Nephrosis (Nephrotic Syndrome)

I. Problem / Condition.

Nephrosis (nephrotic syndrome) is caused by a variety of diseases that all lead to decreased kidney ability to prevent leakage of macromolecules, particularly proteins, into the filtrate. This leakage leads to protein wasting in the urine and can lead to the nephrotic syndrome.

Nephrotic syndrome is characterized by the following:

Proteinuria (>3 g in 24 hours or spot urine protein/creatinine ratio > 3.5 mg protein/g creatinine).

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Hypoalbuminemia (serum albumin < 3 g/dL).

Hyperlipidemia (total cholesterol level usually greater than 300 mg/dL).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Early loss of protein into the urine is asymptomatic and usually only noted on screening urine studies.

Patients who present with signs and symptoms of protein loss or frank nephrotic syndrome will usually present with diffuse edema and less commonly with thromboembolism, infection or hyperlipidemia.

In patients presenting with edema, nephrosis must be distinguished from other causes of decreased oncotic pressure/protein loss such as congestive heart failure, cirrhosis, or severe malnutrition.

Nephrosis also should be distinguished from glomerulonephritis. Glomerulonephritis is primarily characterized by red blood cell casts, dysmorphic red blood cells rather than protein loss in the urinary filtrate.

Nephrotic syndrome can be primary (idiopathic), familial, or secondary. The etiology of nephrotic syndrome may be elicited by history, family history (evaluate for congenital causes) and physical especially in patients with systemic diseases such as diabetes, systemic lupus erythematosus (SLE), HIV, amyloidosis, multiple myeloma, lymphoma, preeclampsia or history of associated medications such as nonsteroidal anti-inflammatory drugs, interferons, bisphosphonates, lithium, gold, or penicillamine.

B. Describe a diagnostic approach / method to the patient with this problem.

The initial step in diagnosis is establishing the presence of protein in the urine on a simple urine dipstick. Once proteinuria is established it can be more precisely quantified through either 24-hour urine or a spot urine protein to creatinine ratio.

Nephrotic syndrome can be divided into primary (idiopathic), familial or secondary causes. In adults, the most common cause of nephrosis is diabetes – historical detail or screening blood glucose or hemoglobin A1C would aid in the diagnosis of diabetic kidney.

Other systemic diseases associated with nephrotic syndrome include amyloidosis, multiple myeloma, lymphoma, preeclampsia, systemic lupus erythematosus and HIV-associated nephropathy. A detailed medication history is also important as nephrotic syndrome has been linked to certain medications.

For non-diabetic patients, renal biopsy will be the definitive test to establish the diagnosis of glomerulonephrosis and determine an underlying cause.

Membranous nephropathy (MN), minimal change disease (MCD) and amyloidosis account for approximately 60% of all cases. Less common causes include focal segmental glomerular sclerosis (FSGS), proliferative nephropathy and diabetic nephropathy.

Membranous glomerulonephritis

The second leading cause of primary nephrotic syndrome and more frequently occurs in adults older than 50 years. It is associated with other conditions including SLE (most commonly Class V lupus nephritis), hepatitis B and C virus infections, malaria, malignancies, and medications such as NSAIDs. It has the highest prevalence of renal vein thrombosis compared to other causes of nephrotic syndrome.

MGN is an immune complex disease and biopsy shows diffuse thickening of the glomerular capillary wall on light microscopy and intramembranous electron-dense deposits located in the subepithelial aspect of the glomerular basement membrane on electron microscopy.

Focal Segmental Glomerular Sclerosis (FSGS)

FSGS is the leading cause of nephrotic syndrome in African Americans and is characterized by nephrotic syndrome, hypertension and elevated serum creatinine. FSGS may be primary, familial, or secondary. Some secondary causes of FSGS include HIV, heroin use, hepatitis B and C, morbid obesity, reflux nephropathy and medications. FSGS has a similar histology to minimal change disease (loss of foot process) but is characterized by scarring or sclerosis involving some (focal) glomeruli, which are affected only in a portion of the glomerular capillary bundle (segmental).

Minimal Change Glomerulopathy (MCG)

MCG is also known as nil disease. As implied by the name, in minimal change disease very few abnormalities are seen on biopsy. The glomeruli appear normal except for podocyte fusion and effacement. While the exact cause of minimal change disease is unclear it is associated with atopic diseases and lymphomas.

Other less common causes of nephrotic syndrome include membranoproliferative GN and IgA nephropathy.

1. Historical information important in the diagnosis of this problem.

Possible etiologies of nephrotic syndrome may be elicited by history including family history to evaluate for congenital causes as well as systemic diseases such as diabetes, systemic lupus erythematosus (SLE), HIV, amyloidosis, myeloma, lymphoma and associated drugs such as nonsteroidal anti-inflammatory drugs, interferons, bisphosphonates, lithium, gold, or penicillamine associated with nephrotic syndrome.

Except in presumed diabetic nephropathy, a biopsy is needed to determine the underlying etiology.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

No physical exam findings are diagnostic for nephrosis. With increasing protein loss in the urine, however, several physical exam findings will emerge:

Diffuse edema, patients will often have peri-orbital edema shortly after awakening.

Lean muscle mass loss.

Muehrcke lines (parallel white lines on fingernails).

Other symptoms may be related to complications of nephrotic syndrome.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Significant proteinuria (>3 g in 24 hours or spot urine protein/creatinine ratio > 3.5 mg protein/g creatinine) is diagnostic of nephrotic syndrome. Urinalysis may demonstrate casts, oval fat bodies, and fatty casts; plain microscopy may reveal maltese crosses under polarized light.

Measurement of serum creatinine to assess the degree of renal impairment, serum albumin, and total cholesterol is also indicated.

Many will follow up with serologic studies to understand the likely source for nephrosis. From the discussion above, this could include ANA and complement levels to help in the diagnosis of SLE; hemoglobin A1C for the diagnosis of diabetes; hepatitis B and C serologies along with serum cryoglobulins for the diagnosis of an underlying hepatitis; serum (and urine) protein electrophoresis for the diagnosis of multiple myeloma and possibly amyloidosis.

While these tests may be helpful in elucidating an underlying source, they are not in themselves diagnostic. The diagnostic test is renal biopsy.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

See discussion above (IIA) for description of patterns seen on renal biopsy.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

See IIB.

III. Management while the Diagnostic Process is Proceeding

A. Management of glomerulonephrosis.

Very little of the management is emergent. The focus should be on the treatment of underlying processes (e.g., diabetes, hepatitis, amyloidosis) and prevention of complications.

Lowering intraglomerular pressures and reducing protein excretion may slow the rate of disease progression through the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists. Monitoring for a decline in GFR and hyperkalemia are needed during the initiation and titration of these medications.

In minimal change disease, steroids can be of benefit. FSGS has a high recurrence rate and progression to ESRD and these patients benefit from steroids and immunosuppression.

Treatment of complications:

Edema-strict salt restriction and use of loop diuretics.

Hyperlipidemia – frequent monitoring of lipids and appropriate therapy with a statin.

Hypercoagulability – while patients can develop both arterial and venous clots, prophylactic anticoagulation is not recommended. Careful attention should be paid to any signs that would suggest an acute clot.

IV. What's the Evidence?

Kerlin, BA, Ayoob, R, Smoyer, WE. “Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease”. Clinical journal of the American Society of Nephrology. vol. 7. 2012. pp. 513-20.

Ruggenenti, P, Mosconi, L, Vendramin, G. “ACE inhibition improves glomerular size selectivity in patients with idiopathic membranous nephropathy and persistent nephrotic syndrome”. Am J Kidney Dis. vol. 35. 2000. pp. 381-391.

Hull, RP, Goldsmith, DJ. “Nephrotic syndrome in adults”. BMJ. vol. 336. 2008. pp. 1185-1189.

Sumnu, A, Gursu, M, Ozturk, S. “Primary glomerular diseases in the elderly”. World J Nephrol. vol. 4. 2015. pp. 263-70.