Evidence for a role of TGFp in diabetic kidney disease

In vitro, TGF-p modulates ECM production in glomerular mesangial and epithelial cells.160161 In addition, TGF-p inhibits the synthesis of collagenases and stimulates the production of metalloproteinase inhibitors, an effect which could lead to reduced degradation of ECM and hence ECM accumulation.162,163 Furthermore, high glucose concentrations increase TGF-p1 mRNA expression in renal cells,157,159 and stimulate TGF-p mRNA expression and bioactivity, cellular hypertrophy, and collagen...

Preface

Over the past half-century, it has become abundantly clear that one of the major medical problems facing the modern world is diabetes mellitus. This systemic disease, with a plethora of complications and comorbid conditions, is a major cause of mortality and morbidity and is associated with a large economic burden on the patients themselves, their families and the health-care systems of most countries. Diabetic nephropathy is a major complication of diabetes and is today one of the major causes...

Natural History Of Dn

The concept of the 'natural' history of DN implies the existence of a process leading to progressive renal damage, which eventually reaches ESRD. However, longitudinal studies of DN in patients with type 1 diabetes over the last 30 years strongly suggest that there has been an amelioration of the rate of progression of DN. Several studies have shown that the rate of progression of both early and late nephropathy in patients with type 1 diabetes and to a lesser extent in type 2 diabetes can be...

Predictive Value Of Aer Below The Microalbuminuric Range

A longitudinal study over 5 years was the first to suggest that incipient nephropathy begins below the accepted cutoff value for microalbuminuria, The 95th percentile for AER in non-diabetic subjects was 7.6 g min. Type 1 diabetic subjects with baseline AER between 7.6 and 20 g min showed a higher rate of progression from normoalbuminuria to microalbuminuria than type 1 diabetic subjects with baseline AER of lt 7.6 g min.73 Three recent studies have also suggested that DN may be predicted by...

Association Of Retinopathy With Nephropathy

Although clinically recognized diabetic retinopathy is more common than DN, it is likely that DN would be diagnosed more frequently if morphological criteria, based on renal biopsy, were used.22 In patients with type 1 diabetes, microalbuminuria has been shown to predict proliferative retinopathy,170 and early nephropathy has been shown to predict visionthreatening retinal disease.171 Patients with DN usually have diabetic retinopathy. Both complications share the risk factors of poor glycaemic...

Advanced glycation endproducts AGEs

Non-enzymatic glycation occurs through a series of biochemical reactions between glucose and other reactive carbonyl compounds, on the one hand, and proteins, lipids or nucleic acids, on the other hand Table 5.1 .4 Early formed and reversible products of these reactions are Schiff bases and Amadori products e.g., haemoglobin A1c . Further rearrangement and modification lead to the formation and accumulation of a heterogeneous group of AGEs, such as3,4 Nt- carboxvmethyl -lvsinc CML and...

Aldose Reductase And Diabetic Nephropathy

Aldose reductase is a key enzyme of the polyol pathway, involved in the metabolism of glucose and the NADPH-dependent reduction of a broad range of carbonyl compounds. In particular, the downstream accumulation of sorbitol and activation of the hexose kinase pathway have been implicated in the pathogenesis of a number of diabetic complications, including nephropathy.86,87 Recent studies have shown that polymorphisms in the aldose reductase gene may be associated with susceptibility to...

Contents

1 THE PATHOGENESIS AND CLINICAL DESCRIPTION OF DIABETIC NEPHROPATHY 2 i Type 2 diabetes description and epidemiology 6 2 ii Type 1 diabetes immunology, genetics and epidemiology 26 3 Diabetic nephropathy epidemiology and clinical description 44 George Jerums, Sianna Panagiotopoulos and Richard MacIsaac 4 Inherited susceptibility to diabetic nephropathy 75 5 Factors influencing the progression of diabetic nephropathy 93 Bieke F Schrijvers, An S De Vriese and Allan Flyvbjerg II THERAPEUTIC...

The Role Of Gender

Gender-specific differences in both the prevalence2829 and progression30 of diabetic nephropathy have also been found, with women being at significantly greater risk. There also appears to be a gender dimorphism in age of onset of nephropathy. This may be especially apparent in type 1 diabetes, where nephropathy generally develops after puberty but before menopause, after which many gender differences may be reduced. Nonetheless, recent studies have demonstrated an excess of diabetic...

Geographical variation

Diabetic Nephropathy Stages

A key epidemiological feature of type 1 diabetes is its impressive geographical variability. There is a 60fold difference between Finland, the country with the highest rate, and Japan, which has the lowest recorded rate of diabetes worldwide Figure 2 ii .2 . The highest reported incidence rates are in Finland and Sardinia approximately 30 100000 per year , with most other European, American and Australian populations having a moderate incidence rate 3-19 100000 per year . The lowest rates are...

Macroalbuminuria And Cardiovascular Disease

Although the prevalence of microalbuminuria is similar in type 1 and type 2 diabetes,64 the rate of progression to overt DN is slower in elderly Caucasian patients with type 2 diabetes, being of the order of 20 over a decade, compared with approximately 80 within a decade for patients with type 1 diabetes in the original studies published in the early 1980s.87 The cumulative risk of ESRD is also less in patients with type 2 diabetes, with one early study showing a cumulative risk of ESRD of 11...

Background

Nephropathy is a common complication of diabetes. However, unlike retinopathy, its occurrence is by no means inevitable. Only a subset of patients with diabetes may be susceptible to the development of diabetic renal disease. After 15 years of diabetes, 30-50 of patients with type 1 diabetes and around 50 of all patients with type 2 diabetes show evidence of clinical nephropathy.1,2 Subsequently, the prevalence of diabetic nephropathy declines, with additional cases falling to less than 0.5 per...

Stages Of Dn

The simplest classification of DN consists of three stages microalbuminuria incipient DN , lasting 5-15 years macroalbuminuria overt DN , lasting 5-10 years and ESRD, lasting 3-6 years without renal replacement therapy Figure 3.2 . Mogensen has suggested a five-stage classification, with two additional Figure 3.2 The natural history of DN in type 1 and type 2 diabetes. The three stages, normo-, micro- and macroalbuminuria, last 5-10 years. Note that a rise in blood pressure generally precedes...

Treatments targeting Dagpkc pathway

Recently, the available pharmacological compounds that inhibit PKC have been reviewed.98 Due to in vivo toxicity and non-specificity, in vivo studies have not been feasible with staurosporine and several of its indolocarbazole derivatives.98,99 The bisindolylmaleimide PKC inhibitors are less potent than staurosporine but show greater selectivity for PKC isoforms. As PKCp is shown to be preferentially activated in kidney in the diabetic state,89 one of the most promising isoform-selective...

Ethnic Variability In Diabetic Nephropathy

Figure 4.2 Increased prevalence of nephropathy in Polynesian patients with a family history of end-stage renal disease ESRD rather than diabetes. D ESRD people with a first-degree relative with ESRD and diabetes N ESRD people with a relative having non-diabetic ESRD D people with a relative with diabetes but no known nephropathy C people with no known relatives with either diabetes or nephropathy D-ESRD vs D, p 0.01, D vs C, p 0.2 . Adapted from Diabetic Medicine with permission.17 Figure 4.2...

References

Krolewski AS, Warram JH, Christlieb AR et al, The changing natural history of nephropathy in type I diabetes, Am J Med 1985 78 785-94. 2. Andersen AR, Christiansen JS, Andersen JK et al, Diabetic nephropathy in type 1 insulin-dependent diabetes an epidemiological study, Diabetologia 1983 25 496-501. 3. ADA, American Diabetes Association Clinical Practice Recommendations 2001, Diabetes Care 2001 24 Suppl 1 S69-72. 4. Fabre J, Balant LP, Dayer PG et al, The kidney in maturity onset diabetes...

Geography

The prevalence of type 2 diabetes varies enormously Table 2 i .1 Diagnostic criteria for diabetes mellitus and related stages of glycemia. glucose concentrations are expressed in mmol l mg dl . The 2-hr post-glucose valuees are those measured after a 75-g oral glucose load. The glucose concentrations differ according to whether they a are determined in venous or capillary samples, or measured in plasma or whole blood adapted from references 2 and 3 . glucose concentrations differ according to...

Hyperfiltration And Dn

Enlargement of the kidneys nephromegaly and increase in GFR hyperfiltration occur frequently in untreated patients with type 1 diabetes, and both can be normalized by insulin treatment.23 Patients with Table 3.3 Stages In diabetic renal disease modified from Mogensen .2 Stage Characterist Duabetes Duration AER g BP mmHg GER ml Treatment min effects Attenuated by strict glycaemic control attenuated, arrested or reversed by strict BP control based on RAS Faster progression with poor glycaemic...

Fabrice Bonnet

Division of Diabetes, Metabolism and Lipoproteins Department of Internal Medicine and Neurology Department of Medicine University of Melbourne Melbourne AUSTRALIA Gabriel Danovitch Kidney Transplant Program UCLA Medical Center UCLA School of Medicine Los Angeles, CA 90095 USA

Histology

The endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets of Langerhans, weighing approximately 1-1.5 g.12 p-Cells produce insulin and constitute about 70 of islet cells and the other predominant cell types are a glucagon-secreting , 5 somatostatin-secreting and PP pancreatic polypeptide-secreting .13 Autopsy studies identified a lymphocyte-rich inflammatory infiltrate in the islets of patients with early diabetes, and this was termed 'insulitis'.9,14...

Renal Disease

Several large population studies6,179 180 have established that substantial ethnic and racial differences exist in the incidence rates of ESRD attributable to type 2 diabetes Figure 3.5 .179 Even after accounting for the higher prevalence of type 2 diabetes in some populations, we find that variations in the incidence of diabetic ESRD still persist. This suggests that some ethnic groups have an inherent susceptibility to diabetic renal disease. High rates of diabetic ESRD have been reported in...