This week in Morning Report, we discussed the case of a patient referred to Internal Medicine for several months of progressively worsening shortness of breath, weight gain, abdominal distension, and swollen legs. After a comprehensive internal medicine evaluation, we landed on a diagnosis of Nephrotic Syndrome secondary to obesity. Let’s recap some of our key learning points from this case!

1. First, have an approach to edema

Edema is an extremely common reason for presentation to primary care, so it is important to have a systematic approach. I start by figuring out the pattern of edema – localized vs. generalized – and then thinking about the principles of what causes edema.

In general, swelling of the tissues happens if something is pushing fluid out (i.e., increased hydrostatic pressure), if there is a lack of things keeping fluid in (i.e., decreased oncotic pressure), or a few miscellaneous diagnoses. This approach is summarized in a nutshell below:

2. Before you understand nephrotic syndrome, understand the pathophysiology of proteinuric renal disease

Loss of protein in the urine is often identified as a cause of edema and/or anasarca. This proteinuria can be nephrotic range (>3.5g/day) or non-nephrotic range, and can occur due to a whole host of inflammatory and non-inflammatory conditions! Protein can be lost from the kidneys in 1 of basically 3 ways:

• Glomerular damage: Some process (e.g., infectious, inflammatory, etc.) is causing glomerular capillaries to be leaky and therefore increasingly permeable to protein. This causes protein to spill into the urine.
• Tubulo-interstitial damage: Some process (infectious, inflammatory, etc.) is altering the renal tubules’ ability to reabsorb protein, thus causing protein wastage.
• Overflow proteinuria: Some systemic process is causing way too much protein to be synthesized in the body, thus causing protein to be wasted in the urine. This can be due to things like paraproteinemia (e.g., multiple myeloma), leukemia, etc.

3. Know the different methods of quantifying proteinuria

There are different ways of quantifying proteinuria – spot collections (e.g., Albumin/Creatinine Ratios and Protein/Creatinine Ratios), or 24-hr collections. Each of these has practical and clinical advantages and disadvantages. These are nicely summarized in a previous CMR Blog post here.

As a key point, proteinuria does not always definitively signal renal disease! For example:

• Proteinuria can be present transiently in any illness state: Shock, infections of any kind including UTI, heavy exercise, significant transient hypertension, severe decompensated diabetes, etc. Always re-test for proteinuria after these conditions have resolved!
• Orthostatic/Postural Proteinuria is a benign condition found mostly in young people where protein excretion increases when the patient is upright, and decreases in the supine position. This is detected through separate daytime and nighttime measurements, generally with the assistance of a nephrologist.

4. Understand the manifestations of Nephrotic Syndrome

You’re all aware of the 4 cardinal manifestations of Nephrotic Syndrome, but there are a few important additional ones to be aware of as well! I have summarized all of these for you in the table below:

5. Have a general approach to Nephrotic Syndrome

Remember that Nephrotic Syndrome is just a collection of clinical findings. The actual disease itself, when examined under a microscope, can have several different pathologic manifestations, and can be due to primary (idiopathic) etiologies, or due to secondary diseases. We went through a high-yield way of thinking about these diseases (3 primary classes, and 2 additional classes with nodular disease manifestations), summarized below:

6. What workup should you send to investigate for nephrotic syndrome?

All patients with suspected nephrotic syndrome should have investigations that help confirm the diagnosis:

• 24hr urine/Cr collection
• Lipid panel
• Serum Albumin
• Routine bloodwork (CBC, lytes, Cr, Liver Enzymes)

Additional investigations to find the cause of nephrotic syndrome include SPEP, UPEP, Serum Free Light Chains, Hep B/C, HIV, VDRL, parasitic screening etc…these are sent based on patient history, clinical presentation, and risk factors.

Above all, never forget: every patient with new nephrotic syndrome should be referred for consideration of renal biopsy to obtain the diagnosis.

7. What are some principles of treatment in nephrotic syndrome?

In general, treatment for nephrotic syndrome involves a) making your patient feel better, b) treating complications of nephrotic syndrome and c) treating the underlying cause of nephrotic syndrome.

These are all nicely summarized in this basic review article!

I hope you enjoyed this Morning Report! Thank you all for participating.