GFR vs. Creatinine Clearance

[WilliamLFreeman]

ESTIMATING GFR (GLOMERULAR FILTRATION RATE)

LDO has had several long postings on the significance to living kidneY donors (LKDs) of their estimated GFR (eGFR) calculated from serum creatinine.  An article in this month's American Journal of Kidney Disease (Mar 2011, volume 57, Supplement 2, page S9-S16) has important new information ( http://www.ajkd.org/article/S0272-6386(10)01594-5/abstract ).  Briefly, the usual equation used to calculate eGFR is called "MDRD" (Modification of Diet in Renal Disease Study), and was developed from 1,628 people already with chronic kidney disease with the average GFR of everyone being 40 mL/min/1.73m2 (= the number of milliLiters of blood filtered per minute adjusted for size of the person).  That equation is known to often underestimate real measured GFR at the upper range (from, say, 50 upward).

A new equation called "CKD-EPI" (Chronic Kidney Disease - Epidemiology Collaborative) was developed from 8,254 people, and validated as a separate data set of 3,896.  Both groups had people both without and with chronic kidney disease, and had an average GFR of 68.  The Kidney Early Evaluation Program Study then used both equations to calculate the eGFR for 116,321 people enrolled, followed them for an average of 3.7 years, determined who had died in that interval.  Using those data, it determined the mortality rate for each group of people defined by their GFR as determined by the MDRD equation and separately by the CKD-EPI equation.  RESULTS:  The CKD-EPI equation was a better predictor of mortality rate than was the MDRD.  In particular, people with eGFR 45-59 by MDRD but 60-89 by CKD-EPI, had a lower mortality rate than even the people with eGFR 60-89 by both equations.  That is, CKD-EPI-defined groups predicted risk more accurately than MDRD's.

The National Kidney Foundation now recommends replacing MDRD with CKD-EPI to calculate eGFR, because CKD-EPI is more accurate.  (Both equations require the laboratory to calibrate its serum creatinine measurements to the Cleveland Clinic Research Laboratory.)

SIGNIFICANCE for us LKDs

If your eGFR results are worrisome, and if your lab or primary care provider (PCP) uses MDRD to calculate eGFR, I recommend that you ask the PCP to use CKD-EPI & re-calculate, and also to check if the lab calibrated its serum creatinine measurements to Cleveland Clinic Research Lab.  If those results are still worrisome, ask to get a measured GFR (mGFR).  The usual mGFR is done by a 24-hour urine collection plus blood test.  (It, too, can be inaccurate.  A more accurate test uses Iothalamate, but is expensive.)

More importantly, please realize what the classification of GFR of 30-60 by itself really means to us LKDs.  By itself, it means to LKDs:  no-one knows!   

That group, "Chronic Kidney Disease Stage 3," is defined by the value of GFR alone; the definition does not require having chronic kidney disease or another disease known to be life-shortening and also adversely affecting GFR -- namely diabetes, high blood pressure, or heart disease -- in people with 2 kidneys.  (CKD 4 and CKD 5 require having chronic kidney disease.)  Most people with 2 kidneys and GFR 30-60 have one or more of those diseases, and thus are at high risk to die prematurely from them.  That definition, however, was not developed in LKDs otherwise healthy, that is, LKDs without chronic kidney disease (shown by abnormal results of urine or blood or other tests) or diabetes or high blood pressure (especially not well controlled) or heart disease -- but simply "GFR 30-60."  That definition also did not account for person's age; because most people's GFR decreases slowly as they get older, even if they remain healthy.

No-one has studied a large group (2,000+ probably is needed) of LKDs of different ages without evidence of chronic kidney disease, diabetes, high blood pressure, or heart disease -- and followed them for several years to see how many died and what happened to their GFR, and compare those results to a similar large group of people with 2 kidneys.  Until such a study (or similar) is done, no-one knows if mGFR of 40-60 is a risk factor at all for LKDs, or carries the same risk as it does for people with 2 kidneys with the same mGFR, or ...?

GFR has more value to the health of us LKDs for a different reason:  it shows trends.  If your/our GFR gets lower relatively rapidly, it may well indicate a problem that needs to be evaluated, diagnosed, and treated.  Thus, the trend of GFR over time is more important than in which group your/our GFR is as defined by and for people with 2 kidneys.

Even more important, of course, is doing what so many have written so frequently on LDO:
  *   measure blood pressure and blood glucose at least yearly;
  *   follow a healthy lifestyle even more carefully than before donating (= low salt, low fat, diet; moderate exercise 30 min/day 5 days a week);
  *   treat early high blood pressure (systolic 130+ or diastolic 80+) with more life-style adjustment (more intense diet, exercise, etc.), and if needed medicines;
  *   treat diabetes with more life-style adjustment (more intense diet, exercise, etc.), and probably medicines.

I have the full article.  If you want to read it, please e-mail me (see my Profile).

Bill

[Sarah in Maine]

Thanks so much for the update, Bill!

[WilliamLFreeman]

ADDENDUM:  You/we can calculate your eGFR using the CKD-EPI formula yourselves, at
   http://www.nephromatic.com/egfr.php
Enter your serum creatinine (in mg/dL -- milligrams per deciLiter) and age, and check whether you are:
  male or female,
  black or other [e.g., white, Asian, Hispanic, etc.],
  CKD-EPI [not MDRD, unless you want to see that calculation].

My own values of eGFR and mGFR show how complicated interpretations may be, however.  In Oct 2009, my serum creatinine was 1.33, my eGFR (estimated GFR) was 55 by CKD-EPI, while my mGFR (measured GFR) was 66.  12 MONTHS LATER, my serum creatinine 1.2, eGFR by CKD-EPI was 61, and mGFR was 64.  From 10/2009 to 10/2010, my serum creatinine improved (i.e., went down), my eGFR improved (went up), but my mGFR was almost the same (given the slight variability around the "true" value of the 24 hour urine collection).  Did my kidney function actually improve from 2009 to 2010?  No.  I had done more intense, heavier, daily exercise in the days before my 24 hour urine collection+blood test in 2009 than in 2010, so my serum creatinine was a bit higher due to the greater amount of muscle breakdown leading to greater release of creatinine into the blood in 2009 than in 2010, while my actual creatinine clearance was basically the same both years.  The point of this example is that level of serum creatinine is determined not only by real GFR, but also by other factors such as amount of heavy muscle use.  Therefore, a single higher serum creatinine value, & consequently lower eGFR, may not be quite as worrisome as at first glance.

Wikipedia gives the 8 (eight!) different CKD-EPI equations if you want to calculate your CKD-EPI values in a spreadsheet.  (Because almost all of us have serum creatinine values more than 0.7 mg/dL, only 1 of 4 equations wouls apply to each of us -- depending on whether we are female of male, and black or non-black.  See
   http://en.wikipedia.org/wiki/Renal_function#Estimated_GFR_.28eGFR.29_using_the_CKD-EPI_formula
No, I have not read about which formula to use for people who are mixed race/ancestry of black plus non-black.  :-)  Probably use the "black" equation.

Bill

[Donna Luebke]

Bill,

Have you read the medical articles about using both ACE-inhibitors and sodium bicarbonate in the setting of low GFR in order to preserve or improve GFR?  I am in the midst of reading about 6 articles which have been published in the last 2 years.  If not, I will PDF them so can read.  Makes sense for us as donors.  The authors comment that has shown a benefit in patients they studied with GFRs on 40s and 50s but could even play a role for those like me who have not dropped this low.  Bicarbonate treats the tubular acidosis which occurs in compensating nephrons.  Need to discuss with my physician at appointment on April 4th.  I am networking with physician/scientist nephrologists without transplant associations have no conflicts of interest. 

[Oldnslow]

It's been 2 years 4 months since I donated.   Just received my lab results back and my creatin level is 1.5 which is pretty much unchanged for the last 1.5 years.   Using the MDRD method my GFR is 51, with the CKD-EPI it's 50, both putting me at a level 3 CKD.   Oh well.  I feel the same as always.   BP is 120/80.     Transplant center says this is a normal range for a donor.   Not much choice, eh? 

Oldnslow

[WilliamLFreeman]

Oldnslow,

Our only choice we can control is to behave as healthily as we can.   

But I agree with your Center -- your eGFR is probably normal for a donor and not-to-worry.  But, as I said in my first & second posts, no-one knows for sure.  But let's not worry about what we do not know, and cannot know for a while at best.

Us oldsters need to stick together!!   

Bill

[Donna Luebke]

Bill,

Just to add--labs that perform a basic metabolic panel which includes the BUN and creatinine may now also include the eGFR.  The goal is to identify individuals who may have CKD which has been undiagnosed.  This is a great move especially if the person needs treated to avoid a further decline.  For those with one kidney, as you note here is much more that needs checked in order to get a more accurate diagnosis as to whether or not this person is in trouble.  Thanks for posting all this detailed info.  Long term monitoring and lifestyle are important.  The American Heart Association website has guidelines folks can follow which also include no smoking. 


My creatinine has been 0.8-1 for the last 17 years.  I keep a BP log for my primary care physician since only see him once per year.  Do my best to live healthy.  The EMR or electronic medical record is good for us, too.  Due to having one kidney, I was flagged as a person with chronic medical issue--very good in that is keeps my health care providers on their toes every time they see me. 

Donna

[stevewin@windstream.net]

BILL/DONNA,You are helping all lkd's  make better choices and healthy lifestyle changes with the info you are writing about. i am starting to meet with a nutritionists next week,trying to get my medical records before and after the transplant. i will let her know of this information .this is usable info for us.     thanks    steve windle

[brenda]

Can someone explain the difference between GFR and Creatinine Clearance?
My pre-donation eGFR was 67; my Creatinine Clearance (CrCl) was 110; my post-donation eGFR = 42, my CrCl = 60. They are based on the same serum creatinine samples.  Obviously these two tests are measuring different things, but what?

My concern is to figure out how my kidney is doing. My transplant center says, "Go with the higher number! You're fine!"
When I read the research, CrCl is not usually the measure reported - though it is easy to calculate from the same serum samples that the subjects gave to get an eGFR.  For this - and many other reasons - I am not reassured by the Georgetown medical staff.  Anybody got a better explanation?

Thank you,
Brenda
Donated 5/17/2011
at Georgetown University Hospital

[Clark]

Dear Brenda,

  Please consult with your primary care physician, and if warranted, seek a referral to an independent nephrologist.  Did you consult with an independent donor advocate before you donated?  Asking that individual for a clearer explanation may or may not get you one, but it should alert the transplant center that there's an as yet unfulfilled need for improvement.  Best wishes.  Do let us know what your learn and if you get better answers from the transplant center.

[Clark]

Also, you may want to print Bill Freeman's excellent thread on this topic and take it with you: https://livingdonorsonline.org/ldosmf/index.php?topic=141.0

[Donna Luebke]

Most electronic medical records use the MDRD-GFR which is one calculation and per your note, this number is low.  While your creatine clearance is 60, this is not the number used in the MDRD-GFR which says if is >60 you are OK.  Ask what is the transplant center lab's cutoff for creatinine clearance.  Get copies of all test and medical record notes the transplant center has and take this to a nephrologist.  If is a surgeon telling you that you are OK, remember that surgeons are not medical experts in kidney function or kidney disease.  Their training is not focused on medical care of patients. 

[WilliamLFreeman]

Brenda,

You already received good advice in the prior responses.  Let me add a bit.

It looks like you thought the answer "Go with the higher number! You're fine!" was not satisfactory.  If I had received it, I would have thought it unsatisfactory, too.  Why go with the "higher" number?  Any "higher" number?  Why not "lower"?  Etc.  Sometimes a simple, quick, re-assurance produces more worry, because it is too simple and too quick.   

"GFR" and "creatinine clearance" and "e-GFR" [= estimated-GFR] refer to the same thing -- Glomerular Filtration Rate [= "GFR"].  But each gets there in different ways.  So, let's start at the beginning.  [This will be a long post.]

The "glomerulus" is the first part of the microscopic unit in the kidney that filters certain chemicals from the blood, such as urea, and passes them out in the urine.  I do not remember how many glomeruli [= plural of glomerulus] a typical person has in their 2 kidneys, but I assume the number is in the 100-thousands to millions.  The total process to produce urine is quite complicated, but we do not need to discuss it here.  The important point is that most chronic kidney disease, including chronic renal failure, is due to a decrease in the effectiveness of that first filtering step, by the glomeruli.

"GFR" is expressed in terms of volume filtered per unit time -- usually "ml/min" [= milliliters per minute {or cc -- cubic centimeters -- per minute}].  The "normal" youngish adult has a GFR of 100 to 130 ml/min.

A way to measure "real GFR" [my term] -- GFR that is totally accurate -- is cumbersome and expensive.  (It is done by injecting a harmless chemical, inulin, into the blood, and then measuring how much inulin is "cleared" or filtered in a given unit of time.)  Moreover, that method measures real GFR [= the filtration rate of all glomeruli added together] only over a short period of time; but real GFR varies somewhat during the course of a day -- asleep vs. awake, exercising vs. resting while sitting, etc.

A simpler method uses creatinine, a chemical that the body makes continually, and that is cleared or filtered by the glomeruli.  That measurement is "creatinine clearance [CrCl]."  It is not quite correct to say that CrCl "is easy to calculate from the same serum samples that the subjects gave to get an eGFR."  CrCl requires not only serum creatinine [Cr], but also the total urine produced over a time period (usually 24 hours).  The time interval is needed to get the "per unit time" of the CrCl.  The urine is needed to get "how much creatinine did the glomeruli filter from the blood into the urine during that time," that is, the Creatinine Cleared [= "filtered"].

To measure CrCl one needs:
  *  serum creatinine level [in milligrams per ml/Dl = milliliters per deciLiter];
  *  total urine volume produced over 24 hours [in milliliters];
  *  total urine creatinine in the total urine [in milligrams].
Note that 2 of the 3 measures needed come from the 24 hour urine.

The formula for CrCl is:  (urine creatinine X urine volume over 24 hours) divided by (serum creatinine X 24 [hrs] X 60 [min]).  The CrCl, then, is a "measured GFR" [mGFR].

Unfortunately, the 24 hr CrCl is not fully accurate, compared to the gold standard method using inulin.  ON AVERAGE, it overestimates "real GFR" by 10% - 20%.  That range of overestimating is an average, meaning that is some people the overestimation is more than 20%, and in others is less than 10%.

CrCl is inexpensive -- but, as we know, is cumbersome for the person collecting the urine.  An even less expensive, and not as cumbersome, method is "eGFR" -- estimating GFR from the serum creatinine.  Several different formulae exist, a recent one being "MDRD" that Donna referred to -- Modification of Diet in Renal Disease.  A more recent formula is "CKD-EPI" -- Chronic Kidney Disease - Epidemiology Collaborative."  See my post listed second from the top of Living Donors Forum p. 1, "ESTIMATING GFR (GLOMERULAR FILTRATION RATE)" for a description of both, and why CKD-EPI may be a closer estimation of real CFR than MDRD.  Both tend to underestimate real GFR, on average, although CKD-EPI less so than MDRD.  (Brenda, the Georgetown Lab probably used MDRD -- feel free to ask to find out.  Also, feel free to ask them to calculate eGFR by the CKD-EPI formula.)  Your eGFR probably was an underestimate of your real GFR.  The "e" of "eGFR" says it was an "estimate by a simply calculation of serum Cr alone."

So, what is YOUR "real GFR"?  You, Georgetown, nephrologists, cannot say for sure, without a more accurate test being done.  (An iothalamate test is more accurate than a 24-hour urine CrCl, but is quite expensive.)

The more important question is, "What will a more accurate GFR mean to you and your life?"  Please see the section "SIGNIFICANCE for us LKDs" in my prior post mentioned above.  Let me summarize that here.

SUMMARY of "SIGNIFICANCE for us LKDS"

  1]   No-one knows what range of values of eGFR or mGFR would represent "Stage 3" of Chronic Kidney Disease in people with one kidney due to having donated the other kidney!  ["Stage 3" in people with 2 kidneys is "less than 60 ml/min" -- specifically, GFR 30-59 ml/min with or without other evidence of kidney disease.  LKDs end up with their GFR being, on average, 65% [60% to 75%] of their pre-donation GFR.]  "No-one knows" because medicine, transplant medicine specifically, has not yet studied the question -- or not yet finished such a study, that would require 20 years of follow-up of thousands of LKDs, recording *EVERYONE's* cause of death, and total renal and cardiovascular disease status.  (For what is it worth, I expect the equivalent value for us LKDs would be something like "less than about 50 ml/min" -- but I do not KNOW that!  Take it or leave it.  ]

  2]   Is there anything Georgetown, I, or anyone can do to reduce your worry?  I recommend the opposite:  all LKDs, including I, should continue to worry, no matter what our eGFR or mGFR is -- but worry productively.  Why do I recommend that all us LKDs be worried?  God, evolution, or God through evolution [your choice], gave us 2 kidneys for a reason.  The second kidney is NOT "superfluous."  It is a kidney in reserve, in case something bad happens to one kidney, or chronic kidney disease starts.  (If people with chronic kidney disease have 2 kidneys, the disease will progress more slowly.)  We LKDs gave away our "reserve kidney" to someone else.  We LKDs thus should worry productively, about what can we to take good care of our one kidney.

  3]   What should productive worry focus on?  Making sure our one kidney is happy and healthy, by adopting a lifestyle that follows what Donna and so many others have preached here on LDO:
   *   measure blood pressure and blood glucose at least yearly;
   *   follow a healthy lifestyle even more carefully than before donating (= low salt, low fat, diet; moderate exercise 30 min/day 5 days a week);
   *   treat "pre- high blood pressure" (systolic 130+ or diastolic 80+) with more life-style adjustment (more intense diet, exercise, etc.), and if needed medicines -- to prevent actual high blood pressure;
   *   if overweight, prevent type 2 diabetes with more life-style adjustment (more intense diet, exercise, etc.);
   *   prevent heart attacks, strokes, and blockage of the larger arteries to the kidneys by keeping cholesterol levels where they should be by diet, and by medicines if needed;
   *   if high blood pressure or diabetes does/do develop, treat / manage it/them aggressively with diet, exercise, weight loss, and probably medicines.

  5]   "What, me worry?"  YES, just enough to make my one kidney happy by keeping it healthy. 


For those who want to see a good schematic drawing of a glomerulus [= an arteriole tuft enclosed in a bag with microscopic holes that let urea etc. out to the surrounding capsule that collects the urine], see http://en.wikipedia.org/wiki/Glomerulus

For those who want to read more detail about GFR, see http://en.wikipedia.org/wiki/Glomerular_filtration_rate

Bill

[Donna Luebke]

Bill

Thanks for this excellent and detailed note.  Many of the lifestyle or health issues you note become more of a concern as we 'age' with one kidney.  There are aging effects that occur to our kidneys so one kidney means we 'worry' just a little more.  I donated in 1994 and yes, I do worry.  I check my blood pressure several times per week, get at least annual bloodwork, and address any risk factors for cardiovascular disease.  My primary physician calculates an estimated creatinine clearance just to be sure my trend is not going south.  I do not have any family risk factors either which has always been reassuring.  No diabetes, heart disease, stroke or hypertension. 

Donna

[sherri]

Bumping up this thread for Nancy