Creatinine, Cystatin C and GFR

First, what are we talking about when we talk about kidney function?  We’re talking about how well the kidneys filter the blood.   This is the glomerular filtration rate (GFR).

Creatinine is a marker for kidney function because it is a substance that is produced by the body in a relatively constant manner and is eliminated by the kidney, mainly by glomerular filtration.  Therefore, when kidney function (GFR) decreases the serum creatinine will increase until it reaches a new steady state.

So the serum creatinine can be higher for 2 reasons

1. Increased production: The body is producing more creatinine
2. Decreased elimination: The kidneys are excreting less creatinine

Increased production: How does the body make creatinine?

Creatinine is made by muscle, therefore the more muscle mass a patient has the higher the creatinine will be for any given level of kidney function.  I said the amount of creatinine the body produces is relatively constant.  This is for a specific individual, the amount of creatinine produced will vary from person to person based on muscle mass.  However, in a given person the amount of creatinine produced should be relatively stable from day to day.

Given the interperson variability in muscle mass and therefore creatinine production, equations have been developed to estimate the glomerular filtration rate (eGFR) eGFR Calculator | National Kidney Foundation for a specific individual.  These equations take into account the age and sex of the patient as these are major determinants of muscle mass.

NOTE: The eGFR is only accurate if the creatinine is stable, in steady state.

• If the creatinine is increasing the eGFR will overestimate the true GFR
• If the creatinine is decreasing the eGFR will underestimate the true GFR.

When is creatinine not an accurate reflection of GFR 

• Situations where a person’s muscle mass is not typical for their age and sex
• Medications that block tubular secretion of creatinine
• Situations with increased creatinine generation
• Creatinine variability

When a person’s muscle mass is not typical for their age and sex

• Lower than normal/typical muscle mass:
  • Frail/ emaciated
  • Amputations, paraplegia, quadriplegia
  • Liver disease

In these cases the serum creatinine will overestimate kidney function.  The body is producing less  so the serum creatinine will be lower for any given level of kidney function (GFR).

• Higher than normal/typical muscle mass:
  • Bodybuilder

In these situations the serum creatinine will underestimate kidney function.  There is higher than normal creatinine generation,  so the serum creatinine will be higher for any given level of kidney function (GFR).

When tubular secretion of creatinine is impaired

Creatinine is the marker for gfr because it is mainly eliminated by glomerular filtration, mainly but not completely.  About 10% of creatinine is excreted by tubular secretion, secretion by renal tubules.   As kidney function declines (ie in CKD) this percentage excreted by tubular secretion increases.

The implication here is that meditations that block tubular secretion Medications that Increase Creatinine @BCNephro – YouTube will result in an increase in creatinine without affecting kidney function (GFR).

These include:

• Trimethoprim (in Bactrim)
• Cimetidine
• Dronedarone (Multaq)
• HIV meds
  • Dolutegravir
  • Cobicistat
• Cancer therapies
  • PARP inhibitors
  • Tyrosine kinase inhibitors

When creatinine generation is increased

Reasons why someone may make more creatinine than normal.

• Muscle breakdown
  • Rhabdomyolysis
  • Myositis
  • Strenuous exercise
• Diet
  • High animal protein diet
  • Creatine supplements

There may be decreased creatinine generation with a low animal protein or vegan diet.

Normal creatinine variation

Serum creatinine can change by 10% from day to day.  I attribute this to:

• Changes in diet
• Changes in hydration status.

I also question the precision of the test.  My experience with labs like labcorp is that if two physicians order a metabolic panel, instead of running the test once and sending a lab report to both physicians they run the same test twice and they get different results in creatinine on the same blood drawn from the same patient at the same time!  If I was labcorp I would be embarrassed by this and be motivated to run the test once.

Options when creatinine is suspected to not accurately reflect GFR

• Cystatin C
• Creatinine clearance
• Nuclear medicine GFR (exogenous filtration marker)

Cystatin C

Cystatin C is another substance that is eliminated by the kidney by glomerular filtration.  However, it is not produced by muscle.  It is produced by all nucleated cells at a relatively constant rate. Therefore in a patient where you may not believe the creatinine is an accurate reflection of kidney function (due to muscle mass as noted above),  you can check the serum Cystatin C to get another estimate of GFR.

Cystatin C is not perfect.  Although not affected by muscle mass it’s generation can be affected by other factors including:

• Thyroid disease
  • Hyperthyroid (increase)
  • Hypothyroid (decrease)
• Diabetes (increase)
• Steroids (increase)
• Obesity (increase)
• Inflammation (increase)

As kidney function is GFR, estimating equations for GFR have been developed for both creatinine and cystatin C.  There is a creatinine equation, cystatin c equation and a combined creatinine/ cystatin c equation.  eGFR Calculator | National Kidney Foundation In general the combined creatinine/cystatin C equation is the most accurate, but in clinical situations where you have reason to question the accuracy of either creatinine or cystatin c you may choose to use the alternate equation.

I often check the Cystatin C in this setting:

• An outpatient with mildly abnormal kidney function (elevated creatinine, decreased eGFR), that is stable
• Without other signs of kidney disease (such as proteinuria)

In these cases the cystatin c eGFR will often be normal.  I then check the CPK to look for a reason for increased creatinine generation such as myositis.

24 hour urine Creatinine Clearance

If the serum creatinine is stable, the amount of creatinine produced by the body each day will be excreted in the urine.  This clearance of creatinine can be measured and is an estimate of GFR.

Creatinine clearance = Urine creatinine (mg/dl) x Volume of urine (liters/24hrs)

                                    Serum Creatinine (mg/dl)

This result will be in:   liters     it is multiplied by       1000 ml/L        to convert to    ml

24 hrs                                   1440 min/day                            min

The 24 hour urine creatinine clearance is limited by the following

• It includes tubular secretion of creatinine (so will overestimate the GFR)
• Inaccuracies in urine collection (more or less than 24 hours)

However, it can be used as another way to estimate GFR in cases where the serum creatinine is believed to be an inaccurate reflection such as significantly decreased or increased muscle mass.

Exogenous Filtration Marker

There are exogenous filtration markers that can be administered and their clearance measured to estimate GFR.  These include:

• Iothalamate
• Iohexol
• EDTA
• DTPA

There are apparently ways to inject these markers and measure their clearance in the serum or in the urine over time. https://journals.lww.com/jasn/pages/articleviewer.aspx?year=2009&issue=11000&article=00008&type=Fulltext

I have never seen this done.  I have seen nuclear medicine split renal function scans report GFR, however my anecdotal impression was that they were underestimates.

Summary

Kidney Function or how well the kidneys clean the blood is assessed by the Glomerular Filtration Rate (GFR).  This is not measured in clinical practice but is estimated most often by the serum creatinine.  There are situations where this estimated GFR based on the serum creatinine may be inaccurate.  In these situations GFR can be estimated with serum cystatin C, 24 hour urine for creatinine clearance, or testing with exogenous filtration markers.