Evaluation of nephrotic syndrome

Diseases

Summary

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] [2] Membranous nephropathy remains the most common cause of nephrotic syndrome in older people.[3] [4]

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] 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]

MCD is a major cause of idiopathic nephrotic syndrome.[6] [7] 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] [9] In 20% to 30% of patients with MCD, there may be an associated acute kidney injury.[5] Risk factors for the development of acute kidney injury include male sex, age >50 years, severe nephrotic syndrome, known hypertension, and arteriosclerosis.[5]

"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] [4] [10] 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]

When FSGS cannot be classified by clinicopathologic assessment, genetic analysis may be offered.[10] 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]

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] [4] 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] [13]

In primary membranous nephropathy, antibodies to M-type phospholipase A2 receptor (PLA2R) have been identified in 70% to 80% of patients.[14] [15] 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] [17]

Citations

Key Articles

Waldman M, Appel GB. Update on the treatment of lupus nephritis. Kidney Int. 2006 Oct;70(8):1403-12.[Abstract]

Referenced Articles

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.[Abstract]
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.[Abstract]
3. Kitiyakara C, Kopp JB, Eggers P. Trends in the epidemiology of focal segmental glomerulosclerosis. Semin Nephrol. 2003 Mar;23(2):172-82.[Abstract]
4. Deegens JK, Wetzels JF. Membranous nephropathy in the older adult: epidemiology, diagnosis and management. Drugs Aging. 2007;24(9):717-32.[Abstract]
5. Meyrier A, Niaudet P. Acute kidney injury complicating nephrotic syndrome of minimal change disease. Kidney Int. 2018 Nov;94(5):861-9.[Abstract]
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.[Abstract]
7. Vivarelli M, Massella L, Ruggiero B, et al. Minimal change disease. Clin J Am Soc Nephrol. 2017 Feb 7;12(2):332-45.[Abstract][Full Text]
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.[Abstract][Full Text]
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.[Abstract]
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.[Abstract][Full Text]
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.[Abstract][Full Text]
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.[Abstract][Full Text]
13. Glassock RJ. Secondary membranous glomerulonephritis. Nephrol Dial Transplant. 1992;7(suppl 1):64-71.[Abstract]
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.[Abstract][Full Text]
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.[Abstract][Full Text]
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.[Abstract][Full Text]
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.[Abstract]
18. Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care. 2004 Jan;27(suppl 1):S79-83.[Abstract][Full Text]
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.[Abstract]
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.[Abstract][Full Text]
21. Real de Asúa D, Costa R, Galván JM, et al. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol. 2014;6:369-77.[Abstract][Full Text]
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.[Abstract][Full Text]
23. Wheeler DC. Lipid abnormalities in the nephrotic syndrome: the therapeutic role of statins. J Nephrol. Nov-Dec 2001;14(suppl 4):S70-5.[Abstract]
24. Barbano B, Gigante A, Amoroso A, et al. Thrombosis in nephrotic syndrome. Semin Thromb Hemost. 2013 Jul;39(5):469-76.[Abstract]
25. Remuzzi G, Mecca G, Marchesi D, et al. Platelet hyperaggregability and the nephrotic syndrome. Thromb Res. 1979;16(3-4):345-54.[Abstract]
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.[Abstract][Full Text]
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.[Abstract]
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.[Abstract]
29. Zhang S, Audard V, Fan Q, et al. Immunopathogenesis of idiopathic nephrotic syndrome. Contrib Nephrol. 2011;169:94-106.[Abstract]
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.[Abstract]
31. Elie 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.[Abstract]
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.[Abstract][Full Text]
33. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9.[Abstract][Full Text]
34. Wenderfer SE. Viral-associated glomerulopathies in children. Pediatr Nephrol. 2015 Nov;30(11):1929-38.[Abstract][Full Text]
35. Scottish Paediatric Renal and Urology Network. Idiopathic nephrotic syndrome in children, management. March 2017 [internet publication].[Full Text]
36. National Institute for Health and Care Excellence. Minimal change disease and focal segmental glomerulosclerosis in adults: rituximab. Evidence summary [ES1]. November 2016 [internet publication].[Full Text]
37. 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.[Abstract][Full Text]
38. Pham TT, Sim JJ, Kujubu DA, et al. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol. 2007;27(3):322-8.[Abstract]
39. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol. 2011 Jul;31(4):341-8.[Abstract]
40. Bacchetta J, Juillard L, Cochat P, et al. Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Hematol. 2009 Apr;70(1):39-58.[Abstract]
41. Luciano RL, Moeckel GW. Update on the native kidney biopsy: core curriculum 2019. Am J Kidney Dis. 2019 Mar;73(3):404-15.[Abstract][Full Text]
42. Bobart SA, De Vriese AS, Pawar AS, et al. Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies. Kidney Int. 2019 Feb;95(2):429-38.[Abstract][Full Text]
43. Stout LC, Kumar S, Whorton EB. Focal mesangiolysis and the pathogenesis of the Kimmelstiel-Wilson nodule. Hum Pathol. 1993 Jan;24(1):77-89.[Abstract]
44. Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol. 2006 Dec;17(12):3458-71.[Abstract][Full Text]
45. Waldman M, Appel GB. Update on the treatment of lupus nephritis. Kidney Int. 2006 Oct;70(8):1403-12.[Abstract]
46. Bradwell AR, Carr-Smith HD, Mead GP, et al. Serum test for assessment of patients with Bence Jones myeloma. Lancet. 2003 Feb 8;361(9356):489-91.[Abstract]
47. Barbour T, Johnson S, Cohney S, et al. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012 Jul;27(7):2673-85.[Abstract][Full Text]