Pathophysiology of Diabetic Nephropathy

Diabetic nephropathy is a devastating chronic microvascular diabetic complication, which represents the major cause of end stage renal failure today. The mechanisms leading to the development and progression of this most feared diabetic complication are mainly poor metabolic and haemodynamic control. We should direct all our efforts into achieving good glycaemic and blood pressure control. Prevention of diabetic nephropathy is our only tool to beat this disease currently.

The prevention and management of diabetes and its renal complication is a huge global challenge: the global number of diabetic patients is believed to be around 180 million and is set to increase to 350-400 million in the next two decades. Patients with type 2 diabetes will account for 90% of all cases, and we expect an increase of new cases of diabetic nephropathy (DN) within the current decade, given the predicted 30-40% prevalence of renal disease in the diabetic population.

The concomitant increase in associated cardiovascular mortality and morbidity (nearly 40 times higher in patients with nephropathy than in patients without nephropathy), and end stage renal disease (ESRD) will result in significant social and economic impact, particularly in the developing world; this is particularly so for populations of Afro-Caribbean and Asian origin, who are known to have a significantly higher risk for renal disease.


Endothelial Changes in Early Disease

The endothelium plays a central role in the pathophysiology of diabetic glomerulopathy. Endothelial dysfunction precedes altered vascular permeability and albuminuria. Markers of endothelial dysfunction such as soluble intercellular and vascular adhesion molecules, Von Willebrand Factor, and altered microvascular reactivity can be observed in patients with diabetes before any clinical manifestation of DN [1].

In the early phase of diabetic kidney disease an increase in the expression of glomerular vascular endothelial growth factor-A (VEGF-A), paralleled by dysregulation of other vascular growth factors such as angiopoietins-1/2, is paralleled by an increase in glomerular capillary length and diameter, increase in glomerular volume, and increased vascular permeability.

In this early phase, the prominent clinical manifestation of diabetic renal disease is characterised by an elevation of renal plasma flow and by an increase in glomerular filtration rate (GFR). Studies on filtration fraction, an indirect measure of glomerular capillary pressure, have shown that, in patients with diabetes, glomerular capillary pressure is elevated and may synergise with the metabolic perturbation in the pathophysiology of the disease. Indeed many studies in experimental models of diabetes and hypertension and in the clinical setting have described an important synergistic effect of metabolic (hyperglycaemia) and haemodynamic (glomerular hypertension) perturbations in the development and progression of DN [2].

In the glomerulus hyperglycemia is paralleled by local upregulation of angiotensin-2 that, by reducing afferent and, to a lower degree, efferent arteriolar tone, alters glomerular capillary auto-regulation. In parallel to angiotensin-2, other factors, such as nitric oxide (NO) and transforming growth factor 1 (TGFβ1) have been implicated in the pathophysiology of glomerular capillary dysregulation.

The resulting increase in glomerular pressure and the consequent disproportionate transmission of the systemic pressure to the glomerular circulation synergise with the raised glucose levels in mediating glomerular damage.

Endothelial Changes in Later Disease

In subsequent more advanced stages of the disease an increase in oxidative stress is the basis of activation of different cellular pathways leading to an increase in inflammation, diffuse inflammatory cell infiltrates, increased extracellular matrix deposition, altered angiogenesis and progressive tissue damage. Typically a progressive accumulation of extracellular matrix is observed in the glomerular and tubular compartment resulting respectively in diffuse glomerulosclerosis and fibrosis of the tubular interstitium and tubular damage [3].

Changes in Other Components of the Glomerular Filtration Barrier

Parallel changes occur in the glomerular filtration barrier with glomerular endothelial cell injury, with loss of glycocalyx and cell apoptosis. The glycocalyx is an aqueous extracellular layer that covers the glomerular capillary lumen side, and plays an important role in glomerular vascular function and permeability [4]. Further thickening of the glomerular basement membrane and podocyte foot process effacement and loss of podocytes in the urine are other mechanisms that characterise the alteration of the permselective properties of the glomerular filtration barrier and disease progression. Podocyte detachment has been positively correlated with urinary albumin excretion and increasing podocyte detachment is associated with decreased permselectivity of the glomerulus and progressive albuminuria.


The relentless worsening of the anatomo-structural parameters in the glomerulus and the tubular compartment is paralleled by a clinical scenario that has been historically depicted as progression through different stages of albuminuria: normo to microalbuminuria, micro to macroalbuminuria, and macroalbuminuria to renal failure.

Although the terms normoalbuminuria (albumin:creatinine ratio <3.5 mg/mmol), microalbuminuria (albumin:creatinine ratio >3.5, <30 mg/mmol) and macroalbuminuria (clinical albuminuria)(albumin:creatinine ratio >30 mg/mmol) describe different categories of urinary albumin excretion rate it is important to remember that they are part of a continuum in the relationship between albumin excretion and renal and cardiovascular risk [5].

Of note recently the Kidney Disease Improving Global Outcomes Initiative (KDIGO) has proposed that a better estimate of patients’ expected outcomes in terms of renal and cardiovascular risk is obtained by combining albuminuria and GFR.

Further the classification of albuminuria has been revisited and 3 categories have been proposed: normal to mildly increased (normoalbuminuria or high-normal albuminuria), moderately increased (microalbuminuria) and severely increased (macroalbuminuria).

It is widely accepted that the rise in albuminuria reflects an increased transglomerular flux of albumin as a consequence of an increased transglomerular pressure gradient and damage of the glomerular filtration barrier.

The yearly progression from normoalbuminuria to microalbuminuria is approximately 2-4% for patients with type 1 or type 2 diabetes; factors favouring this progression include poor glycaemic control, elevated blood pressure and presence of retinopathy, smoking and dyslipidaemia.

In these patients GFR gradually declines in a linear fashion at variable rates (average 3.5-4.5 ml/min/year) depending on control of promoters of progression such as metabolic, and haemodynamic control, degree of albuminuria, and importantly individual response to treatment.

Although variations in fall in GFR exist between patients, in the last few decades with the introduction of inhibitors of the renin angiotensin aldosterone system (RAAS), and more intense glycaemic and hypertension treatment, the time from the onset of clinical albuminuria to death has increased from 7 to 21 years. Despite this, a considerable number of patients (45%) still reach ESRD or die before reaching ESRD (10%).

The decrease in annual incidence rate for diabetes-related ESRD in the last 15-20 years where treatments of risk factors (mostly hypertension) have significantly contributed to this reduction has been significant; nevertheless the pandemic of type 2 diabetes should be considered as a likely determinant for the predicted future absolute increase in number of patients with diabetes-related ESRD.

Future better understanding of the pathophysiology of DN will hopefully open novel drug development for this chronic diabetic vascular complication.


  1. ^ Karalliedde, J., and Gnudi, L. 2011. Endothelial factors and diabetic nephropathy. Diabetes Care 34 Suppl 2:S291-296.

  2. ^ Gnudi, L., Thomas, S.M., and Viberti, G. 2007. Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism. J.Am.Soc.Nephrol. 18:2226-2232.

  3. ^ Gnudi, L. 2012. Cellular and molecular mechanisms of diabetic glomerulopathy. Nephrol Dial Transplant 27:2642-2649.

  4. ^ Satchell, S.C., and Tooke, J.E. 2008. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 51:714-725.

  5. ^ Karalliedde, J., and Viberti, G. 2010. Proteinuria in diabetes: bystander or pathway to cardiorenal disease? J Am Soc Nephrol 21:2020-2027.


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