Article Type : Short commentary
Authors : Hiroshi Bando, Yoshinobu Kato and Yoshikane Kato
Keywords : Chronic kidney disease (CKD); Diabetic kidney disease (DKD); Glomerular filtration rate (GFR); Body surface area (BSA); Cockcroft-Gault formula; Japan Multi-institutional Collaborative Cohort (J-MICC)
Recently, chronic kidney disease (CKD), diabetic kidney
disease (DKD), glomerular filtration rate (GFR) and related matters have been
in focus. Estimated GFR (eGFR) has been usually calculated by serum creatinine
and age corrected by body surface area (BSA). In contrast, Cockcroft-Gault
formula is another way that is not corrected by BSA. When the patient's
physique is significantly larger or smaller, BSA correction may remarkably
change the value of eGFR. Based on the data of Japan Multi-institutional
Collaborative Cohort (J-MICC) study, various factors influencing renal function
were investigated. As a result, problem solving degree in men revealed inverse
relationship with eGFR.
Recently, chronic kidney disease
(CKD), diabetic kidney disease (DKD), glomerular filtration rate (GFR) and
related matters have been in focus [1]. In Jan 2022, American Diabetes
Association (ADA) announced the latest guideline for diabetes management [2].
Authors have continued medical practice and research for various patients with
diabetes, CKD, DKD, hemodialysis (HD) and others [3,4]. Among them, discussion
concerning estimated GFR (eGFR) and pharmacokinetics for CKD has been found
[5]. For this field, several novel categories of diabetic agents were
introduced to clinical practice. They include Glucagon-Like Peptide 1 receptor
agonist (GLP-1RA), dipeptidyl peptidase-4 inhibitor (DPP-4i), and
sodium/glucose cotransporter 2 (SGLT2) [6]. GLP-1RA, DPP-4i and SGLT2 have been
evaluated to show beneficial effects to CKD, DKD, hypertension and others [7]. Some
perspectives for these would be described in this article.
In the light of
fundamentally medical knowledge, blood flow of humans has been well-known as
follows [8]. For a normal person, the amount of blood pumped from the heart is
5 liters per minute. For 20% of them, 1 liter of blood comes to renal blood
flow. Since about half of the blood is plasma, the plasma volume flowing into
the kidneys is calculated to be 500 ml/min. Among them, 100 ml/min is estimated
for the glomerular filtration rate (GFR) that is equivalent of 20% of the
flowing plasma. In the actual clinical practice, the estimated GFR (eGFR) has
been used for long. It has been calculated from the serum creatinine (sCr),
age, and sex that is corrected per 1.73 m2 of body surface area
(BSA).
Before calculating eGFR,
sCr level has to be measured in all subjects and patients. It has been usually
measured using an enzymatic method in the laboratories. The calculation equation
is as follows: i) male: eGFR (mL/min/1.73 m2) = 194 × serum
creatinine-1.094 × Age-0.287, and ii) female = i) x ×
0.739 [9]. The creatinine clearance (Ccr), which is an index of GFR, indicates
how many mL of creatinine (Cr) in plasma is excreted in urine per minute. To be
precise, the calculation is performed from serum Cr and Cr concentration in
livestock urine for a certain period of time. However, in addition to
glomerular filtration, some part of Cr is always secreted from the proximal
tubule. Therefore, the measured values are slightly different, and then Ccr
shows a value about 10-20% higher than GFR.
On the other hand, the
Cockcroft-Gault (C-G) formula is known as another calculation way [10]. In this
method, Ccr is calculated from sCr, age, sex, and body weight, and it may not
be corrected by BSA. The C-G formula (1973) is as follows. CCr = {((140–age) x
weight) / (72xSCr)} x 0.85 (if female). In the original calculation of C-G
formula, sCr was measured by the Jaffe method and showed 0.2mg/dL higher value,
due to the influence of contaminants in serum [11]. However, due to the small
effect of such substances in urine, the Ccr value was lower than the actual Ccr
value and close to the BSA-uncorrected GFR. Currently, sCr is measured by the
enzymatic method. Since this is applied to the C-G formula, a value close to
the actual Ccr can be obtained. Recently, a method including BSA amendment has
been proposed [12].
In the clinical practice,
many renal excretion-type drugs have been used for years. Each package insert
supports dose adjustment by Ccr value. Actually, eGFR is often displayed
automatically when sCr is measured. When considering the adjustment of drug
dose from decreased renal function, it is appropriate to carry out based on GFR
which is not corrected by BSA [13]. Consequently, the following two methods are
recommended for evaluating renal function when administering a renal
excretion-type drug. They are i) add 0.2 mg/dL to the sCr value created by the
enzymatic method and substitute it into the C-G formula to calculate Ccr, ii)
multiply eGFR by BSA/1.73 to obtain uncorrected GFR. The BSA calculation method
uses BSA (m2) = weight (kg) 0.425 x height (cm) 0.725 x
0.00718, that is from the DuBois formula.
The characteristic of
these two methods is that they do not use the numerical values of weight and
height. As renal function is almost normal and sCr is not high, the accuracy of
these methods is rather low. When the patient's physique is significantly
larger or smaller, the BSA correction may remarkably change the value. Then, it
is recommended to use these two methods. In actual medical care, there is no
strict response to the decline in renal function. If the renal function is
mild, the dose is kept to the normal dose. When the renal function is moderate,
the dose would be reduced to 1/2. If the renal function is severe, the dose has
been usually reduced to about 1/3 to 1/4, or the dosing interval is lengthened.
However, it is important to understand the principles of these calculations [14].
Latest impressive report
was found. Concerning risk factors for renal dysfunction, lifestyle-related
factors have been noted such as aging, diabetes, hypertension, obesity,
smoking, drinking, and lack of exercise. Furthermore, psychological stress may
be involved in decreased renal function, including depression and higher
goal-striving stress [15,16].
For examining
gene-environment interactions, the Japan Multi-institutional Collaborative
Cohort (J-MICC) study was launched in 2005. Using these data, various factors
influencing renal function were investigated [17]. Protocol included 70642
subjects (male/female) with 56.0/55.2 years old and eGFR 76.3/80.0 mL/min/1.73
m2. Various stress and coping strategies including problem solving,
emotional support seeking, emotional expression, positive reappraisal, and
disengagement were studied. As a result, problem solving degree in men revealed
inverse relationship with eGFR. For reference, problem solving showed
significantly positive correlation with grip strength [18]. As testosterone may
decrease renal function, men associated with high problem-solving trend
possibly show higher testosterone level and lower eGFR [19].
In summary, recent trends concerning nephrology
were introduced. These informative perspectives will hopefully contribute for
clinical practice for CKD, diabetes and cardiovascular diseases.