Pharmacokinetics: Renal Clearance Methods and Equations

This report delves into the critical aspect of renal clearance of drugs, particularly in the context of acute kidney injury (AKI). It defines renal clearance, emphasizing its importance in drug dosing for patients with AKI to prevent accumulation of harmful metabolites and adverse drug responses. The report explores various methods for measuring renal clearance, including glomerular filtration, renal drug metabolism, and tubular secretion, while also acknowledging the challenges in accurately evaluating these methods due to fluctuations in kidney function and fluid balance. The report highlights the Cockcroft and Gault equation, MDRD equation, CKD-EPI equation, and Jelliffe equation, providing a comprehensive overview of equations used to estimate renal clearance and glomerular filtration rate (GFR). The report concludes by reiterating the significance of renal clearance in guiding drug dosing and dialysis decisions for AKI patients, while also acknowledging the difficulties associated with accurate assessment, emphasizing the need for these equations to determine renal clearance.

Running head: PHARMACOKINETICS
PHARMACOKINETICS
Name of the Student
Name of the university
Author’s note

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Introduction
Renal clearance of drugs mainly reflects the excretion of drugs into urine by the Kidneys.
It is actually the neat result of the active tubular secretion, tubular reabsorption and glomerular
filtration. This paper focuses on the different methods to measure the renal clearance of the
drugs, the reason it is difficult to assess and all possible equations related to the methods. Renal
clearance of drugs is normally done for the dosing of drugs during acute kidney injuries that
requires dialysis.
Renal clearance of drugs
Renal clearance of a drug from the kidney can be defined as the capacity of the kidney by
which a kidney removes a particular drug from the plasma in unit time1.
Need of renal clearance of drugs in patients with Acute Kidney injury (AKI)
Acute kidney injury in patients requires drug dosing and dialysis. In order to accomplish
that it is necessary to determine the rate of the renal clearance of drugs by the kidney. Non
clearance of drugs due to acute kidney injury may facilitate accumulation of the harmful
metabolites in the body which can be detrimental2. Accumulation of the pharmacologically
active drug may give rise to enhanced drug response.
1 Khwaja, A., 2012. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical Practice, 120(4),
pp.c179-c184.
2 Matzke, Gary R., George R. Aronoff, Arthur J. Atkinson, William M. Bennett, Brian S. Decker, Kai-Uwe Eckardt,
Thomas Golper et al. "Drug dosing consideration in patients with acute and chronic kidney disease—a clinical
update from Kidney Disease: Improving Global Outcomes (KDIGO)." Kidney international 80, no. 11 (2011):
1122-1137.

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Drugs like allopurinol, codeine, meperidine and several more can give rise to
hypersensitive drug reaction, anxiety, agitation, depression of the central nervous system2.
The renal clearance of a drug is proportional to the renal function of a kidney. Renal
clearance of drugs is necessary to determine the doses of drugs in patients suffering from acute
kidney diseases. Drug clearance refers to the elimination of the drug form the body by the
kidney. In order to be eliminated, the drug has to be channelized to the kidney by the plasma
flow. Hence it can be said that the rate of drug elimination is proportional to the plasma
concentration3.
The ionized drugs which are not able to cross the liver membrane do not undergo hepatic
metabolism and are likely to undergo renal clearance3.
The kidneys are the primary organs that are responsible for excreting the water soluble
substances from the body. The kidney helps in excreting the drugs that are not absorbed in the
gastrointestinal tract4. Renal filtration accounts for the excretion of most of the drugs. About one
fifth of the plasma is filtered via the pores of the endothelium of the glomerulus tubule4.
To determine whether the dosing rate of the drugs have to be modified depends on the
rate by which the drug is excreted by the kidney and whether there is an increase in the drug
3 Morrissey, Kari M., Sophie L. Stocker, Matthias B. Wittwer, Lu Xu, and Kathleen M. Giacomini. "Renal
transporters in drug development." Annual review of pharmacology and toxicology 53 (2013): 503-529.
4 Tolwani, Ashita. "Continuous renal-replacement therapy for acute kidney injury." New England Journal of
Medicine 367, no. 26 (2012): 2505-2514.

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level which can lead to adverse effects. The value obtained from the renal clearance is sometimes
used to determine the main mechanism involved in the drug clearance by the kidney4.
If the renal clearance is almost found to be equal to the product of the glomerular
filtration by the fraction of the drug that is unbound, then filtration is occurring. If the renal
clearance is less than the product of the glomerular filtration rate and the fraction of the drug that
is unbound, then renal re-absorption can be considered, on the other hand if the renal clearance is
greater than the product of glomerular filtration rate by the unbound fraction of the drug, then it
can be considered that secretion is still occurring5.
There are certain methods that help in the removal of drugs from the kidney. They are-
Glomerular filtration, renal drug metabolism and tubular secretion5.
Difficulty in evaluating renal clearance of drugs
In patients with acute kidney injury, kidney functions are determined for the adjustments
in the drug dosing, adjustment of the nutritional therapies and dialysis.
Kidney function can be estimated by the rate of drug clearance by the kidney, which is
again determined by the estimation of the glomerular filtration rate6. Evaluation of the different
methods of renal clearance can be challenging due to fluctuations in the creatine production,
kidney function and fluid balance. In order to determine the kidney function, the glomerular
5 Vilay, A. Mary, Mariann D. Churchwell, and Bruce A. Mueller. "Clinical review: drug metabolism and nonrenal
clearance in acute kidney injury." Critical Care 12, no. 6 (2008): 235.
6 Evans, Marie, Karlijn J. van Stralen, Staffan Schön, Karl-Göran Prütz, Maria Stendahl, Bengt Rippe, and Kitty J.
Jager. "Glomerular filtration rate-estimating equations for patients with advanced chronic kidney
disease." Nephrology Dialysis Transplantation 28, no. 10 (2013): 2518-2526.

4PHARMACOKINETICS
filtration rate (GFR) is calculated7. The clearance of inulin is the most effective method, but it is
not dine usually owing to the labor intensity of the method. Glomerular filtration rate is the
amount of plasma filtered by the glomerulus in one minute7. The Fructose polymer inulin is the
GFR marker. But it is difficult for assaying in clinical practice. Calculation of the plasma
clearance produces results that are often unreliable and the procedure is cumbersome and can
give erroneous results8.
The determination of the GFR is mainly based on the clearance of creatinine from urine8.
The procedure can also give rise to erroneous results, as in the procedure has to be commenced
with a 24 hour collected urine. And erroneous results may occur due to error in urine collection
especially when the duration of the urine collection is short), analytical assay with the urine
creatinine assay, due to diseases or drug therapies9. Hence, GFR is normally measured by
measuring the serum creatinine level and using the equations.
7 Morrissey, Kari M., Sophie L. Stocker, Matthias B. Wittwer, Lu Xu, and Kathleen M. Giacomini. "Renal
transporters in drug development." Annual review of pharmacology and toxicology 53 (2013): 503-529.
8 Bouchard, Josée, Etienne Macedo, Sharon Soroko, Glenn M. Chertow, Jonathan Himmelfarb, Talat Alp Ikizler,
Emil P. Paganini, and Ravindra L. Mehta. "Comparison of methods for estimating glomerular filtration rate in
critically ill patients with acute kidney injury." Nephrology Dialysis Transplantation 25, no. 1 (2009): 102-107.
9 Schaeffner, E.S., Ebert, N., Delanaye, P., Frei, U., Gaedeke, J., Jakob, O., Kuhlmann, M.K., Schuchardt, M., Tölle,
M., Ziebig, R. and van der Giet, M., 2012. Two novel equations to estimate kidney function in persons aged 70
years or older. Annals of internal medicine, 157(7), pp.471-481.

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Equation of renal clearance
Renal clearance estimation:
CLrenal= Urine flow × Urine concentration
Plasma concentration
Renal clearance estimation from the renal extraction ratio and renal perfusion:
CLrenal= Q x E
fe= CL renal
CLtotal
CL renal = renal clearance
CL total = total clearance
Q = renal perfusion
E = extraction ratio
fe = the excreted fraction
Cockcroft and Gault equation8
CLcr=(140-age (years) × weight (kg) × 0.85 [female])/(Scr (mg/dl) × 72)
MDRD (four-variable) Study equation 8
GFR=186.3·Scr−1.154·Age−0.2031.212 [black]·0.742 [female]

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MDRD (four-variable) Study equation for IDMS serum creatinine 8
GFR=175.6·Scr−1.154·Age−0.2031.212 [black]·0.742 [female]
CKD-EPI equation9
GFRα=141·min (Scr/κ,1)α·max (Scr/κ,1)−1.209·0.993Age·1.159 [black]·1.018 [female]
Abbreviations: CKD-EPI= Chronic Kidney Disease-Epidemiology Collaboration; CLcr=
creatinine clearance; GFR= glomerular filtration rate; IDMS= isotope dilution mass
spectroscopy; MDRD= Modification of Diet in Renal Disease.
Here, κ = 0.7 (females) and 0.9 (males)
α = -0.329 (females) and -0.411 (males)
Min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1 and age
is measured in years.
Jelliffe equation9
CLcr (male) = 98 - 0.8 (A - 20) / Scr
CLcr (female) = 88 - 0.7 (A - 20) / Scr
A = age in years
CLcr = creatinine clearance in mL/min/1.73 m2
Conclusion
Thus, it can be said that renal clearance is a way to evaluate the drug dosing or dialysis in
patients with acute kidney injury. It can be said that a drug's clearance is directly proportional to

7PHARMACOKINETICS
the renal function of the patient. Whether a drug’s dosing rate has to be modified depends upon
whether the drug is being excreted by the kidney. The assessment of the renal clearance involves
a number of procedures, most of which are difficult too assay or is time consuming. In spite of
this the report has put forward some of the equations would be useful for determining the rate of
the renal clearance in patients with Acute kidney injury.

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References
Bouchard, Josée, Etienne Macedo, Sharon Soroko, Glenn M. Chertow, Jonathan Himmelfarb,
Talat Alp Ikizler, Emil P. Paganini, and Ravindra L. Mehta. "Comparison of methods for
estimating glomerular filtration rate in critically ill patients with acute kidney
injury." Nephrology Dialysis Transplantation 25, no. 1 (2009): 102-107.
Evans, Marie, Karlijn J. van Stralen, Staffan Schön, Karl-Göran Prütz, Maria Stendahl, Bengt
Rippe, and Kitty J. Jager. "Glomerular filtration rate-estimating equations for patients with
advanced chronic kidney disease." Nephrology Dialysis Transplantation 28, no. 10 (2013):
2518-2526.
Khwaja, A., 2012. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical
Practice, 120(4), pp.c179-c184.
Matzke, Gary R., George R. Aronoff, Arthur J. Atkinson, William M. Bennett, Brian S. Decker,
Kai-Uwe Eckardt, Thomas Golper et al. "Drug dosing consideration in patients with acute and
chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes
(KDIGO)." Kidney international 80, no. 11 (2011): 1122-1137.
Morrissey, Kari M., Sophie L. Stocker, Matthias B. Wittwer, Lu Xu, and Kathleen M.
Giacomini. "Renal transporters in drug development." Annual review of pharmacology and
toxicology 53 (2013): 503-529.
Schaeffner, E.S., Ebert, N., Delanaye, P., Frei, U., Gaedeke, J., Jakob, O., Kuhlmann, M.K.,
Schuchardt, M., Tölle, M., Ziebig, R. and van der Giet, M., 2012. Two novel equations to

9PHARMACOKINETICS
estimate kidney function in persons aged 70 years or older. Annals of internal medicine, 157(7),
pp.471-481.
Tolwani, Ashita. "Continuous renal-replacement therapy for acute kidney injury." New England
Journal of Medicine 367, no. 26 (2012): 2505-2514.
Vilay, A. Mary, Mariann D. Churchwell, and Bruce A. Mueller. "Clinical review: drug
metabolism and nonrenal clearance in acute kidney injury." Critical Care 12, no. 6 (2008): 235.