#112: The Re(n)al Truth Behind Proteinuria

June 19, 2024 | By Sam Masur

Audio

Summary:

U-r-ine for another urine episode, this time on proteinuria! We join the Kidney Chronicles Podcast, hosted by Drs. Emily Zangla and Annie Kouri, to discuss all scenarios proteinuria. They teach us about proteinuria in CKD, proteinuria in UTI, nephrotic range proteinuria, and why we should be ordering the urine protein to creatinine ratio!

Proteinuria Pearls

1. Urinalysis measures the albumin in the urine. If albumin leaks into the urine, the source is usually the glomerulus
2. Urine Protein to Creatinine ratio is the test of choice to evaluate for proteinuria. There are false positives AND negatives seen on the urinalysis
3. Urine Protein to Creatinine Ratio (PCR) > 0.2 g/g is considered abnormal. PCR > 2.0 g/g is considered nephrotic range proteinuria
4. Proteinuria due to hyperfiltration in chronic kidney disease (CKD) is treated with ACE inhibitors or ARBs
5. The two benign causes of proteinuria that can be evaluated by the generalist are orthostatic proteinuria and proteinuria with fever. Any persistent abnormal urinalysis/UPCR should be repeated during the first morning void
6. Minimal change disease is treated with corticosteroids. Most will relapse, so the anticipatory guidance is that patients with known minimal change disease should dip their urine daily with all infections, vaccines, or edema.

Proteinuria Show Notes

Basics

Urinalysis measures the albumin in the urine, and is reported in general terms. Anything over trace protein is abnormal, however the urinalysis is not the most reliable measure of protein – false positive and false negative rates can be as high as 10% (Parker 2020). The best test is the urine protein to creatinine ratio (PCR), which also quantifies the amount of protein. The urinalysis does not function as a screening test for protein. However, Dr. Zangla reminds us that the urinalysis should not be skipped because it offers other pieces of useful information like blood, specific gravity, etc.

We use the urine protein to creatinine ratio as a surrogate for the 24 hour total urine protein because it is much easier to collect. The ratio is used to control for the concentration of the urine. Urine protein to creatinine ratio greater than 0.2 g protein/g creatinine is considered abnormal. The correlation between 24 hour protein collection and spot protein to creatinine ratio is excellent in children (Huang, 2020)

In general, albumin is seen in the urine when something is wrong with the glomerulus. If something is wrong in the tubules, tubular proteins such as beta-2 microglobulin will be seen in the urine. However, glomerular protein is more associated with CKD, so most nephrologists will follow the urine albumin. Remember, the urine protein to creatinine ratio measures total protein in the urine, not just albumin.

Lastly, nephrologists recommend collecting a first morning urine sample to help exclude orthostatic proteinuria (see more below).

Proteinuria in Chronic Kidney Disease (CKD)

Patients with CKD, such as multicystic dysplastic kidney, can have a compensatory hyperfiltration. The increased pressure eventually leads to injury of the glomerular basement membrane, which will cause albumin to leak into the urine. 

Proteinuria from hyperfiltration is treated with ACE inhibitors to prevent progression of CKD (van den Belt, 2018). ACE inhibitors work to decrease proteinuria by dilating the efferent arteriole and decreasing the pressure through the glomerulus at the expense of the GFR. The ACE inhibitor dose can be titrated to a PCR of < 0.2g protein/g Cr if the blood pressure (or potassium) can tolerate it. Renal function should be tested approximately 1-2 weeks after initiation. The creatinine is expected to rise as well due to reduced filtration pressure related to efferent arteriolar dilation, but most nephrologists will continue treatment if the GFR increase is less than 30%. 

Dr. Kouri’s medications of choice are either lisinopril, enalapril, or losartan. 

Drs. Kouri and Zangla point out that not all CKD develop proteinuria in the same timeline. Therefore, if something isn’t adding up, remember to check for alternative causes of proteinuria.

Benign Proteinuria

Febrile Illness

Proteinuria is common in febrile illness, especially urine tract infections. Inflammation will often lead to capillary leak, including in the basement membrane of the glomerulus. 

Dr. Kouri recommends repeating the urinalysis after recovery for patients who have underlying kidney disease or are symptomatic, including hypertension or edema. Otherwise, the urinalysis likely doesn’t need to be repeated when the patient recovers.

Orthostatic Proteinuria

Proteinuria associated with walking around. This is often seen in adolescents and it is considered physiologic. The cause remains unclear, but it has proven to be benign over long term follow up (NEJM 1981). 

Dr. Kouri’s expert opinion is orthostatic proteinuria should not be nephrotic range proteinuria.

Strenuous Exercise

Proteinuria and hematuria are possible directly after intense exercise. The mechanism of action is unknown. However, Dr. Kouri says this is a diagnosis of exclusion and extraordinarily rare.

Persistent Proteinuria

These are the patients who have abnormal urine protein after undergoing a workup for some other chief complaint. The protein creatinine ratio should be repeated in a first morning sample. If the proteinuria is still present after 2 weeks, Dr. Zangla recommends the following workup:

• Kidney ultrasound to evaluate for congenital defects
• BMP, albumin to assess kidney function
• Blood pressure to assess for hypertension
• Urinalysis for hematuria evaluation
• Refer to nephrology

Nephrotic Range Proteinuria

Nephrotic range proteinuria is considered > 2 g protein/g creatinine. To meet criteria for Nephrotic Syndrome, one must have nephrotic range proteinuria, albumin < 2.5 g/dL, and peripheral edema. After making a diagnosis of Nephrotic Syndrome, Dr. Zangla recommends obtaining a CBC, C3, C4, and UA (if not already done). Hyperlipidemia is not needed to make the diagnosis, therefore the lipid panel can be obtained later in the disease course.

Once Nephrotic Syndrome is diagnosed, the next step is determining the etiology. Most patients ages 1-12 with nephrotic syndrome will have minimal change disease. If the patient is age < 1, age > 12, rapidly rising creatinine, signs of nephritic syndrome, or no response after 6 weeks of treatment, Dr. Kouri will obtain a renal biopsy for more definitive diagnostics.

Minimal Change Disease

Mainstay of treatment is corticosteroids. However, most centers will obtain Hep B, Hep C, and TB testing prior to initiation. Usual treatment algorithm is listed below:

• Prednisone 2 mg/kg/day up to 60 mg for 6 weeks
  • *IV methylprednisolone can be used if the gut has significant edema preventing systemic absorption
• Followed by 1.5 mg/kg every other day up to 40 mg for 6 weeks
• Dr. Zangla recommends famotidine or PPI for gut protection while on high dose steroids
• Treat symptomatic edema with diuretics. Risks of diuretics include increased rates of acute kidney injury and venous thromboembolism
• Salt and fluid restriction until remission
• Statins are only required if the patient is constantly relapsing
• Anticoagulation is not required in minimal change disease except for rare cases like central line placement
• Over 90% of patients who will respond to steroids will respond within the first 2 weeks

Approximately 75% of patients with minimal change disease will relapse. This happens mostly in the first 2 years, usually triggered by common infections or immunizations. However, most patients will usually outgrow the disease by their teenage years without long term complications. If patients have frequent relapses, steroid sparing agents can be used to prevent relapses. These include mycophenolate, rituximab, or tacrolimus. However, every relapse will still require steroids.

For anticipatory guidance, anytime a patient with known minimal change disease is sick or feeling swollen, he/she/they should be checking their urine for nephrotic range proteinuria.

Links

The Kidney Chronicles Podcast

Goal

Listeners will explain the causes of proteinuria, define nephrotic syndrome, and discuss the management of minimal change disease.

Learning Objectives

After listening to this episode listeners will…  

1. Recall the basic definition of proteinuria
2. Be familiar with urinalysis and methods to collect urine protein
3. Describe the differential for proteinuria in different clinical scenarios
4. Learn about nephrotic syndrome
5. Feel comfortable discussing management for minimal change disease

Disclosures

Drs. Zangla and Kouri report no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Wilson S, Zangla E, Kouri A, Masur S, Chiu C, Berk J. “#112: The Re(n)al Truth Behind Proteinuria”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ June 19, 2024.