Diabetic Nephropathy

Core

Overview

Diabetic nephropathy is the commonest cause of nephrotic syndrome and is a glomerulopathy NOT a glomerulonephritis (meaning there is no inflammation of the glomerulus). It is the commonest cause of end-stage renal disease (ESRD), and it is historically quoted that 30-40% of all types of diabetics will eventually develop ESRD (source).

Pathological Changes

There are five pathological changes that occur sequentially:

1. Hyperfiltration and capillary hypertension - this happens before all other changes.
2. Glomerular basement membrane (GBM) thickening
3. Mesangial expansion - the mesangium is the space which is continuous with the smooth muscle of the arterioles and is situated between the capillaries.
4. Podocyte injury
5. Glomerular sclerosis and arteriosclerosis

In diabetes, there is increased glucose and sodium chloride (NaCl) filtration at the glomerulus due to the higher serum levels of these molecules in diabetics. This means there is increased reabsorption of glucose and NaCl.

The decreased delivery of NaCl distally to the macula densa increases feedback which contributes to afferent arteriolar vasodilation, this vasodilation is compounded by hyperglycaemia and high blood amino acid levels. The efferent arteriole vasoconstricts due to high local Angiotensin II level. The vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole leads to high glomerular capillary pressure and thus the Glomerular Filtration Rate (GFR) is initially increased.

The high intraglomerular pressure leads to mesangial expansion and GBM thickening which increases the pore size in the GBM. This in turn causes damage to podocytes. Over time, this causes glomerulosclerosis and hyaline deposition in arterioles resulting in arteriosclerosis.

Clinical Signs and Symptoms

There are a number of clinical signs and symptoms associated with diabetic nephropathy. Again, these occur sequentially and are related to the step-wise changes to the glomerulus.

Increased GFR due to hyperfiltration and hypertrophy is the first clinical sign and is associated with no change in histology. This is followed by a latent stage of the disease in which the GBM thickens and mesangium expands.

Microalbuminuria (moderately increased albuminuria) is usually the first clinical sign detected (assuming the patient is not having their GFR routinely monitored). This is associated with continuing mesangial expansion and sclerosis, increasing GBM thickening, and podocyte damage. The GFR at this stage has lowered from its increased state from the hyperfiltration and is now in the normal range. This is because the mesangial expansion and sclerosis lead to reduced surface area for filtration. The damage is potentially reversible at this stage.

The next sign is overt proteinuria (severely increased albuminuria) this can be detected on a simple urinalysis dipstick. At this stage, the GFR falls in a linear pattern and was previously associated with an inevitable decline to ESRD in 3-7 years, but now while it is still not reversible, progression can be slowed. This is associated with worsening systemic hypertension and microvascular changes (arteriosclerosis) which causes tissue ischaemia.

Risk Factors and Primary Prevention

Not everyone with diabetes will develop diabetic nephropathy, but certain risk factors can increase the chances:

• Genetic susceptibility - a family history of diabetic nephropathy in a first degree relative increases risk in people with Type I Diabetes Mellitus, reflecting inherited susceptibility rather than a fixed probability.
• Hypertension
• Hyperglycaemia
• High level of hyperfiltration
• Increasing age
• Duration of diabetes
• Smoking

Primary prevention is defined as intervening before the negative health effects occur through control of modifiable (changeable) risk factors. Primary prevention of diabetic nephropathy is achieved through tight blood glucose and blood pressure control. There is also some evidence to suggest that SGLT-2 inhibitors, smoking cessation, and statin therapy can help.

Tight glycaemic control through multiple insulin injections or insulin pumps can lead to near normal blood glucose. This can reverse the initial hyperfiltration and delay microalbuminuria. If microalbuminuria has developed, tight glycaemic control can reduce it. Glycaemic control does not slow GFR loss once overt proteinuria develops.

Management

If primary prevention fails and diabetic nephropathy develops, management is aimed at controlling microalbuminuria and proteinuria.

This is achieved through the inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) through the use of ACE inhibitors or angiotensin receptor blockers. This reduces glomerular hyperfiltration primarily through vasodilation of the efferent arteriole. This reduces proteinuria and slows the progression of diabetic nephropathy. Because RAAS inhibition can increase the risk of hyperkalaemia and an initial fall in eGFR, treatment should be used with appropriate monitoring, particularly in more advanced chronic kidney disease.

The inhibition of RAAS is just one part of a multi-faceted therapeutic approach. It is combined with tight blood pressure control (under 130/80 mmHg), statin therapy, moderate protein intake, tight blood glucose control, and cardiovascular risk management (exercise, diet modifications, and stopping smoking).

Edited by: Dr. Maddie Swannack

Reviewed by: Dr. Thomas Burnell

Quiz

Preview the Diabetic Nephropathy quiz