From the Guidelines
Cholesterol and triglycerides (TG) are elevated in nephrotic syndrome primarily due to increased hepatic lipoprotein synthesis and decreased catabolism, as a result of the kidneys leaking protein, particularly albumin, triggering the liver to increase production of lipoproteins to maintain oncotic pressure. When the kidneys leak protein in nephrotic syndrome, the resulting hypoalbuminemia triggers the liver to increase production of lipoproteins as a compensatory mechanism to maintain oncotic pressure. Additionally, there is reduced clearance of lipoproteins due to urinary loss of enzymes like lipoprotein lipase and lecithin-cholesterol acyltransferase (LCAT), which normally help metabolize lipids, as noted in the context of chronic kidney disease and nephrotic syndrome 1. The loss of these regulatory proteins in the urine impairs the body's ability to break down lipids effectively. Furthermore, reduced oncotic pressure leads to enhanced hepatic synthesis of cholesterol and triglycerides. Hyperinsulinemia, which often accompanies nephrotic syndrome, also contributes to increased hepatic lipid production. This combination of increased synthesis and decreased catabolism results in the characteristic hyperlipidemia seen in nephrotic syndrome, with elevations in total cholesterol, LDL cholesterol, VLDL, and triglycerides, while HDL levels may be normal or reduced.
Some key points to consider in the management of hyperlipidemia in nephrotic syndrome include:
- Treatment of hyperlipidemia may be considered in patients with the nephrotic syndrome, particularly for patients with other cardiovascular risk factors, including hypertension and diabetes, as suggested by the KDIGO 2021 clinical practice guideline for the management of glomerular diseases 1.
- The presence of dyslipidemia in patients with chronic kidney disease, including those with nephrotic syndrome, is a significant concern due to its association with increased cardiovascular risk, as highlighted in the scientific statement from the American Heart Association 1.
- The management of hyperlipidemia in nephrotic syndrome should take into account the underlying pathophysiology, including the increased hepatic lipoprotein synthesis and decreased catabolism, as well as the presence of other cardiovascular risk factors.
From the Research
Mechanisms of Elevated Cholesterol and Triglycerides
- The nephrotic syndrome is characterized by hyperlipidemia, with elevated levels of total and low-density lipoprotein (LDL) cholesterol, as well as increased triglyceride levels 2, 3, 4, 5.
- The mechanisms underlying these abnormalities are multifactorial, involving both increased rates of lipoprotein synthesis and defective clearance and catabolism of circulating particles 3, 5.
- The increased lipoprotein synthesis occurs in partly undefined mechanisms related to proteinuria, hypoalbuminemia, and possibly, increased availability of mevalonate as a substrate for cholesterol synthesis 5.
- Urinary loss of high-density lipoprotein (HDL) components and other liporegulatory factors may contribute to decreased activity of lipolytic enzymes and result in impaired clearance of cholesterol- and triglyceride-rich lipoproteins of lower densities and altered composition of HDL 5.
Consequences of Hyperlipidemia
- Hyperlipidemia in the nephrotic syndrome may lead to an increased risk of cardiovascular disease, as well as progression of renal failure 2, 3, 6.
- The elevated cholesterol levels noted in the nephrotic syndrome are caused primarily by enhanced hepatic synthesis, with lesser contributions by decreased clearance and altered enzyme activities 4.
- Hypertriglyceridemia and hypercholesterolemia in the nephrotic syndrome may depend on a reduction in triglyceride-rich lipoproteins catabolism and on an increase in hepatic synthesis of Apo B-containing lipoproteins 6.
Treatment and Management
- Effective therapy of hyperlipidemia, particularly elevated cholesterol levels, is needed as a protection against the complications of the nephrotic syndrome 2.
- Lipid-lowering drugs such as bile acid-binding resins, probucol, and HMGCoA reductase inhibitors have been shown to be safe and effective in nephrotic patients 2, 4.
- Statins, which inhibit cholesterol synthesis, may confer tissue protection through lipid-independent mechanisms, and may be useful in the treatment of hyperlipidemia in the nephrotic syndrome 6.