by George Taniwaki

The most common measure of kidney function is called the glomerular filtration rate (GFR). Traditionally, a GFR level of 90 or higher (measured in mL/min/1.73m^2) is considered normal. Kidney disease is categorized in stages from 1 to 5 with each stage defined by a GFR range. Patients with chronic kidney disease (CKD) generally progress though the stages until they reach stage 5. At this point they will require renal replacement therapy, meaning dialysis or a transplant. Details are given in the table below.


Stage

Description
Estimated GFR (mL/min/1.73m2)
0 Normal kidney >90
1 Slight kidney damage but with normal or increased filtration >90
2 Mild decrease in kidney function 60-89
3 Moderate decrease in kidney function 30-59
4 Severe decrease in kidney function 15-29
5 Kidney failure (requires replacement therapy) <15

Traditional definitions of the five stages of kidney disease, they may not apply to kidney donors with one kidney

Patients with stage 4 and stage 5 are much more likely to also have hypertension (chronic high blood pressure) and are more likely to die from a cardiac event (heart failure). About 20% of patients in these categories die each year.

Estimated versus measured GFR

Before looking at the results of studies, let’s define GFR and how it is measured. Glomerular filtration rate is the volume of fluid (in mL) that can be filtered from the renal (kidney) glomerular capillaries per unit time (in min) adjusted for the body surface area (BSA) of the patient (that’s the reason the 1.73m^2 appears in the denominator; it represents the height of the average male of about 5 foot-8 inches).

The most accurate way to measure filtration rate is to use find a chemical that has a steady level in the blood, is completely filtered by the kidneys (arrow 1 in figure below) and is not reabsorbed (2) or secreted (3).

Physiology_of_Nephron

Schematic of function of kidney. Image from Wikipedia

The most common chemical used in GFR measurement is a protein called creatinine. It is a waste product from muscle cells and is produced at a fairly steady rate. As described in a Mar 2008 blog post, a test called the creatinine clearance rate (CCR) can be used to measure the amount of creatinine removed from the blood and excreted in the urine in a 24 hour period. A blood sample is taken to measure the concentration of creatinine in the plasma. These two measurements are used to calculate GFR. Since the concentration in both the urine and plasma are directly measured, this is called measured GFR or mGFR.

Collecting a 24 hour sample of urine is cumbersome and it is hard to get patients to do it correctly. (I’ve done it three times in the past two years while being evaluated as a kidney donor, so I’ve become accustomed to the routine.) To avoid the 24-hour urine collection, doctors estimate the GFR using just the serum concentration. These estimates are based on the person’s age (muscle mass declines with age), gender (women have less muscle mass then men), weight (thin people have less muscle mass), and race (blacks have higher muscle mass than whites). GFR calculated in this way is called estimated GFR or eGFR.

A scary story for donors

After their surgeries, some kidney donors are told they have low GFR, below 60 ml/min/1.73m^2, and thus have Stage 2 chronic kidney disease. A recent paper presented at the 26th Annual Congress Eur. Assoc. Urology reports that one year after undergoing a live donor nephrectomy, more than half of donors will have CKD as defined by the traditional stages. The paper is described in Renal and Urology News Mar 2011.

In the study, a team led by Nilay S. Patel examined data from 3,424 living donors in the United Kingdom who had preoperative and one-year follow-up data available. “The fall in GFR [following donation] has been underestimated to date,” said Dr. Patel. Potential donors should be informed of the risk of renal function decline following donation.

Well, this is rather scary. Is it safe to donate a kidney?

Rising GFR after donation

In the study above, Dr. Patel notes that after the initial decline in GFR, it appears to remain stable for at least five years. Further, donors rarely suffered adverse cardiovascular events or cardiac mortality.

Among the 784 donors with five years of follow-up data available, only 0.4% experienced non-fatal cardiac events and 0.05% died from cardiac events. New-onset hypertension was diagnosed in 10% of donors.

This is reassuring. Let’s take a look at the results from some other recent studies that investigated GFR after kidney donation.

A study of 237 Japanese donors is reported in Clin. Exper. Nephr. Aug 2010. The authors found that the median estimated GFR at the time of donation was 79, meaning that many donors could be considered to have stage 2 kidney disease. After one year, the average decrease in eGFR was down 40% to 48, meaning most (85%) Japanese kidney donors would be considered having stage 3 kidney disease.

This sounds bad. However, data collected over the next four years shows that on average, the eGFR rose by 1 mg/mL/1.73m^2 per year. This upward change was seen regardless of the absolute values of estimated GFR at the time of donation or one year afterwards. This is unexpected because GFR generally declines with age. Thus, among these Japanese kidney donors, low GFR was not a sign that kidney disease will progress.

A Swedish study published in Nephr. Dialy. Transpl. May 2011 (subscription required) and described in Renal and Urology News Mar 2011 confirms that people who donate kidneys experience an increase in estimated GFR for more than a decade after nephrectomy.

The researchers looked at 573 kidney donors who had a mean age of 47 years at the time of donation and with a mean time since donation of 14 years.

The findings suggest that for 30-year old donors, the median estimated GFR increases for 17 years, then remains constant for 8 years, and then declines thereafter. For a 50-year old donor, the median eGFR increases for 13 years and then declines. The gains were less pronounced for measured GFR. The data, developed using multiregression analysis are shown below.

Median_eGFR Median_mGFR

Curves showing median eGFR (left) and median mGFR (right) for a typical 30-year-old donor (black line) and 50-year-old donor (gray line). Graphics from Nephr. Dialy. Transpl.

Difficulty in measuring GFR

Finally, there is some research that indicates that using the standard calculations for measured GFR and estimated GFR is not appropriate for kidney donors and are not reliable ways to determine if they have kidney disease. An article in Clin. J. Amer. Soc. Nephr. Jan 2010 reports that eGFR underestimated actual kidney function while  mGFR overestimated it. The error was larger the older the donor.

Mark Wedel, a retired MD and kidney transplant recipient, provides the following comment on these studies.

“I think the primary question [these studies raise] is whether or not this change is what one would expect [to occur in these donors] after having half their renal mass removed, and secondarily, does that GFR actually increase as the remaining kidney hypertrophies in response to the donation nephrectomy.

“I’m not aware of any serial data on renal mass following nephrectomy. Ideally, I’d like to see a study correlating GFR with renal mass plotted against time [since transplant].”

Comparing donors to patients

I have drawn two graphs below to represent the change in GFR for two people. On the left is GFR data plotted for a hypothetical 40-year-old woman. Her GFR declines for two years going from 98 to 78 before she is diagnosed as having kidney disease. At this point, which we will call year 0, she has stage 2 kidney disease. Over the following four years her GFR continues to decline and reaches 40 in year 4 meaning she is now at stage 3. If the trend continues we can expect her to reach stage 5 eventually.

On the right is GFR data plotted for another hypothetical 40-year-old woman. Her GFR is relatively flat for two years until she donates a kidney. At her first medical examination after her donation, the lab test show her GFR is 66. We will call this year 0. Her GFR is lower than the 78 level that was used to diagnose the woman in the paragraph above as having stage 2 kidney disease. Should she be concerned? Maybe, maybe not. Let’s see what happens over then next four years. In the case I have illustrated, her annual GFR test results are 76, 83, 88 and  86. These GFR values are still below normal and lower than her pre-nephrectomy values. However, they are trending upward rather than downward. Saying this woman has stage 2 or stage 1 kidney disease doesn’t seem accurate or useful in describing her situation.

This does not mean you can ignore the lab results. However, it means you need to look at the trend as well as the absolute value when evaluating GFR results after a kidney donation.

Note that the same analysis holds true for the kidney transplant recipient as well. Checking to see if GFR is trending upward or downward can play an important role in deciding if the transplant is successful.

GFRpatient   GFRdonor

Change in GFR for a hypothetical kidney patient (left) and a hypothetical kidney donor (right) both show below normal kidney function, but only the one on the left should be considered kidney disease. Graphics by George Taniwaki

[Update: Added byline. Fixed a numerical error and clarified the CKD level.]

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