Diabetic Nephropathy

1. Overview
2. Pathological Changes
3. Clinical Signs and Symptoms
4. Risk Factors and Primary Prevention
5. Management
6. Quiz

• In adults, diabetic nephropathy is the most common secondary cause of nephrotic syndrome (heavy protein loss in the urine, with a low blood albumin and oedema). A secondary cause is a disease outside the kidney, here diabetes.
• It is a serious condition that develops in around 30-40% of people with diabetes. Only a minority of them progress to kidney failure, and modern treatment slows progression.
• Pathological changes to the glomerulus are classically taught as a step-wise progression, matched by a step-wise progression of signs and symptoms, although not every patient follows the same sequence.
• Management is based upon primary prevention. If this fails, blocking the renin-angiotensin-aldosterone system (RAAS, a hormone system that raises blood pressure) is an important part of delaying progression of the disease. In type 2 diabetes, NICE also recommends an SGLT-2 inhibitor (a tablet that makes the kidneys pass more glucose into the urine).

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

The following changes describe the classic teaching model of diabetic nephropathy, listed roughly in the order in which they classically appear. Functional and structural changes can overlap, and individuals do not all progress through a fixed sequence:

1. Hyperfiltration (a raised filtration rate) and capillary hypertension (raised pressure in the glomerular capillaries): early haemodynamic changes (changes in blood flow and pressure). They can occur before overt proteinuria (protein in the urine) or any fall in kidney function, but they do not always come before the structural changes listed below.
2. Glomerular basement membrane (GBM) thickening: the GBM is the middle layer of the glomerular filter, between the capillary lining and the podocytes
3. Mesangial expansion: the mesangium is the central stalk of the glomerulus that supports the capillary loops. It is made of mesangial cells (smooth muscle-like cells) and their matrix.
4. Podocyte injury: podocytes are the cells that wrap around the glomerular capillaries and form the outer layer of the filter
5. Glomerular sclerosis (scarring of the glomeruli) and arteriosclerosis (thickening and hardening of the arteriole walls)

In diabetes, the high blood glucose means more glucose is filtered at the glomerulus. In the proximal tubule, glucose is reabsorbed together with sodium by sodium-glucose co-transporters (mainly SGLT-2). The extra filtered glucose therefore drives increased reabsorption of glucose and sodium chloride (NaCl) in the proximal tubule.

This means less NaCl is left in the fluid that reaches the macula densa (sensor cells in the wall of the distal tubule). The decreased delivery of NaCl distally reduces tubuloglomerular feedback, the signal that normally constricts the afferent arteriole. The result is afferent arteriolar vasodilation (the afferent arteriole carries blood into the glomerulus). This vasodilation is compounded by hyperglycaemia (high blood glucose) and high blood amino acid levels. The efferent arteriole (which carries blood out of the glomerulus) vasoconstricts due to a high local level of angiotensin II (a hormone that constricts blood vessels). 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. The filter also develops some enlarged pores, which let larger proteins leak into the urine. Podocytes are damaged as well, and injured podocytes are thought to disturb the normal upkeep of the GBM. Over time, this causes glomerulosclerosis (scarring of the glomeruli) and hyaline deposition (a build-up of glassy protein material) in arterioles, resulting in arteriosclerosis.

Clinical Signs and Symptoms

Clinical findings in diabetic nephropathy are often described using a classic sequence. In practice, albuminuria (albumin in the urine) and kidney function change in different ways in different people, and the findings do not match fixed stages of structural damage in every patient.

Hyperfiltration may cause an early increase in GFR. This is a change in function, so it does not show that the renal histology (the kidney tissue seen under a microscope) is normal. GBM thickening and mesangial expansion can develop during a clinically silent period before albuminuria becomes evident.

Moderately increased albuminuria (a urine albumin:creatinine ratio, or ACR, of 3 to 30 mg/mmol), traditionally called microalbuminuria, is an early clinical marker in the classic course of diabetic nephropathy. This amount of albumin is too small for a standard urine dipstick to detect, so it is found with the ACR test, which NICE advises doing regularly in people with diabetes. Structural lesions (areas of damaged tissue) may already be present when it is detected. In the classic course, the sustained fall in GFR comes later, but GFR should still be measured rather than assumed to be normal. Albuminuria may regress or progress, and a reduction in albumin excretion does not by itself demonstrate reversal of structural kidney damage. Follow both albuminuria and kidney function over time.

The next sign is overt proteinuria (severely increased albuminuria, an ACR over 30 mg/mmol). This can be detected on a simple urinalysis dipstick (a chemical test strip dipped into a urine sample), although NICE advises using the ACR to detect and monitor it. At this stage, the GFR falls in a linear pattern. Before modern treatment, this was thought to lead to an inevitable decline to ESRD in 3-7 years. The damage is usually not reversible, but treatment can slow its progression. This stage is associated with worsening systemic hypertension and microvascular changes (changes in the small blood vessels, such as arteriosclerosis), which cause tissue ischaemia.

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