Dyslipidaemia in Nephrotic Syndrome

Dyslipidaemia in nephrotic syndrome is a secondary lipid disorder caused by massive proteinuria. It contributes to atherosclerosis and progression of kidney disease.

Massive proteinuria produces high total and low density lipoprotein cholesterol, high triglycerides, raised lipoprotein(a) and abnormal high density lipoprotein.

Total cholesterol is typically 7 to 15 mmol/L, with LDL cholesterol above 4 mmol/L and triglycerides above 2.3 mmol/L in 50% or more of adults with persistent nephrotic syndrome. Levels return to baseline within weeks of remission.

Persistent nephrotic syndrome carries a cardiovascular risk that is several times that of the general population, mostly in adults with membranous nephropathy, focal segmental glomerulosclerosis and diabetic kidney disease.

Pathophysiology. Hypoalbuminaemia and reduced oncotic pressure stimulate hepatic synthesis of apolipoprotein B100 lipoproteins. The following also contribute to the lipid abnormalities:

• Reduced lipoprotein lipase activity (urinary loss of glycosylphosphatidylinositol anchored HDL-binding protein 1 and raised angiopoietin like protein 4).
• Reduced hepatic LDL receptor activity (raised PCSK9).
• Urinary loss of lecithin cholesterol acyltransferase and HDL.

Lipoprotein(a) is raised through hepatic overproduction.

• Usually asymptomatic; recognised on lipid screening.
• Xanthelasma, tendon xanthomas and corneal arcus in prolonged severe disease.
• Eruptive xanthomas, lipaemia retinalis and recurrent abdominal pain in severe hypertriglyceridaemia (above 10 mmol/L).
• Premature atherosclerotic events (myocardial infarction, stroke, peripheral arterial disease) in persistent nephrotic syndrome and in patients with diabetic kidney disease.
• Pancreatitis when triglycerides exceed 10 to 20 mmol/L.

Red flags

• Triglycerides above 10 mmol/L (pancreatitis risk).
• Chest pain, claudication or neurological events.
• Total cholesterol above 12 mmol/L with family history of premature heart disease (consider familial hypercholesterolaemia).
• Persistent nephrotic syndrome beyond 6 months, or steroid resistant disease.

• Fasting lipid profile (total cholesterol, LDL, HDL, triglycerides, non-HDL cholesterol); lipoprotein(a) once; apolipoprotein B where available.
• Exclude other secondary causes: thyroid function, glucose and HbA1c, liver tests, alcohol intake, drugs (steroids, ciclosporin, sirolimus, thiazides, beta blockers, retinoids, antiretrovirals).
• Creatinine, eGFR, urine protein:creatinine ratio, albumin; creatine kinase before statins when risk of myopathy.
• Cardiovascular risk assessment: blood pressure, smoking, diabetes, family history, body mass index.
• Check family history and consider genetic testing when LDL is extreme or there are tendon xanthomas.

Differential diagnosis

• Familial hypercholesterolaemia, hypothyroidism, diabetic dyslipidaemia, cholestatic liver disease, chylomicronaemia syndromes, drug induced dyslipidaemia, nephrotic syndrome from another cause with unrelated primary dyslipidaemia.

First line: treat the nephrotic syndrome (lipids normalise with remission)

• Dietary measures: reduce saturated fat (under 7% of energy), avoid trans fats, limit alcohol and simple sugars, and increase fibre. Aim for weight loss in overweight patients and sodium under 2 g daily.
• Start a statin when nephrotic syndrome persists beyond 3 months or when the LDL cholesterol exceeds 4 mmol/L. Start earlier in patients at high cardiovascular risk (diabetes, previous vascular event, age over 50).

Statins

• Atorvastatin 20 mg daily at night, increasing to 40 to 80 mg when LDL stays over the target (no dose adjustment in kidney impairment).
• Rosuvastatin 5 to 10 mg daily (maximum 10 mg when eGFR is under 30).
• Pravastatin 20 to 40 mg or fluvastatin 40 to 80 mg when interactions with ciclosporin are a concern.
• Targets: LDL cholesterol under 2.6 mmol/L in most patients, and under 1.8 mmol/L (or a fall of at least 50%) in very high risk patients. Non-HDL cholesterol target is under 3.4 mmol/L.
• Check liver tests and creatine kinase at baseline and after 6 to 12 weeks. Stop if alanine transaminase exceeds three times the upper limit, creatine kinase exceeds ten times the upper limit, or myalgia is severe.
• With ciclosporin, avoid simvastatin and limit atorvastatin to 10 mg and rosuvastatin to 5 mg. Avoid gemfibrozil with any statin.

Add on therapy

• Ezetimibe 10 mg daily when LDL stays over the target on the maximum tolerated statin, or when statin intolerance is present.
• PCSK9 inhibitors for refractory, severe or familial disease: evolocumab 140 mg subcutaneously every 2 weeks (or 420 mg monthly) or alirocumab 75 to 150 mg every 2 weeks.
• Bempedoic acid 180 mg daily as an alternative for statin intolerance (monitor uric acid; reduce dose or avoid with eGFR under 30).
• Triglycerides above 5 mmol/L: reduce alcohol and sugar, treat diabetes, and add fenofibrate 145 mg daily or icosapent ethyl 2 g twice daily. Fenofibrate dose is 48 to 67 mg daily when eGFR is 30 to 59; avoid it when eGFR is under 30.
• Triglycerides above 10 mmol/L: urgent specialist input, a very low fat diet, and insulin infusion if pancreatitis is present.
• Refractory nephrotic dyslipidaemia with persistent proteinuria: lipid apheresis through a specialist centre.

Cardiovascular risk reduction. Blood pressure below 130/80 mmHg with ramipril 2.5 to 10 mg daily; dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) when proteinuria persists; stop smoking; aspirin 75 mg daily only for established cardiovascular disease.

Monitoring. Check lipids at 6 to 12 weeks after starting or changing therapy, then every 6 to 12 months. Check liver tests and creatine kinase at the same intervals. Reassess the need for lipid therapy within 3 months of remission. Stop statins in remission only when the lipid profile has normalised in the absence of high cardiovascular risk.

Referral and escalation. Lipid specialist for LDL above 5 mmol/L on treatment, triglycerides above 10 mmol/L, suspected familial hypercholesterolaemia, or pancreatitis; cardiology for symptoms.

Special groups

• Children: lipids normalise with remission. Give statins for persistent dyslipidaemia in steroid resistant disease with specialist input (pravastatin 10 to 20 mg daily from age 8).
• Pregnancy: stop statins before conception and during pregnancy; use dietary measures.
• Kidney transplant recipients: lipid control is complicated by ciclosporin, sirolimus and steroids. Choose statins and doses that avoid interactions (fluvastatin or pravastatin, low dose atorvastatin or rosuvastatin).