Cardiovascular Risk in Patients with Diabetic Kidney Disease

CORINA GRUNANU1, E. MOA1, MARIA MOA1, M.N. PANDURU2, MIHAELA BCU1, IULIA VLADU1
2 1 University of Medicine and Pharmacy, Craiova, Romania N.C.Paulescu National Institute for Diabetes, Nutrition, and Metabolic Diseases, Bucharest, Romania

In the past decades, chronic kidney disease has become a public health problem all over the world. Both the incidence and the prevalence are continually increasing. Diabetic nephropathy is, by far, the most frequent cause of CKD, with a prevalence of 40% in patients with end-stage renal disease (ESRD). Present studies have shown the fact that microalbuminuria and chronic kidney disease are independently associated to a high risk of cardiovascular events, as well as to a high mortality rate of all causes and also of cardiovascular cause, both in the general population and also in patients with high risk or an already present cardiovascular disease. There is a permanent association between the level of urinary albumin excretion and the risk for cardiovascular disease, macroalbuminuria and clinical nephropathy being associated to a higher risk for cardiovascular events than microalbuminuria. Due to the importance of clinical data and low cost, microalbuminuria and glomerular filtration rate should be introduced in the clinical practice for the evaluation of cardiovascular risk, especially in the patients with previously known heart disease. An early identification of the factors that determine the emergence and progression of diabetes complications is essential, in order to reduce the cardiovascular mortality and morbidity. Key words: diabetic kidney disease, cardiovascular disease, microalbuminuria, chronic kidney disease.

Present studies have shown the fact that microalbuminuria and chronic kidney disease are independently associated to a high risk of cardiovascular events, as well as to a high mortality rate of all causes and also of cardiovascular cause, both in the general population and also in patients with high risk or an already present cardiovascular disease.
DEFINITIONS OF MICROALBUMINURIA AND CHRONIC KIDNEY DISEASE (CKD)

Microalbuminuria as a predicting factor for diabetic nephropathy in patients with type 1 diabetes was first described in 1982 by Viberti et al. [1], and since then, the definition of albuminuria has been permanently readjusted in order to include all the possible determination methods for urinary albumin excretion. Currently, microlbuminuria is defined as the urinary albumin excretion between 30 and 300 mg/ day if measured in a 24 hrs urine collection, 20 200 g/min if measured in a timed urine collection or 30300 mg/g if there is measured the urinary albumin/ creatinine ratio in a spot urine collection. Values under these limits are considered to be
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normal and those above reflect the presence of macroalbuminuria or clinical proteinuria [2]. Chronic kidney disease is defined as the kidney damage confirmed by kidney biopsy or by markers of damage, or as the decline of glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, for a period longer than 3 months. Decreased kidney function starts at GFR < 89 mL/min and it is considered to be pronounced if the eGFR is < 60mL/min, which corresponds to 1.5 mg/dL of creatinine in men and 1.3 mg/dL in women [35]. 2530 years ago, diabetic nephropathy was identified with Kimmelstiel-Willson nodular glomerulosclerosis. In time, there was proven that all types of kidney lesions overlap in each patient and, depending on the genetic susceptibility, they may lead to the progression towards chronic kidney disease. Because various authors associate the notion of diabetic nephropathy with the old concept, there should be more and more suggested the adoption of a new terminology, like diabetic kidney disease (DKD), which includes all the lesions that appear at kidney level in a patient with diabetes mellitus.

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PREVALENCE OF CHRONIC KIDNEY DISEASE AND DIABETIC NEPHROPATHY (DN)

In the past decades, chronic kidney disease has become a public health problem all over the world. In the National Health and Nutrition Examination Survey (NHANES) III (19881994), the prevalence of CKD in adult population was of 11% in the USA, approximately 20 million of American adults suffering from CKD, out of which 8 million having GFR < 60 mL/min/1.73 m2. Both the incidence and the prevalence are continually increasing. Diabetic nephropathy is, by far, the most frequent cause of CKD, with a prevalence of 40% in patients with end-stage renal disease (ESRD). The microalbuminuria incidence in patients with type 1 diabetes was of 12.6% over a period of 7.3 years in the European Diabetes (EURODIAB) Prospective Complications Study Group [6] and of 33% in a study performed over a period of 18 months in Denmark [7]. In patients with type 2 diabetes, the microalbuminuria incidence was of 2.0% per year, with a prevalence of 25% after 10 years after diagnosis in the U.K. Prospective Diabetes Study (UKPDS). The proteinuria prevalence is between 15 and 40% in patients with type 1 diabetes, with a high incidence 1520 years after diagnosing diabetes, while in patients with type 2 diabetes, the proteinuria prevalence varies more, between 5 and 20% [79].
NATURAL PROGRESSION OF DIABETIC KIDNEY DISEASE (DKD)

Primary studies highlighted a high prevalence of microalbuminuria in patients suffering from diabetes, but recent studies did not confirm these outcomes. These prevalence variations may be attributed to differences regarding age, race, blood pressure (BP), or DKD stages in the studied population, as well as to the determination methods of microalbuminuria. The incidence of microalbuminuria is of 2.0% per year since the diagnosis, the progression of microalbuminuria to macroalbuminuria is of 2.8% per year and from macroalbuminuria to high values of seric creatinine is of 2.3% per year. In the UKPDS Study, after 10 years since the diagnosis, microalbuminuria was present in 24.9% of the patients, macroalbuminuria or clinical proteinuria in 5.3% of the patients and seric creatinine was high in 0.8% of the patients [8].

The progression rate of diabetic nephropathy as well as the cardiovascular risk seem to be lower in patients with a good glycaemic and blood pressure control [10]. The Diabetes Control and Complication Trial (DCCT) performed on 1.441 volunteers with type 1 diabetes compared the effects of a standard control versus the intensive glycemic control and it showed that a well-balanced metabolism slows down the emergence and progression of kidney and eye damage. The Epidemiology of Diabetes Intervention and Complications Study (EDIC) has shown that an intensive glycemic control reduced the risk for cardiovascular events with 42% and death from cardiovascular causes with 57% [11] [12]. A poor glycemic control is a major risk factor for microalbuminuria, while the progression to advanced stages of diabetic kidney disease is influenced by high blood pressure, dyslipidaemia and genetic factors [13]. Recently, there has been brought into discussion the HbA1C variability and the risk for diabetes complications. Theoretically, a variable glycemic profile may determine a high risk for diabetes complications by the increase of oxidative stress. In the FinnDiane Study, performed on 2107 patients with type 1 diabetes, the HbA1C variability was associated to the progression of chronic kidney disease (HR 1.92) and to the presence of cardiovascular events (HR 1.98) [14]. The impact of lipids in the progression of diabetic kidney disease was studied within the same prospective study (FinnDiane). High values of triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL3-cholesterol predict microalbuminuria. The progression to macroalbuminuria was associated to triacylglycerol and apolipoprotein (Apo) B [15]. Also, there has recently been noticed that high seric levels of uric acid in patients recently diagnosed with type 1 diabetes are associated to an increased risk for later development of diabetic nephropathy [16].
MICROALBUMINURIA AND THE CARDIOVASCULAR RISK

The first in reporting an association between microalbuminuria and cardiovascular disease was Yudkin et al. [17]. Since then, various studies performed either on the general population or on high risk patients have reported an association between microalbuminuria and traditional cardiovascular risk factors (age, high blood pressure,

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obesity, smoking, cholesterol, LDL-cholesterol, high triglycerides, low HDL-cholesterol), as well as other new risk factors (insulin-resistance, endothelial dysfunction, oxidative stress) [1827]. Lipoprotein subclasses, measured by NMR spectroscopy increase the prediction for coronary heart disease in patients with type 1 diabetes [28]. That is why the risk factors for atherosclerosis may also be risk factors for diabetic kidney disease: oxidative stress, circulant immune complexes containing LDL oxidation, adhesion molecules play an important part in the progression of diabetic nephropathy [29]. Systemic inflammation markers and cellular adhesion molecules are high since the early stages of diabetic kidney disease, before the onset of the end-stage renal disease. High levels of C-reactive protein (CRP) may favour lipid aterogenity and may induce the expression of cellular adhesion molecules (ICAM-1) [30]. Moreover, there has been suggested that microalbuminuria is an independent risk factor for morbidity and mortality of cardiovascular cause, both in patients with and without diabetes. Further on, there were performed prospective studies that confirmed the independent association between microalbuminuria and cardiovascular or total cause mortality [3134]. Also, the post-hoc analysis of long-term clinical trials points out the association between albuminuria and cardiovascular risk. In the Heart Outcomes Prevention Evaluation (HOPE) Study, performed on patients with a history of cardiovascular disease or diabetes mellitus, microalbuminuria was correlated to major cardiovascular events (relative risk RR 1.83), to all-cause mortality ((RR 2.09) and to hospitalization for congestive heart ((RR 3.23), the relative risk being similar in patients with or without diabetes. The risk for developing cardiovascular events started at the level of urinary albumin excretion under the cut-off value for microalbuminuria and has gradually increased. For each growth of urinary albumin excretion of 0.4 mg/mmol, the risk for cardiovascular events increased by 5.9% [35]. In a subpopulation of the NHANES II study, examined between 1976 and 1980 and monitored on a period of 16 years, the hazard rate for cardiovascular and all-cause mortality was of 1.57 and 1.64 for patients with proteinuria between 30 299 mg/dL, and 1.77, 2.00 respectively, in patients with urinary protein excretion of 300 mg/dL in comparison to the patients with levels below 30 mg/ dL [36].

The results of the European Prospective Investigation into Cancer and Nutrition Study, Norfolk, UK (the EPIC-Norfolk Study) support the information above after a monitoring period of 6.27.2 years the presence of albuminuria was independently associated with a significant greater risk of 36% for incident CHD, 49% for stroke, 103% for CV mortality and 48% for all-cause mortality. The important fact is that the risk for cardiovascular events was higher in the presence of macroalbuminuria [37]. In a recent analysis of the New ONTARGET Study, the doubling of albuminuria after 2 years, observed in 28% of the participants, was associated to a dramatic mortality growth (50%) (HR 1.47; p<0.0001) [38]. It is still unknown if the decrease of urinary albumin excretion is correlated to the reduction of cardiovascular events. Many factors intervention in early stages of diabetic nephropathy may reduce the risk for clinical nephropathy [39]. The reduction of albuminuria in the first 6 months seems to provide a cardiovascular protection according to the results obtained in the RENAAL Study [40]. Also, the ADVANCE Study, including 12877 patients with type 2 diabetes, resulted in the reduction of albuminuria progression by 22%, the reduction of major kidney objective, the doubling of creatinine by 21% as well as the reduction by 14% of coronary events and by 18% of cardiovascular mortality [41]. Surprisingly, in a recent study performed by Mauer, inhibiting the RAA system did not reduce the microalbuminuria incidence, the decline in kidney function or the development of morphological kidney lesions. The incidence of microalbuminuria after 5 years was of 6% in the placebo group and significantly higher, 17%, in the Losartan group (P=0.02), but not in that with Enalapril 4% (P=0.96) [42]. The screening for microalbuminuria may be an important method for identifying the patients with high cardiovascular risk. Patients with diabetes, high blood pressure, dyslipidaemia and other risk factors for cardiovascular disease progress to major cardiovascular events, passing through an asymptomatic stage, characterized by a subclinical damage of target organs (left ventricular hypertrophy (LVH), peripheral atherosclerosis). Microalbuminuria was associated to LVH and to a high left ventricle mass in various studies, that is why microalbuminuria is considered to be a subclinical factor for cardiovascular damage [43].

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In the Left Ventricular Function and Hemodynamic Features of Inappropriate LVH in Patients With Systemic Hypertension (LIFE) Study, urinary albumin excretion was correlated to LVH, initially and after one year of treatment, independently of age, blood pressure and glucose level [44]. Recently, McQuarrie has also shown that the level of urinary albumin excretion is associated with the left ventricle mass independently of BP. The left ventricle mass was measured by magnetic resonance imaging, a method that is not dependent on the volume, like echocardiography [45]. The level of urinary albumin excretion is associated to the severity of ischaemia and reperfusion, albuminuria early increases in patients with acute myocardial infarction (heart attack), and its level is proportional to the severity of the infarction [46].
CHRONIC KIDNEY DISEASE AS A CARDIOVASCULAR RISK FACTOR

When the therapy for substituting kidney functions is initiated, the cardiac function is severely affected in the majority of patients with CKD, which suggests the fact that risk factors act even from the early stages of chronic kidney disease [47]. There is a permanent association between the level of urinary albumin excretion and the risk for cardiovascular disease, macroalbuminuria and clinical proteinuria being associated to a higher risk for cardiovascular events than microalbuminuria [48 50]. Due to the fact that macroalbuminuria is a symptom of clinical nephropathy and is associated to a more rapid damaging of the kidney function, it is likely that the mechanisms involved in the increase of the cardiovascular risk in patients with macroalbuminuria to be different from the patients with microalbuminuria. The cardiovascular risk for patients with macroalbuminuria may be attributed both to the generalized vascular damage, as microalbuminuria, and to the presence of some specific factors of uremia. Alongside the traditional risk factors (diabetes, high blood pressure, dyslipidaemia, obesity) or the non-traditional risk factors (hyperhomocysteinemia, high fibrinogenous), while the eGFR decreases under 60 ml/min/1.73 m2 and the physiological kidney functions are damaged, there appear other risk factors correlated to the decrease of kidney function, factors that contribute to the increase of cardiovascular risk. These factors become clinically obvious when eGFR drops under 45 ml/min/1.73 m2.

Anemia secondary to the reduction of erythropoietine by the damaged kidneys and alteration of the phosphorus-calcium metabolism are the most important specific factors of uremia. Anemia is a major risk factor, associated to adverse cardiovascular effects by favouring the development of LVH [51]. Alterations of the parathormone metabolism, of calcemia and seric phosphorus are associated to cardiovascular calcifications, to arteriosclerosis and to a high cardiovascular risk [5254]. Recent studies have shown that hyperphosphatemia induces the proliferation and differentiation of vascular endothelial cells into cells with a similar activity to that of osteoblasts and, thus, promoting vascular calcification [55]. Also, there has recently been shown that low seric values of Vitamin D contribute to the increase of cardiovascular cause mortality in patients with chronic kidney disease. Correction of Vitamin D deficit and anemia, as well, may decrease the risk for cardiovascular risk in these patients [56]. The fact that patients with chronic kidney disease have a high risk for cardiovascular cause mortality was noticed 30 years ago. Since then, various studies have investigated the association between renal function and cardiovascular or allcause mortality in patients with CKD, with or without any cardiovascular disease [57] [58]. Several studies have shown that a slight or moderate increase of the creatinine level is associated to a high risk for cardiovascular events and cardiovascular mortality [5962]. The limitations of these studies are due to various factors, like: the use of creatinine for evaluating kidney function, a small number of subjects, the selection of cardiovascular disease or aged population. Also, a recent analysis has examined the association between kidney function in patients with cardiovascular disease and chronic heart failure in a population within the Candesartan in Heart Failure Program: Assessment of Reduction in Mortality and Morbidity (CHARM). After a monitoring period of 34.4 months, the hazard rate for primary events, cardiovascular cause mortality or hospitalization for the exacerbation of chronic heart failure was of 1.54 in the patients with eGFR between 45 60 ml/min/1.73 m2, and 1.86 in those with eGFR< 45 mL/min/1.73 m2, comparatively to those with eGFR > 60 mL/min/1.73m2. This fact did not correlate with the ejection fraction of the left ventricle, which is an independent predictor for cardiovascular risk [63]. Due to the importance of clinical data and low cost, microalbuminuria and the rate of glomerular

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filtration should be introduced in the clinical practice for the evaluation of cardiovascular risk, especially in the patients with previously known heart disease. An early identification of the factors that determine the emergence and progression of diabetes complications is essential, in order to reduce the cardiovascular mortality and morbidity.

For a better understanding regarding diabetes mellitus and its complications, further clinical studies are necessary. At present, there are current clinical trials that study therapies preventing the adverse effects of hyperglycaemia: advanced glycation end products inhibitors, protein kinase C inhibitors and aldose reductase inhibitors.

Fig. 1. Cardiovascular mortality rate associated to eRFG, Am J Epidemiol., 2008, 167:12261234.

___________________________________________________________________ n ultimele decenii boala cronic de rinichi (BCR) a devenit o problem de sntate public n toat lumea. Incidena i prevalena este n continu cretere. Nefropatia diabetic este, de departe, cea mai frecvent cauz a BCR cu o prevalen de aproximativ 40% la pacienii cu BCR n stadiul final. Studiile efectuate pn n prezent au evideniat faptul c microalbuminuria i boala cronic de rinichi sunt independent asociate cu un risc crescut de evenimente cardiovasculare, precum i cu o mortalitate crescut de toate cauzele i de cauz cardiovascular, att n populaia general, ct i la pacienii cu factori de risc sau cu boal cardiovascular deja prezent. Exist o asociere permanent ntre nivelul excreiei urinare de albumin i riscul de boal cardiovascular, macroalbuminuria i proteinuria clinic manifest sunt asociate cu un risc mai mare de evenimente cardiovasculare dect microalbuminuria. Datorit importanei lor clinice i costului sczut, microalbuminuria i rata filtrrii glomerulare ar trebui introduse n practica clinic pentru evaluarea riscului cardiovascular, n special la pacienii cu boal cardiac cunoscut. Este esenial identificarea precoce a factorilor care determin apariia i progresia complicaiilor diabetului pentru a reduce mortalitatea i morbiditatea cardiovascular. ___________________________________________________________________
Corresponding author: Dr. Grunanu Corina, MD Clinical Emergeny Hospital Craiova, Romania, Nephrology Clinic 1, Tabaci Str., Craiova, Romania E-mail: grcorina07@yahoo.com

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