Review
The cardiorenal syndrome in diabetes mellitus

https://doi.org/10.1016/j.diabres.2010.05.022Get rights and content

Abstract

The cardiorenal syndrome in patients with diabetes mellitus represents a systemic condition that affects both the cardiovascular and renal systems. Diabetes is a well established risk factor for cardiovascular disease (CVD), and a significant proportion of diabetic patients go on to develop clinically significant nephropathy. In the diabetic state the kidney is involved by progressive sclerosis/fibrosis and proteinuria, due most likely to overactivity of the transforming growth factor-beta system and, to some extent, the vascular endothelial growth factor system, respectively. The pathogenesis of CVD in diabetes is multifactorial, involving hemodynamic forces, humoral/metabolic factors, and oxidative stress. Additionally, it has been suggested that endothelial dysfunction may lead to simultaneous development and progression of renal and cardiac pathology in diabetes. The risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 and type 2 diabetes mellitus whereas benefit to the cardiovascular system is less clear. However, intensified intervention involving other CVD risk factors like hypertension and dyslepidemia and interception of the rennin-angiotensin-aldosterone system in patients with type 2 diabetes have been shown to be associated with significant reduction in the risk for renal disease progression that was paralleled by a significant reduction in cardiovascular disease burden.

Introduction

The appreciation of the interaction between heart and kidney during dysfunction of each or both organs has major clinical implications for the practical prevention and treatment strategies in a spectrum of acute and chronic situations. Such interactions represent the pathophysiological basis for an emerging clinical entity called the cardiorenal syndrome (CRS). Recently, the definition of CRS was expanded to better reflect the dual and reciprocal heart–kidney interactions [1]. The new definition was restated as ‘a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ’. To further stress the complicated interactions between these organ systems, a classification was introduced with four types in which the etymology reflects the presumptive primary and secondary abnormality and their chronologies and a fifth subtype that includes systemic conditions that cause both cardiac and renal dysfunction, with diabetes mellitus being the typical example of the latter subtype (Table 1). There is limited systematic information on type 5 CRS, although there is an appreciation that as more organs fail in this setting, mortality increases. There is limited insight, also, into how combined renal and cardiovascular failure may differentially affect such an outcome. It is clear, however, that diabetes can affect both organs simultaneously and that the disease induced in one can affect the other and vice versa (Fig. 1).

Section snippets

Diabetes and the kidney

According to a recent report by the International Diabetes Federation diabetes currently affects nearly 250 million people worldwide and this number is expected to reach 380 million by year 2025 [2]. The high prevalence of diabetes will further burden the health care system by its long-term complications particularly the macrovascular and the microvascular associated diseases. Diabetic nephropathy is the most common chronic kidney disease in the industrialized world and is the leading cause of

Diabetes and the heart

In addition to increased morbidity, diabetic patients suffer high mortality rate, with cardiovascular disease (CVD) being the major cause of death accounting for some 50% of all diabetes fatalities [2]. Identification of diabetes as a high-risk condition for macrovascular diseases is based on the fact that there is a high long-term risk for developing CVD. Various studies showed that the risk for cardiovascular events increase two to fourfold in patients with type 2 diabetes compared to

Micro- and macroalbuminuria and risk of CVD in diabetes

Microalbuminuria is a common complication of diabetes and has been long known to be a strong predictor of subsequent development of overt nephropathy. Of patients with type 1 diabetes 50% of childhood onset and 35% of adult onset will develop microalbuminuria after almost 20 years [10], [11]. In addition, 15% of patients in both groups will have macroalbuminuria by then. In newly diagnosed type 2 diabetes, 28% of patients will develop microalbuminuria and 7% will have macroalbuminuria after 15

CKD and CVD in diabetes

Various studies have shown that CVD risk factors, CVD surrogates, and clinical CVD are more prevalent in patients with reduced glomerular filtration rate (GFR). For example, the HOPE study, the Cardiovascular Health Study (CHS), the Hypertension Optimal Treatment (HOT) Study, the Framingham and Framingham Offspring Studies, and the Atherosclerosis Risk In Communities (ARIC) Study, have shown that higher systolic blood pressure and total cholesterol are associated with decreased GFR. In

Pathogenesis

The mechanisms by which the diabetic milieu causes kidney injury have been extensively studied. The associated hyperglycemia, glycated proteins, and oxidative stress cause hemodynamic stress and activate metabolic pathways that induce a group of growth factors in the kidney. It is widely believed that the fibrogenic cytokine transforming growth factor-beta (TGF-β) and the vascular endothelial growth factor (VEGF) are implicated in the development of the cardinal features of diabetic

Treatment

Both microvascular and macrovascular complications contribute to the increased morbidity and mortality in diabetes. Although microvascular complications predispose to premature mortality, CVD is the leading cause of death in diabetes. In addition to the defined role of hyperglycemia, other modifiable risk factors for late complications in patients with diabetes, including hypertension and dyslipidemia, increase the risk of a poor outcome. Results from randomized controlled trials have

Conclusions

Cardiorenal syndrome in diabetes refers to pathophysiologic conditions where the heart and the kidneys are simultaneously affected by a systemic disorder leading to injury and/or dysfunction of both organ systems. The presence of nephropathy in diabetic patients appears to be a significant independent contributing factor in the tally of overall risks for and outcomes from vascular complications and mortality. As such, the pathogenesis of the accelerated course of CVD in diabetic patients with

Conflict of interest

None.

References (69)

  • M.M. O’Brien et al.

    Modest serum creatinine elevation affects adverse outcome after general surgery

    Kidney Int

    (2002)
  • R.N. Foley et al.

    Clinical and echocardiographic disease in patients starting end-stage renal disease therapy

    Kidney Int

    (1995)
  • R.P. Donahue et al.

    The influence of sex and diabetes mellitus on survival following acute myocardial infarction: a community-wide perspective

    J Clin Epidemiol

    (1993)
  • P.A. McCullough et al.

    Benefits of aspirin and betablockade after myocardial infarction in patients with chronic kidney disease

    Am Heart J

    (2002)
  • T.M. Keough-Ryan et al.

    Outcomes of acute coronary syndrome in a large Canadian cohort: impact of chronic renal insufficiency, cardiac interventions, and anemia

    Am J Kidney Dis

    (2005)
  • D.E. Forman et al.

    Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure

    J Am Coll Cardiol

    (2004)
  • K. Sonoki et al.

    Glycoxidized low-density lipoprotein enhances monocyte chemoattractant protein-1 mRNA expression in human umbilical vein endothelial cells: relation to lysophosphatidylcholine contents and inhibition by nitric oxide donor

    Metabolism

    (2002)
  • M.V. Shestakova et al.

    Role of endothelial dysfunction in the development of cardiorenal syndrome in patients with type 1 diabetes mellitus

    Diabetes Res Clin Pract

    (2005)
  • C.A. Stehouwer et al.

    Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus

    Lancet

    (1992)
  • L. Hansson et al.

    Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial

    Lancet

    (1998)
  • C. Ronco et al.

    Cardiorenal and renocardiac syndromes: the need for a comprehensive classification and consensus

    Nat Clin Pract Nephrol

    (2008)
  • R. Sicree

    Diabetes Atlas

    (2008)
  • United States Renal Data System, USRDS. Annual data report. Bethesda, MD, 2007. http://www.kidney.niddk.nih.gov...
  • M.E. Molitch et al.

    Nephropathy in diabetes

    Diabetes Care

    (2004)
  • J.B. Buse et al.

    Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association

    Circulation

    (2007)
  • J.M.M. Evans et al.

    Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies

    BMJ

    (2002)
  • L.A. Simons et al.

    Diabetes and coronary heart disease

    N Engl J Med

    (1998)
  • A. Avogaro et al.

    Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location

    Diabetes Care

    (2007)
  • R. Amin et al.

    Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study

    BMJ

    (2008)
  • P. Hovind et al.

    Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study

    BMJ

    (2004)
  • H.L. Hillege et al.

    Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

    Circulation

    (2002)
  • P. Rossing et al.

    Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study

    BMJ

    (1996)
  • S.F. Dinneen et al.

    The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus: a systematic overview of the literature

    Arch Intern Med

    (1997)
  • H.C. Gerstein et al.

    for the HOPE study investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals

    JAMA

    (2001)
  • Cited by (34)

    • Different profiles of advanced heart failure among patients with and without diabetes mellitus. Findings from the EPICTER study

      2022, European Journal of Internal Medicine
      Citation Excerpt :

      Patients with advanced HF and DM had the highest rate of CKD. In an advanced diabetic state, progressive fibrosis and proteinuria worsen as a result of many factors related to endothelial dysfunction [22], which are also implicated in the progression of heart disease. Therefore, this association could be useful for determining advanced disease in these patients.

    • Hypercoagulability and cardiovascular disease in diabetic nephropathy

      2013, Clinica Chimica Acta
      Citation Excerpt :

      Diabetic patients have a 2- to 4-fold increased risk of heart disease and stroke than people without diabetes. Cardiovascular complications are the leading cause of morbidity and mortality among diabetic patients, accounting for some 50% of all diabetes fatalities [2,3]. Diabetic nephropathy is the most common cause of end stage renal disease (ESRD), contributing to approximately 45% of new cases, and is an independent risk factor for cardiovascular disease [3].

    • Over-nutrition and metabolic cardiomyopathy

      2012, Metabolism: Clinical and Experimental
      Citation Excerpt :

      In recent years, a lot of attention has been focused on the cardiorenal metabolic syndrome as a pre-existing condition to the development of diabetes and cardiovascular disease [16]. The cardiorenal metabolic syndrome can be summarized as a loosely defined group of risk factors, such as insulin resistance, dyslipidemia, high blood pressure and the main feature of central or abdominal obesity, that predispose to well-characterized medical conditions such as diabetes and cardiovascular disease [16,17]. The central feature of abdominal obesity may predispose to the development of the other characteristics of the cardiorenal metabolic syndrome, which may develop later [16–18].

    View all citing articles on Scopus
    View full text