Definition

Characterized by severe (>3.5grams/day) proteinuria, edema, hypoalbuminemia (<3.5mg/dL), hypercholesterolemia (increased hepatic production due to hypoalbuminemia as a stimulus), and lipiduria (increased glomerular permeability to serum proteins). Many patients will not have the complete syndrome.

Etiology

Typically separated into idiopathic/primary disease and secondary forms in which renal protein loss is a consequence of systemic disease. Primary and secondary causes can lead to common histopathological changes.

Primary glomerular diseases:

• Membranous (30% of the time): most common cause of nephrotic syndrome in Caucasian adults. 70% of cases are idiopathic and most are associated with phospholipase A2 receptor antibodies. 
  • Secondary form associated with systemic autoimmune diseases (e.g., SLE), infections (HBV, HCV, malaria, schistosomiasis, and syphilis), cancer (especially in patients over 60), drugs (NSAIDs, penicillamine, gold) and sarcoidosis.
  • Associated with thrombosis, especially renal vein and DVT. Maintain high suspicion for thrombosis, due to 50% cumulative incidence of thrombosis (33% with PE).
• Minimal change disease (20%): primary form most commonly seen in children, but a second spike occurs in adulthood (mean age 40 years old). 
  • Usually does not progress to ESRD.
  • Secondary forms associated with Hodgkin’s lymphoma and drugs (e.g., NSAIDs).
  • Note: minimal change disease from NSAIDs is often (though not always) seen with superimposed ATN.
• Focal segmental glomerulosclerosis (FSGS) (40%): primary FSGS is the most common cause of nephrotic syndrome in African Americans (excluding DM nephropathy). 
  • Secondary forms seen with IV heroin use, HIV infection (collapsing variant), morbid obesity, obstructive sleep apnea, chronic urinary reflux, sickle cell disease, pamidronate, and chronic kidney disease (due to glomerular hyperfiltration and nephron loss).
• Membranoproliferative (5%): may present as a combined nephrotic-nephritic picture. Two distinct types are described: 
  • Type I: low C3. Associated with infections (e.g. hepatitis C and B, bacterial, fungal), immune complex disease (e.g. SLE, cryoglobulinemia, Sjogren’s), lymphoproliferative disorders, idiopathic.
  • Type II (dense deposit disease): auto-antibodies block inactivation of C3 convertase = C3 nephritic factor (+). Mostly in pediatric patients.
• IgA nephropathy: while primarily a nephritic disorder, nephrotic range proteinuria can occur in up to one-third of patients. 
  • Fibrillary/immunotactoid glomerulopathy (1%).
  • Mesangial proliferative GN (likely atypical forms of MCD or FSGS, 55%).

Secondary causes of nephrotic syndrome:

• Diabetic nephropathy: most common cause of proteinuria in adults, which can progress to nephrotic range proteinuria. 
  • GBM thickening and extracellular matrix accumulation leads to enlarged kidneys.
  • Frequent progression to ESRD.
• Amyloidosis: the most common forms include AL amyloidosis (from monoclonal gammopathies) and AA amyloidosis from chronic infections (e.g., skin-popping, TB) and chronic inflammation (e.g., rheumatological disease and inflammatory bowel disease).
• SLE: five classes by biopsy results defined by the WHO. Mostly mixed nephritic-nephrotic picture. Class V (membranous nephritis) is characterized by nephrotic range proteinuria and severe edema.
• Drugs/Toxins/Immune reaction: heroin, gold, penicillamine, NSAIDs, interferon alpha.
• Cryoglobulinemia: typically presents with membranoproliferative GN.
• Infections: HIV (HIV-associated nephropathy, HIVAN), syphilis, hepatitis B or C, schistosomiasis.
• Malignancy: lymphoma, multiple myeloma, solid-organ carcinoma, melanoma.
• Pre-eclampsia: presents as HTN and proteinuria +/- edema. Occurs after 20 weeks gestation up to as late as 4-6 weeks postpartum.

Evaluation

• History: 
  • Dependent edema is a common presentation.
  • Foamy urine (pearl: the other substance that makes urine foam when shaken is bilirubin!).
  • A thrombotic complication, such as a DVT or PE, may be the first presentation for nephrotic syndrome.
• Physical examination: 
  • Edema, especially around the eyes and legs. Anasarca, pleural effusions and ascites may develop.
  • Hypertension and hematuria may be present.
  • Search for physical exam evidence of systemic causes, such as DM, SLE, amyloidosis, infections, malignancy.
• Labs/imaging: there is no agreement about how to evaluate nephrotic patients so nephrology consultation prior to ordering numerous and expensive serologies is prudent. However, it is reasonable to order tests based on your patient’s history (e.g., untreated HCV history). 
  • Urine studies: UA with microscopy (3+ or 4+ protein usually noted on urine dipstick; 3+ approximately equal to 300mg/dL protein), urine sediment exam (waxy casts, oval fat bodies, fatty casts, Maltese crosses with polarized light), spot UProt/UCr (not accurate in AKI) and/or 24-hour urine protein collection.
  • Serum studies: chem10, serum albumin, fasting lipid profile (elevated LDL), coagulation studies.
  • Renal US (enlarged kidneys favor diabetes, HIV or amyloidosis).
  • Work-up for secondary causes: HgbA1C+retinopathy (presumed DM), HIV screen, viral hepatitis serologies, ANA, C3/C4, SPEP/UPEP, ?fat pad bx, RPR, phospholipase A2 receptor ab.
    • ANCA and ASO are generally not indicated as they are associated with nephritic presentations.
• Diagnosis is ultimately made by renal biopsy, which is the only definitive diagnostic test. Serologies in nephrotic patients are merely suggestive (unlike nephritic disease where serologies may be so helpful that they obviate the need for biopsy in some scenarios).

Management

** Remember that patients are relatively immunosuppressed especially from encapsulated organisms due to loss of Ig), at increased risk for thrombosis (specifically, but not limited to, renal vein thrombosis) due to loss of ATIII and other endogenous anticoagulation factors, and more malnourished due to protein loss.

• Prophylactic anticoagulation is controversial and not favored unless patient is otherwise highly thrombophilic; consider more if serum albumin <2 with membranous nephropathy.
• Vaccinate for encapsulated organisms: pneumovax.
• All patients need BP management: goal BP 130/80, some recommend <125/75. High dose (BID or TID) diuretics, salt restriction.
• Edema: start with Lasix and can escalate Bumex given low-albumin state and to high-dose diuretics if needed.
• All patients, even normotensive, benefit from ACEI or ARB to control proteinuria to prevent higher risk of progression to ESRD. No longer recommend combination ACEI/ARB therapy.
• Dietary protein restriction has NOT been shown to be effective in slowing progress of CKD.
• Treatment is cause-specific:     
  • Minimal change: typically responsive to steroid therapy (although less responsive in adult disease compared to pediatrics).
  • FSGS: if primary, treat with steroids ± cytotoxic agents. If secondary, treatment is conservative (ACE-inhibitor, BP control). Decreased renal function and HTN common.
  • Membranous: roughly 30% spontaneously resolve, so conservative treatment is often selected for about 6 months; treatment may be started sooner if certain risk factors for rapid progression are present (male, >50 years, >4g/day of proteinuria, elevated creatinine, thromboembolism); consider age appropriate cancer screening.

Key Points 

• The nephrotic syndrome is characterized by massive proteinuria (>3.5g/d), edema, hypoalbuminemia and hypercholesterolemia.
• Patients are relatively immunosuppressed and pro-thrombotic.
• ACEI and/or ARBs to control proteinuria are important even if patient is normotensive.

Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185-9.

Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009 Nov 15;80(10):1129-34.

Madaio MP, Harrington JT. The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med 2001;161:25-34.

Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med 1998;338:1202-1211.