Applicability and Accuracy
of Formulae


The equations that estimate glomerular filtration rate (GFR) and creatinine clearance (CLcr) should not be used in patients undergoing dialysis, in patients with muscular dystrophy, muscle trauma or rhabdomyolysis. Except for the Brater’s equation,[1] they are not applicable for situations accompanied by instability of glomerular filtration rate, such as in acute kidney injury. Under these conditions, it is advisable to determine the conventional creatinine clearance, in periods of time as short as four hours.[9,10] NKDEP (National Kidney Disease Educational Program) suggests that all of these equations can be used to adjust drug dosage in kidney diseases.[11]

APPLICABILITY: The attribute of being useful and appropriate for estimating the value of the glomerular filtration rate of patients, such as the results of laboratory tests* or validation studies carried out in target populations.

* For example: creatinine measurement by means of a kit where the standard is traceable to mass spectrometry with isotope dilution method (IDMS).

ACCURACY: Equation property of reproducing, with the closest approximation possible, the true value of the patient's glomerular filtration rate.

Cockcroft-Gault (C-G)

Valid only for adults over 18 years old. Low accuracy in GFR > 60 mL/min. Since it was developed based on older creatinine determination methods, when using creatinine standardized by IDMS the result of CLcr will be higher. It is even so considered as the more suitable formula for the adjustment of drug doses in renal failure. For obese or swollen patients, use the ideal weight.

Unstable renal function (Brater)

Valid only for adults over 18 years old. Uses two consecutive creatinine values (creatinine 1 and creatinine 2). Since it was developed based on older creatinine determination methods, it should not be applied when using creatinine standardized by IDMS due to the overestimation of CLcr. May be used for drug adjustment in AKI, with frequent estimates of CLcr for new dosing, if necessary.[1]


Applicable to the elderly. Since it was developed based on older creatinine determination methods, it should not be applied when using creatinine standardized by IDMS, due to the overestimation of CLcr. This formula considers serum albumin, which is commonly at lower levels in the elderly and may result in hypovolemia and reduction in renal plasma flow and glomerular filtration rate.

Simplified MDRD (1)

The equation is not applicable to standardized IDMS creatinine. It was not validated in children, pregnant women and patients over 85 years old. The equation underestimates the GFR of individuals with higher levels of glomerular filtration rate, especially above 60 ml/min/1.73m2.

Simplified MDRD (2)

The equation was revised, in the simplified form, to the use of creatinine standardized by IDMS. Applicable to adults, the equation underestimates GFR of individuals with higher levels of glomerular filtration rate, especially above 60 ml/min/1.73m2.


Applicable to adults. Based on the simplified MDRD four variables, the equation was submitted to a mathematical modeling of the relationship between creatinine and glomerular filtration rate in order to correct the underestimation of the glomerular filtration rate for values above 60 mL/min/1.73m2. Valid only for creatinine standardized by IDMS. The accuracy of the equation is similar to that of MDRD in GFR < 60 ml/min/1.73m2 but outperforms MDRD or CG for GFR levels > 60ml/min/1.73m2.


Better performance in comparison to other equations based on serum creatinine or cystatin-C alone. Developed from results of 5352 patients in 13 studies and validated in 1119 participants from five different studies.[2] It may be useful as a confirmatory test for chronic kidney disease, especially if estimates of equations CKD-EPI and CKD-EPI-Cystatin-C do not differ by more than 40%.[3]


Cystatin-C gives a better estimate of RFG than the formulae based on serum creatinine.[4] The concentration of cystatin-C avoids the phenomenon of "creatinine blind area" (GFR range between 40 and 90 ml/min/1.73m2, in which creatinine concentrations remain within the normal range, despite the reduction in glomerular filtration rate).

Cystatin-C (Larsson)

A meta-analysis published in 2002 concluded that cystatin-C seems to outperform the formulae based on serum creatinine as a GFR marker.[5] Larsson determined the RFG by measuring the plasma clearance of iohexol and used the results to calculate the equation that converts cystatin-C plasma concentration into GFR.[6]

Schwartz (1)

Traditional Schwartz’s formula was developed based on creatinine not standardized by IDMS. Applicable to infants, children and adolescents.[7,8]

Schwartz (2)

Formula developed for use with creatinine standardized by IDMS, based on a Cohort study consisting of 349 children, aged between one to sixteen years old, with chronic renal disease. Nicknamed "Schwartz at the bedside”. Applicable to children and adolescents.[9]

BIS-1 and Bis-2

Equations BIS-creatinine (BIS-1) and BIS-creatinine-cystatin-C (BIS-2), developed by Berlin Initiative Study (BIS)[12] showed a good accuracy with individuals with 70 years old or more with normal renal function or mild to moderately reduced. These equations, in this study, were not validated with african descendants.

Here in Brazil, a study conducted in Escola Paulista de Medicina (UNIFESP)[13] with these same equations obtained a higher accuracy in comparison to the results obtained with the use of other formulae with creatinine or cystatin-C alone. This study comprised 95 octogenarian and nonagenarian patients, 7% of which were non-Caucasian, and 70% female. In the absence of cystatin-C measurements, the study suggests the use of equations CKD-EPI or BIS-creatinine (BIS-1) in the elderly population. At glomerular filtration rate levels below 60 ml/min/1.73m2, BIS-1 seemed the best option.[13]


Clearance of endogenous creatinine determined on urine collected in variable intervals, as short as 2-4 hours, until the usual interval of 24 hours, in patients with Acute Kidney Injury or patients with Chronic Renal Failure. Other situations in which the calculated CLcr is indicated: extremes of age and body size; severe malnutrition or obesity; paraplegia or quadriplegia; vegetarian diet; and pregnancy.[11]

Four hours Creatinine Clearance
in Acute Kidney Injury

"Repeated 4-hour creatinine clearance measurements in critically ill patients allow earlier detection of AKI, as well as progression and recovery compared to plasma creatinine." [10]


Aiming to simplify drugs dosing in renal failure, the "Nefrocalc 2.0" uses the formula of Giusti-Hayton-Tozer,[14,15] that finds an adjustment factor (AF) based on the clearance of the patient's creatinine and on the larger fraction of active substances (drugs or metabolites) excreted by the kidneys in normal conditions (fe). The reversion of the standardized creatinine clearance (ml/min/1.73m2) to unstandardized measurement (ml/min) should be done to determine the AF, especially when body surfaces are very different (higher or lower) from 1.73m2. To determine the dosing in renal failure, this software uses the following operational methods: D (reduced dose, normal dosing intervals); I (extended dosing intervals, standard dose) and D/I (combination of both).
The choice of drugs is made through a drop-down list box, with the drug names accompanied, where appropriate, by notes [HDs] , [HDhp], [HD] or [PD] to indicate the need of "Post-Dialysis Drug Replacement" for conventional filters or high permeability capillary filters usage, and post-peritoneal dialysis, respectively.[16,17,18] Similarly, letters "a" to "s" [a,...s] following the drugs names refer to "Special Care" and the listing can be found below the dosage calculations.
The use of this calculator does not replace the professional common sense and his/her expertise in clinical pharmacology for the safety of the patient in therapeutic courses.


FA = 1/[fe(CLcr/120-1)+1]

The need for drug dosage adjustment in renal failure is less frequent when glomerular filtration rates (GFR) exceed 50 ml/min. If the unchanged active drugs, or their active metabolites, excreted in urine, have fe<0.50, the dosage adjustment is usually unnecessary, regardless the renal function levels. [19] Some may consider most suitable a more lower range: fe≤0,30[20,23] or fe≤0,25-0,50.[21]
The application of the Giusti-Hayton-Tozer's formula as a tool to adjust maintenance dosage in renal impairment requires the assumption of a series of points, according to the following.[20,22,23]

1) Drugs that follows first-order pharmacokinetics within the therapeutic range.

Notice however that, with few exceptions, such as cefadroxil and mezlocillin, most drugs with zero-order kinetics have fe<0.30.* Thus, the application of Giusti-Hayton-Tozer’s formula will result in an AF (adjustment factor) equal to or very close to the unit, indicating no need for dosage correction (AF=1), or only a little rounding of the dose and dosing interval (AF<1.43).

2) Pharmacokinetics that can also be described by one-compartment model without substantially affecting the body disposition profile of the drugs.

3) Adjustment factors (AF) calculated by the renal excretion fraction (fe) of the active drugs.

4) If an active metabolite has a larger fe value than that of the active parent substance, the metabolite's fe should be used.

5) No significant differences in drug absorption between renal failure and healthy patients.

6) Except for the renal excretion, no significant drug disposition differences, such as bioavailability, distribution volume, liver metabolism, among others, compared to a healthy patient.

7) In renal failure, no significant differences on pharmacodynamics compared to healthy patient.

8) Direct relationship between creatinine clearance and renal drugs clearance.

9) Stable renal function.

* Renal excretion fraction (fe) of therapeutic substances with zero-order pharmacokinetics: Aspirin (0.05), Cefadroxil with dosages ≥ 500mg (0.80), Clarithromycin (0.20), Dipyrone (0.15), Phenylbutazone (0.01), Phenytoin (0.02), Phenobarbital - high dosage (0.25), Fluoxetine (0), Fluvoxamine (0), Heparin (0), Methylprednisolone (<0.01), Metoclopramide (0.20), Mezlocillin (0.65), Nefazodone (0), Paroxetine (<0.02) Theophylline - some patients (0.10), Thiopental - high dosage (0), Tolbutamide (0), Valproic Acid (<0.03).


1. Brater DC. Creatinine clearance from changing serum creatinine, page 2. In: Pocket manual of drug use in clinical medicine, third edition. B.C. Decker Inc., Toronto, 1987.

2. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS, others CKD-EPI Investigators. Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. N Engl J Med 2012; 367:20-9.

3. Grubb A, Nyman U, Bjork J. Improved estimation of glomerular filtration rate (GFR) by comparison of eGFRcystatin C and eGFRcreatinine. Scand J Clin Lab Invest. 2011; 72(1):73-77.

4. Madero M, Sarnak MJ, Stevens LA. Serum cystatinC as a marker of glomerular filtration rate. Curr Opin Neph Hypertens 2006; 15(6):610-616.

5. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002; 40(2):221-226.

6. Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in mL/min from plasma cystatin C values in mg/L. Scand J Clin Lab Invest 2004; 64: 25-30.

7. Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr 1984 Jun; 104(6):849-54.

8. Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 1985 Mar; 106(3):522-6.

9. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009 Mar;20(3):629-37.

10. Pickering JW, Frampton CM, Walker RJ, Shaw GM, Endre ZH. Four hour creatinine clearance is better than plasma creatinine for monitoring renal function in critically ill patients. Critical Care 2012; 16:R107 (

11. Frequently Asked Questions About GFR Estimates. National Kidney Foundation, 2011.

12. Schaeffner ES, Ebert N, Delanaye P, Frei U, Gaedeke J, Jakob O, Kuhlmann MK, Schuchardt M, Tolle M, Ziebig R, van der Giet M, Martus P. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Intern Med 2012; 157: 471-81.

13. Lopes MB, Araújo LQ, Passos MT, Nishida SK, Kirsztajn GM, Cendoroglo MS, Sesso R. Estimation of glomerular filtration rate from serum creatinine and cystatin C in octogenarians and nonagenarians. BMC Nephrology 2013; 14: 265.

14. Giusti DL, Hayton WL. Dosage regimen adjustments in renal impairment. Drug Intel Clin Pharm 1973; 7: 382–387.

15. Tozer TN. Nomogram for modification of dosage regimens in patients with renal function impairment. J Pharmacokin Biopharm 1974; 2(1):13-28.

16. Johnson CA. 2010 Dialysis of Drugs. CKD Insights, LLC. Verona, Wisconsin, USA. Available from URL:
(Accessed: January 09, 2015).

17. Bailie GR, Mason NA. 2013 Dialysis of Drugs. Renal Pharmacy Consultants, LLC. Saline, Michigan, USA. Available from URL:
(Accessed: January 09, 2015).

18. Bailie GR, Mason NA. 2014 Dialysis of Drugs. Mobile app for iOS, Android and Kindle. Renal Pharmacy Consultants, LLC. Saline, Michigan, USA.

19. Drug use in renal impairment. Clinical Pharmacology Bulletin. Department of Clinical Pharmacology. Christchurch Hospital. Canterbury, NZ.
Available from URL:
(Accessed: August 21, 2015).

20. Matzke GR. Principles of Drug Therapy in Patients with Reduced Kidney Function. In: Primer on Kidney Diseases 5th Ed. National Kidney Foundation 2009. Saunders Elsevier. Philadelphia, PA. Chapter 39: 322-29.

21. Cervelli MJ. Considerations for Drug Regimen Modifications in Patients with Renal Impairment. In: The Renal Drug Reference Guide. Page 6. Edited by Matthew J Cervelli, 2008. Adelaide, Australia.

22. Bochner F, Carruthers G, Kampmann J, Steiner J. Drugs and Renal Disease. In: Handbook of Clinical Pharmacology 2nd Ed. 1983; Little, Brown Co. Boston, MA. Chapter 4:26-33.

23. Matzke GR and Dowling TC. Renal Drug Dosing Concepts. In: Murphy JE. Clinical Pharmacokinetics 5th Ed, 2012. American Society of Health-System Pharmacists, Bethesda, MA. Chapter 6 pages: 77-78.