NephMadness: Collecting Tubule Region – Principal Cell Group

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(1) MDRD Equation vs (16) CKD-EPI Equation

Creatinine based estimations of glomerular filtration rates are valuable tools clinicians use to monitor kidney function, because regular inulin clearance evaluation would be absurd.

MDRD Equation

The MDRD equation was recommended by the 2002 CKD K/DOQI guidelines. It is the most widely used creatinine-based eGFR equation.  It was developed in 1999 by using the cohort from the first MDRD study, 1,628 subjects with chronic kidney disease.  In 2006, the MDRD equation was subtly changed for use with IDMS traceable (i.e., “standardized”) creatinine assays.  Clinically, it is easy to use by providers who have access to the patient’s age, serum creatinine, gender and ethnicity.  The MDRD equation provides a more accurate estimation of GFR than either the Cockcroft Gault formula or 24-hour creatinine clearance.

CKD-EPI Equation

The new kid on the block.  Developed in 2009 using 12,150 diverse participant and (in 2011 and 2012 studies) using a standardized creatinine assay, CKD-EPI is the most accurate eGFRcr formula in patients with normal or near-normal GFRs.  In fact, data suggests that CKD-EPI may be more accurate in risk stratification for all-cause mortality and cardiovascular events.  Age, serum creatinine, gender and ethnicity are needed to compute eGFR, which is simple with any smartphone or computer. KDIGO was so impressed with CKD-EPI’s performance that it is recommended in the 2013 guidelines.

(3) 24-hour CrCl vs (14) Cockcroft Gault Equation

24-hour Creatinine Clearance

CrCl eq

The 24 hour creatinine clearance is another approach use to estimating GFR. The CrCl technique is particularly valuable in patients who have unusual amounts of muscle mass, this includes the body builder, the patient with dwarfism, the patient with multiple amputations. Measurement of the daily creatinine excretion controls for variations in creatinine production (or creatine and creatinine intake, for that matter). Like all creatinine based formulas, the 24-hour creatinine clearance depends on a stable serum creatinine. The most common source of error with a 24-hour collection is an inadequate collection, this could be missed voids, poor precision in the timing, additional family members contributing to the collection etc. One unavoidable source of error is tubular secretion of creatinine which increases urinary creatinine without filtration. Normally about 5-10% of creatinine is excreted this way but the proportion rises with decreased renal function. Thus, 24-creatinine clearance overestimates GFR in general and even more as CKD progresses.

Cockcroft Gault Equation

Cockcroft Gault

The Cockcroft Gault equation was initially described in 1976. This description was based upon 249 patients and was a popular tool to convert creatinine to eGFR.  I remember having to memorize this equation during my medical school training. It is quite impressive that this formula was used for so many years.  It wasn’t until the MDRD equation in 1999 that Cockcroft Gault fell out of favor.  The adoption of eGFR calculation with the Cockcroft Gault equation was a huge advance in nephrology and allowed for doctors to recognize patients that , though they may have normal creatinines have significant renal insufficiency.  The main disadvantage of this formula was that it was derived from an entirely male population of hospitalized veterans and was designed to estimate creatinine clearance and not GFR.  This formula does not work well at extremes of age or BMIs.

(5) Winter’s Formula vs (12) TTKG

Winter’s Formula


The goal of the equation is to estimate whether a given pCO2 reflects appropriate respiratory compensation for a primary metabolic acidosis, or whether one is dealing with a mixed acid-base disorder.  The concept and formula are remarkably important in clinical practice and easy to apply.  Unlike formulas to estimate renal compensation for primary respiratory acid-base disorders, there is no need to alter the formula to account for the acuity or chronicity of disease.  Dr. Robert Winter’s formula has been used since the mid-1960s and is still going strong.

Transtubular Potassium Gradient


The TTKG attempts to assess the distal nephron’s ability to maintain potassium homeostasis.  A “normal” value when evaluating hyperkalemia is considered 8-9%, with values <7 suggestive, and <5 highly suggestive of hypoaldosteronism. The equation only applies when urine is not hypotonic and distal sodium delivery is adequate to allow for maximum kaliuresis.  However, twenty-five years after the initial studies were published, the original authors present a hypothesis that may further limit the clinical utility of the TTKG:  An important assumption of the TTKG model is that no significant osmols are reabsorbed in the medullary collecting tubules. Recent observations show significant urea recycling with reabsorbtion in the inner medulla, making this assumption invalid.

(7) FENA vs (10) FEUrea


One of the fundamental questions facing clinicians when they are evaluating a patient with decreased renal function is whether this is ischemic damage or hemodynamic changes from decreased perfusion. Or in the worlds of Rajiv Poduval is it a case of:

No BP? No Pee pee.

One strategy to differentiate these two similar conditions is to use the kidneys’ sodium handling behavior to determine if this is hemodynamic or ischemic damage. One way to do this is a random urine sodium. This measure is confounded by ADH which can increase the urine sodium concentration by reabsorbing water in the medullary collecting duct.

FENa math

This pitfall can be avoided by directly measuring sodium handling. The fractional excretion of sodium is literally the amount of sodium excreted divided by the amount of sodium filtered at the glomerulus. Through clever algebra the calculation can be done with a single spot urine and a blood sample.

The fractional excretion of sodium does an excellent job at reflecting renal sodium handling but unfortunately, renal sodium handling does a less good job at predicting hemodynamic renal disease. There are numerous situations in which a sodium avid kidney is not dysfunctional due to decreased effective circulating volume and likewise situations where increased sodium loss occurs despite volume depletion.

See the landmark FENa study here.



One of the most common causes of a falsely elevated fractional excretion of sodium is diuretics. Diuretics directly increase sodium excretion, increasing the FENa without regard to natural renal sodium handling. The fractional excretion of urea circumvents this by measuring renal handling of urea, a molecule not affected by diuretics. With decreasing renal blood flow the kidney autoregulates to maintain a stable GFR. One of the results for this autoregulation is an increase in the fraction of renal plasma flow that is filtered through the glomerulus, the filtration fraction. The increased filtration fraction means that the serum albumin, which is not filtered, is dissolved in less plasma so is found at a greater concentration and thus exerts increased osmotic pressure drawing water, sodium and urea from the proximal tubule back to the blood. This lowers the excretion of urea. This decreased clearance of urea with decreased effective circulating volume decreases the fractional excretion of urea and its unaffected by diuretics. This is also the mechanism for the increased BUN:Cr ratio seen with volume depletion,

filtration fraction and proximal tubule resorption

Picture by Joel Topf, used with permission.

See Carvounis CP, Nisar S, Guro-Razuman S. Kidney Int. 2002 Dec;62: 2223-9.

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2 Comments on NephMadness: Collecting Tubule Region – Principal Cell Group

  1. Edgar Lerma // March 17, 2013 at 8:32 pm // Reply

    MDRD 24hr CrCl Winter’s FENa

  2. CKD-EPI as a 16 seed. A travesty.
    Andy Levey

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