides <1.7 mmol/l, and HDL cholesterol >1.0 mmol/l for men and >1.3 mmol/l for women (25). Microalbumin and HbA 1c were measured spectrophotometrically by turbidimetric immuno-inhibition (Olympus AU600, Beckman-Coulter, USA). Results of HbA 1c (%) are expressed in the DCCT-equivalent. Glucose, cholesterol and triglycerides in serum were measured by an enzymatic colorimetric method, HDL directly and HDL2 and HDL3 indirectly, after precipitation with polyethylene glycol on an automatic spectrophotometer (Olympus AU600, Beckman-Coulter, USA). Complete blood count was determined on an automatic blood counter (Advia 120, Siemens Diagnostic Solutions, USA). The study protocol complies with the Declaration of Helsinki as well as with local institutional guidelines, and was approved by the local Ethics Committees. Data are expressed as means±sd for normally distributed values, as median with range for non-normally distributed values, and percentage. Differences between groups were examined, depending on the nature of the data, parametric (t-test) or nonparametric tests (Mann-Whitney). Pearson s correlation coefficients were used to calculate correlations between normally distributed values, and Spearman s rank correlation coefficients were used for non-normally distributed values. Separate multivariate logistic regression models were used to assess associations of serum lipids and risk of higher UAE taking account of potential confounders. Two models were constructed for each lipid: model A, unadjusted; model B, adjusted for age, sex, HbA 1c, duration of diabetes and BMI. Level of statistical significance was set at α=0.05. Statistical analysis was performed by statistical package STATA/IC ver RESULTS The characteristics of the study subjects are listed in Table 1. The average age was approximately 34 yr, most were not overweight and 51% of subjects were female. Mean/median values of BMI, WHR, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides were within the normal range for patients with diabetes, with slightly elevated levels of HbA 1c, total and LDL cholesterol. The majority of patients had high HDL cholesterol (for men 1.0 mmol/l, 96% of patients; for women 1.3 mmol/l, 95% of patients). The mean GFR estimated by the CKD-EPI was 106 ml min m 2. Clinical and metabolic characteristics of patients depending of level of UAE are presented in Table 2. Lownormoalbuminuric subjects had higher levels of total HDL and HDL3 cholesterol as well as lower systolic and diastolic blood pressure in contrast to high-normoalbumin- Table 1 - Clinical and metabolic characteristics of all patients. Variable Value Age (yr) 34 (18-65) Duration of diabetes (yr) 12 (1-42) Body mass index (kg/m 2 ) 24 (15-37) Waist-to-hip ratio 0.81±0.07 Fasting glucose (mmol/l) 5.4 ( ) HbA 1c (%) 7.43±1.63 Systolic blood pressure (mmhg) 120 (79-180) Diastolic blood pressure (mmhg) 80 (50-100) Total cholesterol (mmol/l) 5.0±0.8 LDL cholesterol (mmol/l) 2.8±0.7 HDL cholesterol (mmol/l) 1.7±0.4 HDL2 cholesterol (mmol/l) 0.52±0.1 HDL3 cholesterol (mmol/l) 1.1±0.3 Triglycerides (mmol/l) 0.91 ( ) Serum creatinine (µmol/l) 71±14 egfr (ml min m -2 ) 106±16 Urinary albumin excretion (mg/24h) 11.0 ( ) HbA 1c : glycated hemoglobin; egfr: estimated glomerular filtration rate. 575

3 HDL and albuminuria in Type 1 diabetes Table 2 - Clinical and metabolic characteristics of patients depending on level of urinary albumin excretion rate (UAE). UAE UAE <11.0 mg/24h 11.0 mg/24h Age (yr) 34 (18-60) 35 (18-65) 0.09 Sex (m/f) 73/84 79/ Duration of diabetes (yr) 11 (1-42) 13 (1-42) 0.07 Body mass index (kg/m 2 ) 24 (17-34) 24 (15-37) 0.6 Waist-to-hip ratio 0.81± ± Fasting glucose (mmol/l) 5.4 ( ) 5.3 ( ) 0.5 HbA 1c (%) 7.2± ± Total cholesterol (mmol/l) 5.0± ± LDL cholesterol (mmol/l) 2.8± ± HDL cholesterol (mmol/l) 1.7± ± HDL2 cholesterol (mmol/l) 0.5± ± HDL3 cholesterol (mmol/l) 1.2± ± Triglycerides 0.82 ( ) 0.93 ( ) 0.07 Systolic blood pressure (mmhg) 120 (90-180) 120 (79-180) 0.04 Diastolic blood pressure (mmhg) 80 (60-90) 80 (50-150) 0.01 HbA 1c : glycated hemoglobin. uric subjects. Age, duration of diabetes, BMI, WHR, HbA 1c, total, LDL, HDL2 cholesterol and triglycerides levels did not differ between two groups. We also explore the relationship between serum lipids among those in the 2 nd, 3 rd and 4 th quartiles of UAE compared to those in quartile 1 (<6.8 mg/24h). Stratifying serum lipids for degree of UAE, trends across quartiles for serum lipids were not statistically significant, but subjects in the 1 st quartile of UAE had elevated levels of total cholesterol, total HDL, and HDL3 cholesterol, and decreased levels of LDL cholesterol and triglycerides compared to subjects in 2 nd, 3 rd and 4 th quartiles (data not shown). Associations of renal parameters with anthropometric and metabolic variables are presented in Table 3. UAE was significantly associated with duration of diabetes, total Table 3 - Spearmans correlation analysis of associations of renal parameters with metabolic and anthropometric variables. Variable UAE Serum creatinine egfr Age * Duration of diabetes 0.14* * Body mass index * 0.10 Waist-to-hip ratio * 0.01 Fasting glucose * HbA 1c * 0.15* Total cholesterol * LDL cholesterol * HDL cholesterol 0.13* 0.19* 0.17* HDL2 cholesterol * 0.21* HDL3 cholesterol 0.14* 0.13* 0.14* Triglycerides 0.11* Systolic blood pressure * 0.08 Diastolic blood pressure 0.23* *p<0.05; UAE: urinary albumin excretion rate; HbA 1c : glycated hemoglobin; egfr: estimated glomerular filtration rate. p HDL, HDL3 cholesterol, triglycerides, and diastolic blood pressure, with diastolic blood pressure showing the strongest correlation (r=0.23, p<0.001). Serum creatinine was significantly associated with BMI, WHR, HbA 1c, total HDL, HDL2, HDL3 cholesterol and systolic blood pressure, with WHR showing the strongest correlation (r=0.39, p<0.001). Estimated GFR using CKD-EPI formula significantly correlated with even 9 parameters (age, duration of diabetes, fasting glucose, HbA 1c, total, LDL, HDL, HDL2, and HDL3 cholesterol). The magnitude of these associations was strongest for age and duration of diabetes (r= 0.60, and 0.29, respectively, all p<0.001). We also divided patients according to different cutoff points of BMI (<22, 22<24, 24<26, and 26 kg/m 2 ) and evaluated the associations of serum lipids and UAE in different classes of BMI. After stratifying patients in different groups of BMI, correlations between UAE and serum lipids were statistically significant only in group of overweight patients with BMI 26 kg/m 2. In addition, associations were significant only for total HDL, HDL2 and HDL3 cholesterol (r= 0.34, 0.25, and 0.29, respectively, all p 0.01) (data not shown). In logistic regression analysis, total HDL and HDL3 cholesterol were significantly associated with risk of higher UAE in our subjects (p 0.01), with odds ratios of 0.39 to 0.51 (Table 4, Model A). Odds ratio for total HDL and HDL 3 cholesterol were attenuated slightly but remained significant after adjustment for age, sex, duration of diabetes, HbA 1c and BMI (Table 4, Model B). The magnitude of these associations was strongest for HDL3 cholesterol (p=0.009). DISCUSSION A range of experimental and clinical studies suggests that serum lipids may play a significant independent role in the development of diabetic nephropathy, decline in renal function and progression of albuminuria (2, 7-9, 11-15, 21). In addition, it seems that abnormalities in lipid and lipoprotein disturbances are more closely related to micro- than to macrovascular diseases in patients with T1D (12). Our high-normoalbuminuric subjects have higher HbA 1c, duration of diabetes and blood pressure in contrast to low-normoalbuminuric subjects, which has been observed as risk factor for progression of diabetic kidney disease (2-5). However, UAE in our normoalbuminuric subjects significantly correlated mainly with serum lipids, Table 4 - Multivariate logistic regression analysis of serum lipids with development of higher urinary albumin excretion rate (UAE) in normoalbuminuric Type 1 diabetic patients. Independent variable Model A Model B Total cholesterol 0.99 ( ) 0.87 ( ) LDL cholesterol 1.08 ( ) 0.95 ( ) HDL cholesterol 0.51 ( )* 0.43 ( )* HDL2 cholesterol 0.51 ( ) 0.46 ( ) HDL3 cholesterol 0.39 ( )* 0.34 ( )* Triglycerides 1.30 ( ) 1.15 ( ) Data are OR (95% CI) from separate models. Model A crude; model B adjusted for age, sex, duration of diabetes, body mass index (BMI), glycated hemoglobin. *p<

4 T. Bulum, B. Kolaric, and L. Duvnjak especially with total HDL and HDL3 cholesterol, and modestly with other clinical and metabolic parameters. In multiple logistic regression analysis, only total HDL and HDL3 cholesterol levels were independently related to UAE, even after adjusting for glycemic control and other risk factors. It has been argued that in T1D increased HbA 1c, as a marker of chronic hyperglycemia, is the most important risk factor for progression of diabetic kidney disease (2-4, 26). It was also suggested that relationship between serum lipids and albuminuria in T1D subjects were related to the worse glycemic control observed in subjects with albuminuria (13). However, mean HbA 1c levels (7.4%) in our subjects were significantly lower than in most previous studies. In addition, our high-normoalbuminuric subjects have higher HbA 1c but lower fasting glucose, and HbA 1c did not significantly correlate with UAE. Although patients with T1D have a high risk of developing end-stage renal disease (1), only 30-40% of patients will develop diabetic kidney disease, even with poor gylcemic control (27). It seems that some additional factors may protect some individuals from progression of renal disease. Although most studies that have examined the impact of serum lipids on the development of nephropathy in T1D have focused on LDL cholesterol, it has been demonstrated that those individuals without nephropathy have HDL cholesterol levels higher than those with nephropathy (12, 14, 19-22, 28). In a 10-yr prospective study it was found that low total HDL cholesterol is a risk factor for renal disease in T1D (29). In addition, protective effect of HDL cholesterol levels on cardiovascular diseases is well founded and described (30, 31). Moreover, HDL composition predicts new-onset cardiovascular disease in patients with T1D (19). It was also suggested that HDL is not only involved in reverse cholesterol transport but also may have a number of other protective effects on the endothelium (29). In contrast, others demonstrate that HDL cholesterol is unaltered in the presence of complications in T1D patients and that HDL metabolism is unaffected by diabetes complications (32). In addition, it was found that baseline HDL cholesterol levels, which were similar to that in our subjects, were not associated with progression to microalbuminuria (15). HDL cholesterol can be subdivided into 2 major subclasses, HDL2 and HDL3 cholesterol, which are thought to differ in ability to protect against atherosclerosis (33). In non-diabetic subjects it was found that total HDL and HDL3 cholesterol, but not HDL2 cholesterol, were significantly and inversely associated with the risk of incident coronary heart disease (34). In a prospective study including 2304 adult patients with T1D, it has been found that HDL3 cholesterol has positive predictive value for the development of microalbuminuria in T1D patients (21). In contrast, in our subjects HDL3 cholesterol has negative predictive value for the development of higher UAE in normoalbuminuric range. However, our patients have significantly higher levels of total HDL and especially HDL3 cholesterol that could explain the discrepancy between the two studies. In addition, a large proportion of our subjects (>95%) had high HDL cholesterol. It is possible that HDL3 cholesterol was more closely associated with risk of higher UAE than HDL2 cholesterol in our study because HDL3 cholesterol represented 68% of total HDL cholesterol. However, it is not known what is the mechanism of salutary effects of high HDL cholesterol on glomerulus, and the relative importance of HDL2 and HDL3 cholesterol in early diabetic nephropathy is still unclear. The present study has a number of potential limitations. First, our study was cross-sectional, which limited our ability to infer a causal relation between serum lipids and risk for the development of microalbuminuria. Second, our analyses were based on measurement of traditional lipoprotein markers. However, it is likely that in clinical practice the measurement of conventional lipoprotein parameters is sufficient to assess the risk of albuminuria in T1D, in contract to additional parameters which make little predictive impact (12). Third, our analyses were based on measurement of UAE on two consecutive days that may not reflect the relation over time. In conclusion, we have shown that elevated total HDL and HDL3 cholesterol levels are associated with lower UAE in normoalbuminuric T1D patients. However, whether the detection of elevated total HDL and HDL3 cholesterol levels in normoalbuminuric T1D patients has protective value for development of microalbuminuria needs to be assessed in further follow-up studies. ACKNOWLEDGMENTS Disclosure statement The authors disclose that they did not receive any financial support for the study. No proprietary interest is involved in the study. REFERENCES 1. Nordwall M, Bojestig M, Arnqvist HJ, Ludvigsson J. Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of type 1 diabetes: the Linkoping Diabetes Complications Study. Diabetologia 2004, 47: Raile K, Galler A, Hofer S, et al. Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care 2007, 30: Coonrod BA, Ellis D, Becker DJ, et al. Predictors of microalbuminuria in individuals with IDDM. 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