Diabetic Nephropathy - Pathology

Microangiopathy - updated: 15 March 2008

The changing epidemiology of diabetic microangiopathy in type 1 diabetes

Diabetologia. 2005 Aug;48(8):1439-44. Epub 2005 Jun 29

Rossing P.

Diabetic microvascular complications in the kidney and the eye are a major burden for diabetic patients due to increased morbidity and mortality. Furthermore, diabetic nephropathy is the leading cause of end-stage renal disease and diabetic retinopathy is the leading cause of blindness in younger patients, representing a major public health concern. During the past two decades beneficial effects of, in particular, aggressive antihypertensive control and strict glycaemic control have been demonstrated in randomised controlled clinical trials. Technological improvements in diabetes care have made good metabolic control easier to achieve. Has this led to an improved prognosis? In observational studies from dedicated centres, a decrease from 47 to 13% has been reported in the incidence of proliferative diabetic retinopathy after 20-25 years of diabetes, and the incidence of overt diabetic nephropathy after 20 years has decreased from 28 to 5.8%. Even functional and morphological remission of diabetic nephropathy has been reported. Despite this, recent population-based studies have failed to demonstrate a decrease in the incidence of blindness caused by diabetes, and the incidence of end-stage renal disease has progressively increased. This may, in part, be the result of a combination of increasing numbers of diabetic patients and a lag phase between improvement in management and a decline in end-stage complications. It is of concern, however, that the results from specialised centres may not apply to routine diabetes care. It is, therefore, mandatory that the beneficial effects of pharmacological and non-pharmacological interventions demonstrated in clinical trials and recommended by treatment guidelines are translated into clinical practice to ensure a widespread improvement in prognosis.

Publication Types:

• Review

Preventing microvascular diabetic complications in children and adolescents: looking beyond glycaemic control

Expert Opin Pharmacother. 2003 Apr;4(4):525-32

Verrotti A, Trotta D, Salladini C, Laura M, Chiarelli F.

Type 1 diabetes mellitus is associated with the development of micro- and macrovascular disease, and diabetic angiopathy in children and adolescents. It is represented mainly by microangiopathy, characterised by structural changes in the eye, renal glomeruli and peripheral nerves. The pathogenesis of the vascular complications of diabetes is controversial, but without any doubt, endothelial dysfunction play an important role in the pathogenesis of glomerulosclerosis and atherosclerosis. Preventive strategies for these three major complications are discussed in this review. Appropriate surveillance for the earliest evidence of microvascular disease should begin at the onset of puberty, and after 3 - 5 years of diabetes. Therapeutic interventions, particularly excellent metabolic control, may be almost effective in preventing complication onset, or significantly retarding the rate of progression.

Publication Types:

• Review

Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.

Hypertension. 2001 Feb;37(2 Part 2):744-8

Goligorsky MS, Chen J, Brodsky S.

Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications. Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction. Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention.

Publication Types:

• Review

Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy

Int J Clin Pharmacol Res. 2003;23(4):129-34

Yamagishi S, Takeuchi M, Inagaki Y, Nakamura K, Imaizumi T.

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic derangements. In this review, we discuss the molecular mechanisms of diabetic retinopathy and nephropathy, especially focusing on advanced glycation end products (AGEs) and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in diseases, including diabetic microangiopathy, will be discussed in the next review article.

Publication Types:

• Review

Diabetic microangiopathy: pathology and current understanding of its pathogenesis

Verh Dtsch Ges Pathol. 2002;86:91-100

Yagihashi S, Wada R, Yamagishi S.

Recent drastic increase in diabetic population poses serious problems in both health sciences and socioeconomic conditions. The most important issue in the clinical practice of diabetic patients is the treatment and care of chronic complications. It is not fully clear, however, as to the pathophysiology of diabetic microangiopathy and its pathogenesis. Recent studies on microvessel pathology in diabetic patients and molecular analyses on the diabetic animal models disclosed novel features of the dynamic changes of specific organ pathology affected by diabetes and factors involved in its pathogenesis. Under long-term hyperglycemia, early stimuli elicit adaptive reactions of tissues showing acute inflammatory processes of vessel walls and then late irreversible and regressive changes of microangiopathy. Consequently, remodeling of vascular cells and excessive matrix production are cardinal feature. The precise mechanisms of how these tissue changes occur remain speculative; increased polyol pathway, excessive non-enzymatic glycation, increased protein kinase C activity, as well as oxidative stress are all interrelated for the cause and development of the microangiopathy.

Publication Types:

• Review

Approaches to prevention of cardiovascular complications and events in diabetes mellitus

Drugs. 2007;67(7):997-1026

Coccheri S.

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years.Diabetes is an important component of the complex of 'common' cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness.In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes. Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those 'common' to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases 'unique' to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE. Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy.In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.Recent studies have shown that some GAG compounds are able to reduce micro- and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients. Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status. Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.

Publication Types:

• Review

Publication Types:

• Review