Diabetic Nephropathy - Pathology

Proteinuria - updated: 15 March 2008

Cellular and molecular mechanisms of proteinuria in diabetic nephropathy

Nephron Physiol. 2007;106(2):p26-31. Epub 2007 Jun 6

Wolf G, Ziyadeh FN.

One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman's space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy--which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement--correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-beta1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman's capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.

Publication Types:

• Review

Predicting the development of diabetic nephropathy and its progression

Adv Chronic Kidney Dis. 2005 Apr;12(2):202-11

William J, Hogan D, Batlle D.

Diabetes remains the number one cause of end-stage renal disease worldwide. Only about one third of diabetic patients develop nephropathy, and the risk appears to be, in part, genetically determined. In this article, we review clinical and genetic markers for the development and progression of diabetic nephropathy. Microalbuminuria remains the best available predictor of the subsequent development of nephropathy, even though in recent years it has become clear that less than 50% of individuals with type 1 diabetes progress to overt proteinuria over a period of less than 10 years. It is of great interest for early recognition of risk of nephropathy that small elevations in nighttime blood pressure predict microalbuminuria in type 1 diabetes. Genetic markers for diabetic nephropathy have not been conclusively identified. The occurrence of renal events in diabetic patients, however, appears to be influenced by the angiotensin-converting enzyme (ACE) genotype, with a dominant deleterious effect of the D allele (D/D or I/D) versus I/I genotype. Some patients with the DD genotype also appear less susceptible to the renoprotective effects of conventional doses of ACE inhibitors, suggesting that ACE genotyping might be useful in selecting those patients that could benefit from higher doses of ACE inhibitors and more aggressive treatment to prevent or delay disease progression.

Publication Types:

• Review

Proteinuria and microalbuminuria in adults: significance, evaluation, and treatment

South Med J. 2004 Oct;97(10):969-79

Venkat KK.

This paper reviews current concepts regarding the pathophysiology, diagnostic evaluation, and treatment of microalbuminuria and proteinuria in adults. Microalbuminuria (in diabetics) and proteinuria are early markers for potentially serious renal disease, and are associated with increased risk of atherosclerotic cardiovascular disease. Proteinuria also contributes to renal scarring, and accelerates the progression of chronic kidney disease to end-stage renal failure. Screening of diabetics for microalbuminuria, and the initial workup of proteinuria, should occur in the primary care setting. Reduction of microalbuminuria in diabetics may retard its progression to overt diabetic nephropathy. Therapy of renal diseases should aim for optimal blood pressure control and the maximum possible reduction in urinary protein excretion. Angiotensin-converting enzyme inhibitor (ACE-I) and/or angiotensin-receptor blocker (ARB) therapy is the most effective measure to achieve this. These drugs also provide protection against the cardiovascular problems that are highly prevalent in this patient population.

Publication Types:

• Review

Diabetes monitoring – albuminuria - Frequently asked questions

Patrick J Phillips MBBS, MA(Oxon), FRACP, MRACMA, GradDipHealth Econ(UNE), is Senior Director, Department of Endocrinology, The Queen Elizabeth Hospital, South Australia.

George Phillipov BSc, MSc, PhD, is Research Laboratory Director, Osteoporosis Centre, The Queen Elizabeth Hospital, Woodville, South Australia.

I am treating this man’s blood glucose, blood pressure and blood fats already. Why check for microalbuminuria if it won’t change my management? Detecting microalbuniuria is important for two reasons. The onset of microalbuminuria marks a major increase in the risk of morbidity and mortality (Figure 1). Microalbuminuria does not indicate early renal damage, it is just the earliest indicator we have. By the time microalbuminuria occurs renal biopsy would show widespread glomerular damage. Moreover, just as the endothelium of the glomerular has been so significantly damaged that it now ‘leaks’ albumin, so the endothelium of many other vascular beds is disrupted.

Publication Types:

• Review