From the Guidelines
Hyperlipidaemia is a complication of nephrotic syndrome primarily due to increased hepatic lipoprotein synthesis and decreased lipid catabolism, as evidenced by the liver's response to protein loss and the resulting imbalance in lipid metabolism. In nephrotic syndrome, the kidneys leak large amounts of protein, particularly albumin, into the urine, leading to hypoalbuminaemia. The liver responds to this protein loss by increasing production of proteins, including lipoproteins such as very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), as noted in the kdigo 2021 clinical practice guideline for the management of glomerular diseases 1.
Pathophysiology of Hyperlipidaemia in Nephrotic Syndrome
The pathophysiology of hyperlipidaemia in nephrotic syndrome involves several key mechanisms:
- Increased hepatic lipoprotein synthesis: The liver increases production of lipoproteins, including VLDL and LDL, in response to protein loss.
- Decreased lipid catabolism: Reduced activity of lipoprotein lipase, an enzyme responsible for breaking down triglycerides, contributes to elevated lipid levels.
- Loss of regulatory proteins: Urinary loss of proteins, such as VLDL receptor proteins, impairs lipid metabolism.
- Dyslipidaemia: Elevated levels of total cholesterol, LDL cholesterol, and triglycerides, while HDL cholesterol may be normal or reduced.
Management of Hyperlipidaemia in Nephrotic Syndrome
According to the kdigo 2021 clinical practice guideline for the management of glomerular diseases 1, management of hyperlipidaemia in nephrotic syndrome may involve:
- Non-statin therapy, such as bile acid sequestrants, fibrates, nicotinic acid, ezetimibe, or PCSK9 inhibitors, in individuals who cannot tolerate statins or are at high risk of atherosclerotic cardiovascular disease (ASCVD).
- Lifestyle modifications, including a plant-based diet and avoidance of red meat, as a primary means of reducing mild to moderate hyperlipidemia.
- Regular assessment of fasting lipids and safety indicators to monitor adherence to treatment and potential side effects.
Key Considerations
The severity of hyperlipidaemia typically correlates with the degree of proteinuria and hypoalbuminaemia, and it usually improves when the underlying nephrotic syndrome is treated effectively. Reduced eGFR and albuminuria are independently associated with an elevated risk of ASCVD, highlighting the importance of managing hyperlipidaemia in patients with nephrotic syndrome 1.
From the Research
Hyperlipidaemia as a Complication of Nephrotic Syndrome
Hyperlipidaemia is a common complication of nephrotic syndrome, characterized by elevated levels of total plasma cholesterol and triglyceride levels, as well as increased levels of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol 2. The mechanisms underlying these abnormalities are multifactorial, involving both increased rates of lipoprotein synthesis and defective clearance and catabolism of circulating particles.
Causes of Hyperlipidaemia in Nephrotic Syndrome
The causes of hyperlipidaemia in nephrotic syndrome include:
- Increased synthesis of lipoproteins, partly due to proteinuria, hypoalbuminemia, and increased availability of mevalonate as a substrate for cholesterol synthesis 3
- Decreased clearance of lipoproteins, due to urinary loss of high-density lipoprotein (HDL) components and other liporegulatory factors, resulting in impaired clearance of cholesterol- and triglyceride-rich lipoproteins 3
- Changes in the expression and activities of key proteins involved in lipid and lipoprotein metabolism, including apoproteins A, B, C, and E, and enzymes such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase and fatty acid synthase 4
Consequences of Hyperlipidaemia in Nephrotic Syndrome
The consequences of hyperlipidaemia in nephrotic syndrome include:
- Increased risk of cardiovascular disease, due to the association between lipoprotein abnormalities and atherosclerosis 2, 5
- Accelerated renal injury, due to the potential of lipid abnormalities to exacerbate kidney damage 2
- Reduced body mass and impaired exercise capacity, due to changes in lipid metabolism that limit delivery of lipid fuel to muscles and adipose tissues 4
Treatment of Hyperlipidaemia in Nephrotic Syndrome
Treatment of hyperlipidaemia in nephrotic syndrome may involve lipid-lowering agents, such as statins, bile acid sequestrants, fibrates, and ezetimibe, as well as lipid apheresis 6. However, the need for such intervention and the potential long-term benefits of lipid-lowering therapy in patients with nephrotic syndrome require further study 2.