Question

How does diabetes mellitus lead to chronic renal failure? (pathophysiology) at a basic cellular level.

Answer 1

Diabetes mellitus, usually called diabetes, is a disease in which your body does not make enough insulin or cannot use normal amounts of insulin properly. Insulin is a hormone that regulates the amount of sugar in your blood. A high blood sugar level can cause problems in many parts of your body.

What does diabetes do to the kidneys?

The main job of the kidneys is to filter wastes and extra water out of your blood to make urine. Your kidneys also help control blood pressure and make hormones that your body needs to stay healthy.

With diabetes, the small blood vessels in the body are injured. When the blood vessels in the kidneys are injured, your kidneys cannot clean your blood properly. Your body will retain more water and salt than it should, which can result in weight gain and ankle swelling. You may have protein in your urine. Also, waste materials will build up in your blood.

Diabetes also may cause damage to nerves in your body. This can cause difficulty in emptying your bladder. The pressure resulting from your full bladder can back up and injure the kidneys. Also, if urine remains in your bladder for a long time, you can develop an infection from the rapid growth of bacteria in urine that has a high sugar level.

Pathophysiology

Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy.

First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins.

Second, thickening of the glomerular basement membrane (GBM) occurs.

Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli).
These different histologic patterns appear to have similar prognostic significance.

The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix.

Light microscopy findings show an increase in the solid spaces of the tuft, most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be observed within these areas. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules.

Immunofluorescence microscopy may reveal deposition of albumin, immunoglobulins, fibrin, and other plasma proteins along the GBM in a linear pattern, most likely as a result of exudation from the blood vessels, but this is not immunopathogenetic or diagnostic and does not imply an immunologic pathophysiology. The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis.

In advanced disease, the mesangial regions occupy a large proportion of the tuft, with prominent matrix content. Further, the basement membrane in the capillary walls (ie, the peripheral basement membrane) is thicker than normal.

The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral basement membrane and mesangium and matrix expressed as a fraction of appropriate spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or matrix/glomerulus).

The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).

In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing glomerular filtration rate [GFR]) generally develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature.

hypertension associated with obesity, metabolic syndrome, and diabetes may play an important role in the pathogenesis of diabetic nephropathy. Central obesity, metabolic syndrome, and diabetes lead to increased blood pressure.

Central obesity induces hypertension initially by increasing renal tubular reabsorption of sodium and causing a hypertensive shift of renal-pressure natriuresis through multiple mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as physical compression of the kidneys. Hypertension, along with increases in intraglomerular capillary pressure and the metabolic abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to accelerate renal injury.

Similar to obesity-associated glomerular hyperfiltration, renal vasodilation, increases in the glomerular filtration rate and intraglomerular capillary pressure, and increased blood pressure also are characteristics of diabetic nephropathy. Increased systolic blood pressure further exacerbates the disease progression to proteinuria and a decline in the glomerular filtration rate, leading to end-stage kidney disease.