Which clinical manifestation is appropriate when assessing a child for possible nephrotic syndrome

Nephrotic syndrome is defined as the presence of proteinuria (>3.5 g/24 hours), hypoalbuminemia (<3.0 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease are also frequently seen. Despite heavy proteinuria and lipiduria, the urine contains few cells or casts. This is in contrast to 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 etiology 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 specialized input and assessment.

This topic provides an overview of the evaluation of nephrotic syndrome and the individual diseases that cause heavy proteinuria.

Etiology

Nephrotic syndrome may occur in connection with a large assortment of primary and secondary diseases. The probable etiology differs depending on the patient's age, ethnicity, and the presence of specific comorbidities (e.g., diabetes, amyloidosis, or systemic lupus erythematosus).

The most common cause of nephrotic syndrome in young children is minimal change disease (MCD). Renal biopsy is not performed if children with MCD are steroid sensitive (steroid sensitive nephrotic syndrome). Children with steroid resistant nephrotic syndrome (SRNS) undergo renal biopsy, with the pathology most likely to be focal segmental glomerulosclerosis (FSGS). In older children/adolescents, the incidence of MCD starts to decrease, and other causes of nephrotic syndrome increase in incidence.

In adults, FSGS is an increasingly common cause of nephrotic syndrome. FSGS incidence is similar to, or exceeds that of, the most common historical cause of unexplained nephrotic syndrome in adults, membranous nephropathy.[1]Haas M, Meehan SM, Karrison TG, et al. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis. 1997 Nov;30(5):621-31. http://www.ncbi.nlm.nih.gov/pubmed/9370176?tool=bestpractice.com [2]Braden GL, Mulhern JG, O'Shea MH, et al. Changing incidence of glomerular diseases in adults. Am J Kidney Dis. 2000 May;35(5):878-83. http://www.ncbi.nlm.nih.gov/pubmed/10793022?tool=bestpractice.com Membranous nephropathy remains the most common cause of nephrotic syndrome in older people.[3]Kitiyakara C, Kopp JB, Eggers P. Trends in the epidemiology of focal segmental glomerulosclerosis. Semin Nephrol. 2003 Mar;23(2):172-82. http://www.ncbi.nlm.nih.gov/pubmed/12704577?tool=bestpractice.com [4]Deegens JK, Wetzels JF. Membranous nephropathy in the older adult: epidemiology, diagnosis and management. Drugs Aging. 2007;24(9):717-32. http://www.ncbi.nlm.nih.gov/pubmed/17727303?tool=bestpractice.com

Diabetic nephropathy is the most common cause of nephrotic syndrome in adults with a history of long-standing diabetes.

Patients with IgA nephropathy, membranoproliferative glomerulonephritis, and postinfectious glomerulonephritis may demonstrate some features of nephrotic syndrome (nephrotic range proteinuria with a low serum albumin). However, these causes of renal disease are predominantly nephritic and investigations will reveal hematuria, red cell casts, and possibly renal dysfunction.

Minimal change disease (MCD)

MCD accounts for approximately 95% of cases of nephrotic syndrome in children before adolescence.[5]Meyrier A, Niaudet P. Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int. 2018 Nov;94(5):861-9. http://www.ncbi.nlm.nih.gov/pubmed/29980292?tool=bestpractice.com In children younger than 10 years, MCD accounts for 70% to 90% of cases of nephrotic syndrome. This figure decreases to 50% in older children, and to between 10% and 20% in adults.[5]Meyrier A, Niaudet P. Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int. 2018 Nov;94(5):861-9. http://www.ncbi.nlm.nih.gov/pubmed/29980292?tool=bestpractice.com

MCD is a major cause of idiopathic nephrotic syndrome.[6]Filler G, Young E, Geier P, et al. Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis. 2003 Dec;42(6):1107-13. http://www.ncbi.nlm.nih.gov/pubmed/14655180?tool=bestpractice.com [7]Vivarelli M, Massella L, Ruggiero B, et al. Minimal change disease. Clin J Am Soc Nephrol. 2017 Feb 7;12(2):332-45. https://www.doi.org/10.2215/CJN.05000516 http://www.ncbi.nlm.nih.gov/pubmed/27940460?tool=bestpractice.com In a minority of cases, it may be associated with an underlying secondary cause, such as nonsteroidal anti-inflammatory drug (NSAID) use or Hodgkin lymphoma.[8]Audard V, Larousserie F, Grimbert P, et al. Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature. Kidney Int. 2006 Jun;69(12):2251-60. https://www.doi.org/10.1038/sj.ki.5000341 http://www.ncbi.nlm.nih.gov/pubmed/16672913?tool=bestpractice.com [9]Farruggia P, Trizzino A, Maringhini S, et al. Hodgkin lymphoma and nephrotic syndrome in childhood. Indian J Pediatr. 2010 Oct;77(10):1147-9. http://www.ncbi.nlm.nih.gov/pubmed/20872097?tool=bestpractice.com In 20% to 30% of patients with MCD, there may be an associated acute kidney injury.[5]Meyrier A, Niaudet P. Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int. 2018 Nov;94(5):861-9. http://www.ncbi.nlm.nih.gov/pubmed/29980292?tool=bestpractice.com Risk factors for the development of acute kidney injury include male sex, age >50 years, severe nephrotic syndrome, known hypertension, and arteriosclerosis.[5]Meyrier A, Niaudet P. Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int. 2018 Nov;94(5):861-9. http://www.ncbi.nlm.nih.gov/pubmed/29980292?tool=bestpractice.com  

"Minimal change" refers to light microscopic findings that often reveal normal glomeruli or mild mesangial proliferation with negative immunofluorescence and no immune complex deposition. Electron microscopy, however, classically demonstrates diffuse effacement of the epithelial cell foot processes. MCD is typically responsive to steroids. If resistance is noted, alternative etiologies should be considered, in particular FSGS.

Focal segmental glomerulosclerosis (FSGS)

FSGS can be either primary (idiopathic), secondary, or genetic. Differentiating between primary and secondary FSGS is key in determining management, as the former responds to immunosuppression, while secondary causes are treated with reducing intraglomerular pressure (renin-angiotensin blockade).

Secondary causes of FSGS can be divided into those caused by conditions such as HIV infection, reflux nephropathy, class III obesity (BMI 40 or above), chronic glomerular hyperfiltration from a solitary kidney, or any other cause of extensive nephron loss (e.g., renal obstruction, prior glomerulonephritis), or to certain drugs (such as pamidronate or heroin).[3]Kitiyakara C, Kopp JB, Eggers P. Trends in the epidemiology of focal segmental glomerulosclerosis. Semin Nephrol. 2003 Mar;23(2):172-82. http://www.ncbi.nlm.nih.gov/pubmed/12704577?tool=bestpractice.com [4]Deegens JK, Wetzels JF. Membranous nephropathy in the older adult: epidemiology, diagnosis and management. Drugs Aging. 2007;24(9):717-32. http://www.ncbi.nlm.nih.gov/pubmed/17727303?tool=bestpractice.com [10]De Vriese AS, Sethi S, Nath KA, et al. Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. J Am Soc Nephrol. 2018 Mar;29(3):759-74. https://www.doi.org/10.1681/ASN.2017090958 http://www.ncbi.nlm.nih.gov/pubmed/29321142?tool=bestpractice.com HIV is associated with collapsing FSGS, characterized by collapse and sclerosis of the entire glomerular tuft (nonsegmental). 

Genetic forms of FSGS usually present in childhood. A recessive mutation in one of four genes (NPHS1, NPHS2, LAMB2, WT1) accounts for 85% of cases of SRNS presenting by 3 months, and 66% presenting in the first year of life.[11]Hinkes BG, Mucha B, Vlangos CN, et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics. 2007 Apr;119(4):e907-19. https://www.doi.org/10.1542/peds.2006-2164 http://www.ncbi.nlm.nih.gov/pubmed/17371932?tool=bestpractice.com

When FSGS cannot be classified by clinicopathologic assessment, genetic analysis may be offered.[10]De Vriese AS, Sethi S, Nath KA, et al. Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. J Am Soc Nephrol. 2018 Mar;29(3):759-74. https://www.doi.org/10.1681/ASN.2017090958 http://www.ncbi.nlm.nih.gov/pubmed/29321142?tool=bestpractice.com This is particularly relevant in young adult patients. A cohort study demonstrated that a single-gene cause of SRNS was found in 29.5% of patients presenting before the age of 25.[12]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://www.doi.org/10.1681/ASN.2014050489 http://www.ncbi.nlm.nih.gov/pubmed/25349199?tool=bestpractice.com

FSGS commonly presents with hematuria, hypertension, and reduced renal function. Edema may be present. Light microscopy shows segmental areas of mesangial collapse and sclerosis affecting some but not all glomeruli (focal disease). Patients are often resistant to steroids and renal biopsy is required to confirm diagnosis.

Membranous nephropathy

Membranous nephropathy is the most common cause of nephrotic syndrome in older adults but is rare in children.[3]Kitiyakara C, Kopp JB, Eggers P. Trends in the epidemiology of focal segmental glomerulosclerosis. Semin Nephrol. 2003 Mar;23(2):172-82. http://www.ncbi.nlm.nih.gov/pubmed/12704577?tool=bestpractice.com [4]Deegens JK, Wetzels JF. Membranous nephropathy in the older adult: epidemiology, diagnosis and management. Drugs Aging. 2007;24(9):717-32. http://www.ncbi.nlm.nih.gov/pubmed/17727303?tool=bestpractice.com Microscopy demonstrates basement membrane thickening without associated cellular proliferation or infiltration. Immunofluorescence reveals diffuse, granular IgG deposition throughout the capillary walls and electron microscopy shows electron dense deposits in the subepithelial space. New basement membrane growth between subepithelial immune deposits leads to the classic "spike and dome" appearance.

The majority of cases of membranous nephropathy are primary (70%), with the remaining 30% associated with malignancy, infections (e.g., hepatitis B, hepatitis C, syphilis, malaria, or tuberculosis), autoimmune disease (e.g., lupus membranous nephropathy), or drugs (e.g., gold, penicillamine, and NSAIDs).[4]Deegens JK, Wetzels JF. Membranous nephropathy in the older adult: epidemiology, diagnosis and management. Drugs Aging. 2007;24(9):717-32. http://www.ncbi.nlm.nih.gov/pubmed/17727303?tool=bestpractice.com [13]Glassock RJ. Secondary membranous glomerulonephritis. Nephrol Dial Transplant. 1992;7(suppl 1):64-71. http://www.ncbi.nlm.nih.gov/pubmed/1337185?tool=bestpractice.com

In primary membranous nephropathy, antibodies to M-type phospholipase A2 receptor (PLA2R) have been identified in 70% to 80% of patients.[14]Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2;361(1):11-21. https://www.doi.org/10.1056/NEJMoa0810457 http://www.ncbi.nlm.nih.gov/pubmed/19571279?tool=bestpractice.com [15]Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med. 2011 Feb 17;364(7):689-90. http://www.nejm.org/doi/full/10.1056/NEJMc1011678 http://www.ncbi.nlm.nih.gov/pubmed/21323563?tool=bestpractice.com Measurement of anti-PLA2R antibody titer is now a routine part of clinical care, contributing to the diagnosis and prognosis, as well as helping to guide treatment decisions.[16]Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-ohospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol. 2015 Oct;26(10):2545-58. https://www.doi.org/10.1681/ASN.2014070640 http://www.ncbi.nlm.nih.gov/pubmed/25804280?tool=bestpractice.com [17]Kim YG, Choi YW, Kim SY, et al. Anti-phospholipase A2 receptor antibody as prognostic indicator in idiopathic membranous nephropathy. Am J Nephrol. 2015;42(3):250-7. http://www.ncbi.nlm.nih.gov/pubmed/26484659?tool=bestpractice.com

Diabetic nephropathy

About 20% to 30% of patients with type 1 or type 2 diabetes develop evidence of diabetic nephropathy.[18]Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care. 2004 Jan;27(suppl 1):S79-83. https://www.doi.org/10.2337/diacare.27.2007.s79 http://www.ncbi.nlm.nih.gov/pubmed/14693934?tool=bestpractice.com This is usually heralded by microalbuminuria (≥30 mg/day). Left untreated, persistent microalbuminuria will progress to frank proteinuria in a proportion of patients over the subsequent 10 to 15 years. These patients are at risk of progressing to end-stage renal disease.

Patients with non-proteinuric diabetic kidney disease, such as hypertensive glomerulosclerosis or tubulointerstitial disease, are also at risk of decline in renal function.[19]Hobeika L, Hunt KJ, Neely BA, et al. Comparison of the rate of renal function decline in nonproteinuric patients with and without diabetes. Am J Med Sci. 2015 Dec;350(6):447-52. http://www.ncbi.nlm.nih.gov/pubmed/26624901?tool=bestpractice.com [20]Piccoli GB, Grassi G, Cabiddu G, et al. Diabetic kidney disease: a syndrome rather than a single disease. Rev Diabet Stud. 2015 Spring-Summer;12(1-2):87-109. https://www.doi.org/10.1900/RDS.2015.12.87 http://www.ncbi.nlm.nih.gov/pubmed/26676663?tool=bestpractice.com

A combination of pathogenic processes occurs including glomerular hyperfiltration, hyperglycemia, and glycation of matrix proteins. Rarely, the heaviness of proteinuria caused by diabetic nephropathy can lead to nephrotic syndrome. Diabetic nephropathy is defined by characteristic mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis leading to the development of Kimmelstiel-Wilson nodules.

Amyloidosis

Amyloidosis is responsible for around 10% of nephrotic syndrome cases. The main subtypes of amyloidosis include:[21]Real de Asúa D, Costa R, Galván JM, et al. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol. 2014;6:369-77. https://www.doi.org/10.2147/CLEP.S39981 http://www.ncbi.nlm.nih.gov/pubmed/25378951?tool=bestpractice.com [22]Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013 Feb 20;8:31. https://www.doi.org/10.1186/1750-1172-8-31 http://www.ncbi.nlm.nih.gov/pubmed/23425518?tool=bestpractice.com

• AL primary amyloid, a light-chain dyscrasia where monoclonal light chains form amyloid fibrils; can affect several organs and have differing presentations

• AA amyloid, which is associated with chronic inflammation (e.g., rheumatoid arthrtis, inflammatory bowel disease) and chronic infections; usually affects the kidneys

• Hereditary amyloidosis, usually caused by transthyretin (TTR) amyloidosis; a multisymptom disease that most commonly presents with a neuropathy, but can cause nephropathy, gastrointestinal impairment, cardiomyopathy, or ocular deposition.

Investigations should search for the presence of a monoclonal paraprotein in the urine or plasma.

Pathophysiology

Each kidney has approximately one 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 pathologic processes resulting in the development of high-grade glomerular proteinuria.

In FSGS, the podocyte is the target of an unknown circulating factor. In membranous nephropathy, the podocyte is the target of an antibody response, and in genetic causes of SRNS, the genetic mutation affects the podocyte or the filtration barrier.

Hypoalbuminemia

Patients become hypoalbuminemic 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 LDL and VLDL and lipoprotein(a), contributing to the development of lipid abnormalities including hypercholesterolemia and hypertriglyceridemia.[23]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 recognized life-threatening complication of nephrotic syndrome. It occurs as a result of loss of anti-thrombin III, protein C, and protein S in the urine; increased hepatic synthesis of pro-coagulant factors; and increased platelet activation.[24]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 [25]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

Edema

Edema is due to a combination of a decrease in oncotic pressure from hypoalbuminemia, as well as a primary renal sodium retention in the collecting tubules.[26]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 [27]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-S10. 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.

Differential diagnosis

Nephrotic syndrome is a relatively rare but important manifestation of kidney disease. In the US, its annual incidence among children is reported to be 2 to 7 cases per 100,000.[28]van Husen M, Kemper MJ. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011 Jun;26(6):881-92. http://www.ncbi.nlm.nih.gov/pubmed/21229269?tool=bestpractice.com [29]Zhang S, Audard V, Fan Q, et al. Immunopathogenesis of idiopathic nephrotic syndrome. Contrib Nephrol. 2011;169:94-106. http://www.ncbi.nlm.nih.gov/pubmed/21252513?tool=bestpractice.com [30]Gbadegesin R, Lavin P, Foreman J, et al. Pathogenesis and therapy of focal segmental glomerulosclerosis: an update. Pediatr Nephrol. 2011 Jul;26(7):1001-15. http://www.ncbi.nlm.nih.gov/pubmed/21110043?tool=bestpractice.com [31]lie V, Fakhoury M, Deschênes G, et al. Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. Pediatr Nephrol. 2012 Aug;27(8):1249-56. http://www.ncbi.nlm.nih.gov/pubmed/21710250?tool=bestpractice.com [32]El Bakkali L, Rodrigues Pereira R, Kuik DJ, et al. Nephrotic syndrome in the Netherlands: a population-based cohort study and a review of the literature. Pediatr Nephrol. 2011 Aug;26(8):1241-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119807 http://www.ncbi.nlm.nih.gov/pubmed/21533870?tool=bestpractice.com In adults, nephrotic syndrome has an incidence of around 3 new cases per 100,000 each year.[33]Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9. http://www.bmj.com/content/336/7654/1185.long http://www.ncbi.nlm.nih.gov/pubmed/18497417?tool=bestpractice.com Incidence varies among adults depending on the incidence of underlying causes for the condition, particularly diabetes mellitus.

In most cases, family history, drug history, symptom history, examination, and investigations (of which a renal biopsy is key) lead to the diagnosis of an underlying cause for nephrotic syndrome.

Clinically, categorizing glomerular renal disease into syndromes, such as nephrotic syndrome and nephritic syndrome, helps to narrow the differential diagnosis. The differential diagnosis is generally the same for patients with nephrotic syndrome and for nephrotic-range proteinuria.

Common differential diagnoses of nephrotic syndrome include minimal change nephropathy, FSGS, membranous nephropathy, diabetic nephropathy, primary glomerular diseases (e.g., IgA nephropathy), fibrillary glomerulopathies (the most common being amyloidosis), lupus nephritis, and multiple myeloma (e.g., light-chain deposition diseases).[33]Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9. http://www.bmj.com/content/336/7654/1185.long http://www.ncbi.nlm.nih.gov/pubmed/18497417?tool=bestpractice.com Membranoproliferative glomerulonephritis is a relatively rare cause of nephrotic syndrome, though more common as a cause of isolated non-visible hematuria and proteinuria.

Nephrotic syndrome is an uncommon presentation of rare renal diseases such as Fabry disease, Alport syndrome, and nail-patella syndrome. Rarely accelerated phase hypertension can present this way.

Nephrotic syndrome may cause of severe edema (or anasarca). It can be differentiated from edema caused by congestive heart failure (CHF) or hepatic disease by the presence of severe proteinuria, which makes examination of the urine mandatory. Patients with edema from nephrotic syndrome can often comfortably lie flat, allowing them to develop facial edema. Generally, patients with CHF or severe liver disease cannot comfortably lie flat and tend not to develop facial edema.