Nephrotic syndrome is defined as the presence of proteinuria (>3.5 g/24 hours), hypoalbuminaemia (<30 g/L), and peripheral oedema. Hyperlipidaemia and thrombotic disease are also frequently seen.
Despite heavy proteinuria and lipiduria, the urine contains few cells or casts. This differs from nephritic syndrome, which is typically defined as the presence of acute kidney injury (renal dysfunction), hypertension, and an active urinary sediment (red cells and red cell casts).
Nephrotic syndrome is not a single disease; it is a constellation of several symptoms that can be caused by several renal diseases. The challenge is to determine the underlying aetiology causing the nephrotic syndrome in any given patient.
Patients with nephrotic syndrome are at risk of chronic kidney disease and end-stage renal disease. Nephrotic syndrome is associated with significant morbidity and mortality; therefore, these patients require specialised input and assessment.
Pathophysiology
Each kidney has approximately 1 million glomeruli, which are the sites of blood filtration. The layers of the glomeruli include the fenestrated endothelium of the capillary, the glomerular basement membrane, and the foot processes of the podocytes. Together these crucial structures are known as the glomerular filtration barrier, with the connection between adjacent podocyte foot processes called slit diaphragms.
Proteinuria
Glomerular proteinuria develops when the components of the filtration barrier are disrupted by disease. The podocyte is the major target of pathological processes resulting in the development of high-grade glomerular proteinuria.
In focal segmental glomerulosclerosis (FSGS), the podocyte is often the target of an unknown circulating factor.[1]Müller-Deile J, Sarau G, Kotb AM, et al. Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis. Sci Rep. 2021 Feb 25;11(1):4577.
https://www.nature.com/articles/s41598-021-83883-w
http://www.ncbi.nlm.nih.gov/pubmed/33633212?tool=bestpractice.com
In idiopathic membranous nephropathy, the podocyte is the target of an antibody response, and in genetic causes of steroid-resistant nephrotic syndrome (SRNS), the genetic mutation affects the podocyte or the filtration barrier.[2]Pozdzik A, Brochériou I, David C, et al. Membranous nephropathy and anti-podocytes antibodies: implications for the diagnostic workup and disease management. Biomed Res Int. 2018 Jan;2018:6281054.
https://onlinelibrary.wiley.com/doi/10.1155/2018/6281054
http://www.ncbi.nlm.nih.gov/pubmed/29511687?tool=bestpractice.com
[3]Sadowski CE, Lovric S, Ashraf S, et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2015 Jun;26(6):1279-89.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4446877
http://www.ncbi.nlm.nih.gov/pubmed/25349199?tool=bestpractice.com
Hypoalbuminaemia
Patients become hypoalbuminaemic due to the urinary loss of albumin. The liver tries to compensate for this protein loss by increasing the synthesis of albumin, as well as other molecules including low-density lipoprotein, very low-density lipoprotein, and lipoprotein(a), contributing to the development of lipid abnormalities including hypercholesterolaemia and hypertriglyceridaemia.[4]Wheeler DC. Lipid abnormalities in the nephrotic syndrome: the therapeutic role of statins. J Nephrol. Nov-Dec 2001;14(suppl 4):S70-5.
http://www.ncbi.nlm.nih.gov/pubmed/11798150?tool=bestpractice.com
The lipid abnormalities correlate with the extent of proteinuria. These lipid abnormalities increase the patient’s risk of cardiovascular disease.
Hypercoagulability and thrombosis
Hypercoagulability and thrombosis (deep vein thrombosis, pulmonary emboli, renal vein thrombosis) is a recognised life-threatening complication of nephrotic syndrome.[5]Gigante A, Barbano B, Sardo L, et al. Hypercoagulability and nephrotic syndrome. Curr Vasc Pharmacol. 2014 May;12(3):512-7.
http://www.ncbi.nlm.nih.gov/pubmed/22724465?tool=bestpractice.com
It occurs as a result of loss of antithrombin III, protein C, and protein S in the urine; increased hepatic synthesis of pro-coagulant factors; and increased platelet activation.[6]Barbano B, Gigante A, Amoroso A, et al. Thrombosis in nephrotic syndrome. Semin Thromb Hemost. 2013 Jul;39(5):469-76.
http://www.ncbi.nlm.nih.gov/pubmed/23625754?tool=bestpractice.com
[7]Remuzzi G, Mecca G, Marchesi D, et al. Platelet hyperaggregability and the nephrotic syndrome. Thromb Res. 1979;16(3-4):345-54.
http://www.ncbi.nlm.nih.gov/pubmed/516000?tool=bestpractice.com
Oedema
Occurs due to a combination of a decrease in oncotic pressure (also known as colloid osmotic pressure) from hypoalbuminaemia, as well as a primary renal sodium retention in the collecting tubules.[8]Rodriguez-Iturbe B, Herrera-Acosta J, Johnson RJ. Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: a unifying hypothesis. Kidney Int. 2002 Oct;62(4):1379-84.
http://www.sciencedirect.com/science/article/pii/S0085253815486818
http://www.ncbi.nlm.nih.gov/pubmed/12234309?tool=bestpractice.com
[9]Kim SW, Frokiaer J, Nielsen S. Pathogenesis of oedema in nephrotic syndrome: role of epithelial sodium channel. Nephrology (Carlton). 2007 Dec;12(suppl 3):S8-10.
http://www.ncbi.nlm.nih.gov/pubmed/17995529?tool=bestpractice.com
Patients with nephrotic syndrome are at increased risk of infection due to loss of immunoglobulins, complement, and other compounds in the urine. Immunotherapy may exacerbate the infection risk.[10]Wong ZY, Teo CY, Fiona Wong YQ, et al. Immunosuppression for adult steroid-dependent or frequently relapsing nephrotic syndrome: a systematic review and meta-analysis. PLoS One. 2024 Jul 31;19(7):e0307981.
https://www.doi.org/10.1371/journal.pone.0307981
http://www.ncbi.nlm.nih.gov/pubmed/39083488?tool=bestpractice.com
[11]Nishi S, Ubara Y, Utsunomiya Y, et al. Evidence-based clinical practice guidelines for nephrotic syndrome 2014. Clin Exp Nephrol. 2016 Jun;20(3):342-70.
https://www.doi.org/10.1007/s10157-015-1216-x
http://www.ncbi.nlm.nih.gov/pubmed/27099136?tool=bestpractice.com