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Definition, Etiology, PathogenesisTop
Nephrotic syndrome is a clinical condition characterized by proteinuria >3.5 g/d, hypoalbuminemia, and edema. In contrast to nephritic syndrome, patients can often have normal glomerular filtration rate (GFR) at presentation. Normal daily urinary protein excretion is <150 mg (on average 50 mg). Damage to the podocytes, which are the epithelial cells responsible for forming the glomerular filtration barrier, leads to urinary loss of plasma proteins.
In children, minimal change disease (MCD) is the most common cause of nephrotic syndrome, such that it is treated empirically without a renal biopsy. In adults, the etiology of nephrotic syndrome is more varied and requires a biopsy for diagnosis. Focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in African Americans. Primary FSGS routinely presents with nephrotic syndrome, whereas in secondary FSGS the degree of proteinuria is typically less severe. Membranous nephropathy is the most common cause of nephrotic syndrome in whites and is usually primary or idiopathic. Other causes of nephrotic syndrome in adults include MCD, membranoproliferative glomerulonephritis (MPGN), IgA nephropathy, amyloid, and diabetes mellitus.
Edema often occurs when protein loss is >5 g/d and serum albumin concentration is ≤25 g/L, although variability occurs. Two proposed mechanisms exist for the development of volume overload and edema. One mechanism—overfill theory—involves a collecting tubule defect leading to a significant impairment of sodium and volume excretion. The second mechanism—underfill theory—suggests that the reduction of oncotic pressure from significant hypoalbuminemia leads to the loss of fluid from the intravascular into the extravascular compartment, leading to the activation of the renin-angiotensin-aldosterone system and subsequent sodium and volume retention.
Clinically, foaming of urine (due to the high protein content) may be observed. Pitting edema is usually symmetric and its location depends on the body position (facial edema is frequently observed in the morning, edema of the feet and lower legs in the evening), although edema is often severe enough that lower limb edema is persistent. Orthostatic hypotension may occur in elderly patients with severe hypoalbuminemia.
Hypercholesterolemia and hypertriglyceridemia develop mainly as a result of the decreased rate of catabolism of lipoproteins, increased synthesis of very low–density lipoprotein in response to hypoalbuminemia, and urinary losses of high-density lipoprotein cholesterol. Hyperlipidemia can often be severe and contributes to an increased risk of coronary artery disease if prolonged. Xanthelasma can be seen in severe hypercholesterolemia.
Nephrotic syndrome leads to a significant increase in the risk of both venous and arterial thrombosis. The mechanism is not completely understood but likely involves urinary loss of antithrombin III and plasminogen as well as increased hepatic synthesis of procoagulant factors. Increased platelet activation has also been described. Thrombosis occurs in 10% to 50% of patients (more commonly in primary membranous nephropathy). Renal venous thrombosis may be asymptomatic, but it can also present with acute kidney injury, flank pain, or hematuria. Additionally, patients with nephrotic syndrome are at risk of infection. Urinary loss of IgG is the main cause for increased susceptibility to infection. This particularly decreases the ability to respond to encapsulated organisms such as pneumococcus, and both conjugate and polysaccharide pneumococcal vaccinations are recommended.
1. Urinalysis/microscopy: Severe proteinuria and microscopic hematuria may be seen. Lipiduria is manifested by oval fat bodies or “Maltese crosses” on microscopy.
2. Twenty-four–hour urine collection: While urinalysis and the urine albumin-to-creatinine ratio (ACR) will demonstrate significant proteinuria, a 24-hour urine collection should be done to quantify the degree of proteinuria.
3. Blood tests: Hypoalbuminemia and hypercholesterolemia are hallmarks of nephrotic syndrome. Other abnormalities may include increased creatinine and urea, hypocalcemia (primarily a reduction in the concentration of protein-bound nonionized calcium), vitamin D deficiency, and hypogammaglobulinemia. Additional investigations to assess for the cause of nephrotic syndrome should include antinuclear antibodies (ANAs), antibodies to phospholipase A2 receptors, serum and urine electrophoresis, quantitative immunoglobulins, fasting glucose, chronic hepatitis serologies, complement levels, and HIV testing.
4. Imaging studies: Renal ultrasonography is rarely diagnostic but should be done prior to renal biopsy.
5. Renal biopsy: In the majority of cases, renal biopsy is required in adults to determine the cause of nephrotic syndrome, unless it is obvious (eg, patients with diabetes with retinopathy and/or neuropathy and a history of progressive proteinuria).
Treatment includes diagnosis and management of the underlying condition as well as addressing complications of nephrotic syndrome. Edema can be significant and should be treated with sodium restriction (<2 g/d), although loop diuretics are usually required. Loop diuretics are protein-bound, which leads to decreased delivery to the kidney in hypoalbuminemia and increased binding of the medication in the tubules because of albuminuria, resulting in the requirement of larger than usual doses to achieve diuresis. Combination with a thiazide diuretic or addition of IV albumin may assist with diuresis.
Reduction of proteinuria results in decreased progression of chronic kidney disease regardless of the underlying etiology. As a result, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are recommended in nephrotic syndrome and can reduce proteinuria by approximately 50%.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Heerspink HJ, Kröpelin TF, Hoekman J, de Zeeuw D; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium. Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis. J sAm Soc Nephrol. 2015 Aug;26(8):2055-64. doi: 10.1681/ASN.2014070688. Epub 2014 Nov 24. Review. PubMed PMID: 25421558; PubMed Central PMCID: PMC4520175.
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are routinely used to treat the hyperlipidemia associated with nephrotic syndrome. In the absence of specific recommendations for targets in nephrotic syndrome, general cardiovascular guidelines are used.
Thromboembolic events should be treated as per usual therapy. The role of prophylactic anticoagulation is controversial; it is not routinely done, although it can be considered in patients with primary nephrotic syndrome and severe hypoalbuminemia (<20 g/L).