Nephrology Week 2 Summary

Question 6

Calculate the creatinine clearance in a patient with a stable serum creatinine of 278 micromol/L and a 24 hour urine collection with 1.2 L and 9.4 mmol/L creatinine.

Creatinine clearance (CrCl) represents the volume of blood that is cleared of creatinine by the kidney per unit time. If we assumed that all creatinine in the urine got there by being filtered through the glomerulus, then the total volume of blood cleared of creatinine (CrCl) multiplied by the concentration of creatinine in the serum should equal the total amount of creatinine found in the urine.

CrCl * SCr = Total urine creatinine

Since urine creatinine can be calculated by multiplying the urine creatinine concentration by the total volume of urine, the formula can be converted to:

CrCl * SCr = UCr * V

Which converts to:

CrCl = [UCr * V] / SCr

This formula determines the total volume cleared in a given period of time, which by convention we measure over 24 hours but report as ml/min.

Please note that the term [UCr * V] / SCr solves for a volume. This must then be divided by the total time of 1 day or 24 hours or 1440 minutes.

In this case:
CrCl = [UCr * V] / SCr
CrCl = [(9.4 mmol/L * 1.2 L) / 0.278 mmol/L]/day
= 40.58 L/day
= 40.58 L/day * 1000 ml/L * 1/1440min/day
= 28.2 ml/min

Calculate creatinine clearance online or using the Calculate by QxMD mobile app

Why does this likely represent an overestimation of the true glomerular filtration rate (GFR)?

This is an overestimation of true GFR because some of the urinary creatinine was secreted, in addition to majority that was filtered. Creatinine secretion accounts for a larger proportion of urinary creatinine at lower GFRs. This results in the urine creatinine (UCr) being higher than it should be. This makes the term:

CrCl = [UCr * V] / SCr

higher than it should be as the numerator is increased.

Therefore, creatinine clearance calculated based on a 24 hour urine collection tends to over-estimate true GFR, especially in patients with more advanced chronic kidney disease.

Review more details about renal function measurement:
Rosner MH, Bolton WK. Renal function testing. Am J Kidney Dis. Jan 2006;47(1):174-83.

Question 7

In a patient with non-anion gap metabolic acidosis, calculating the urine anion gap can help differentiate between diarrhea and renal tubular acidosis (RTA) as the etiology.

What is the urine anion gap and how is it calculated?

In response to consumption or loss of bicarbonate, the kidney generates and retains bicarbonate while excreting ammonium. While we do not measure urinary ammonium directly, we can infer its presence. When there is large urinary excretion of ammonium (a positively charged molecule), it will be excreted with a negatively charged particle, usually chloride, in order to maintain electroneutrality. So, while we do not measure urinary ammonium, we can infer its presence by a larger than expected chloride concentration.

The urine anion gap (AG) is defined by:

Urine AG = Urine (Na + K – Cl)

A negative urine anion gap means that the concentration of chloride exceeds that of potassium and sodium combined – this suggests a large amount of unmeasured urinary ammonium (which is balancing the urinary chloride). A negative urine anion gap would be expect in diarrhea as the normal kidney attempts to regenerate bicarbonate and excrete ammonium.

In renal tubular acidosis, the kidney is unable to excrete ammonium normally. Therefore the urine AG is “inappropriately” positive in the setting of a non-anion gap metabolic acidosis.

In summary, in the setting of a non-anion gap metabolic acidosis, a negative urine AG suggests diarrhea bicarbonate loss and a positive urine AG suggests an RTA.

In the following case, please determine if the patient has a non-anion gap metabolic acidosis due to diarrhea or RTA:

A 24 year old male dancer comes to attention due to a low serum bicarbonate on routine blood work. Additional results include:

Na: 140 meq/L
K: 3 meq/L
HCO3: 14 meq/L
Cl: 116 meq/L

Na: 50 meq/L
K: 30 meq/L
Cl: 40 meq/L

In the case provided, bicarbonate is reduced with a normal anion gap. This suggests either a renal tubular acidosis (RTA) or GI bicarbonate losses. Since the urine anion gap is positive, this suggests* that this man has a renal tubular acidosis (which will require further investigation).

*For keeners only: NB. There are exceptions when the above rules do not apply.

  1. When urinary Na and Cl concentrations fall considerably in severe volume depletion.If chloride excretion becomes very low, ammonium excretion will be limited. In this situation, the urine anion gap will not be negative as we would expect despite the underlying etiology of the acidosis being diarrhea.
  2. When there are significant amounts of unmeasured anions in the urine, such as hippurate due to toluene (glue) sniffing and the ketoacid anions ß-hydroxybutyrate and acetoacetate in ketoacidosis.In these situations, the unmeasured anions are excreted with sodium and potassium to maintain electroneutrality. This can lead to a positive urine AG even though ammonium excretion may be increased. This can be picked by measuring an increased urinary osmolal gap (the gap will be made up of ammonium and the other unmeasured anions):Calculated urine osmolality = 2 * ([Na + K]) + [urea nitrogen] / 2.8 + [glucose] / 18
    when glucose and BUN are measured in mg/dLCalculated urine osmolality = 2 * ([Na + K]) + [urea] + [glucose]
    when glucose and BUN are measured in mmol/L

Question 8

What does the term ‘TTKG’ mean and how do you calculate it? What assumptions are necessary for the formula to be valid?

Consider this case:

A 42 year old male with HIV is admitted with PCP pneumonia. They are treated with high dose Septra. On day 5 of admission, the following results are noted:

Serum K = 6 mmol/L
Serum osmolality = 300 mosmol/L
Urine osmolality = 480 mosmol/L
Urine K = 20 mmol/L.

In the preceding patient with hyperkalemia, calculate the TTKG. What does this tell you about their ability to excrete potassium? Can you explain why this is happening?

The etiology of hyperkalemia is often due to impaired excretion of potassium in the distal nephron. Aldosterone function in the cortical collecting duct can be estimated by measuring the potassium concentration in tubular fluid at the end of the cortical collecting duct. Since this cannot be measured directly, it can be estimated by the transtubular potassium (K) gradient (TTKG). The TTKG is defined by formula:

TTKG = [Urine K ÷ (Urine osmolality / Plasma osmolality)] ÷ Plasma K

This formula effectively determines the ratio of urine to plasma potassium, but uses a correction factor (urine osmolality/plasma osmolality) to take into account the fact that water is reabsorbed along the medullary collecting duct.

To use the TTKG, the following assumptions must be valid:

  • There is no potassium reabsorption or secretion in the medullary collecting tubule.
  • Urine osmolality at the end of the cortical collecting tubule is similar to that of the plasma.

In the case provided:

TTKG = [Urine K ÷ (Urine osmolality / Plasma osmolality)] ÷ Plasma K
= [20 ÷ (480/300)] ÷ 6
= 2.1

In the setting of hyperkalemia, one would expect a TTKG of >10. The suppressed TTKG suggests inadequate aldosterone or an impaired response of the distal nephron to aldosterone. In this patient, the trimethoprim blocks the epithelial sodium channel in the cortical collecting duct and effectively acts like a potassium-sparing diuretic and inhibits the effect of aldosterone.

Calculate TTKG online or with the Calculate by QxMD mobile app


Ethier JH; Kamel KS; Magner PO; Lemann J Jr; Halperin ML. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990 Apr;15(4):309-15.

H. Velazquez, M. A. Perazella, F. S. Wright and D. H. Ellison. Renal Mechanism of Trimethoprim-induced Hyperkalemia. Ann Intern Med 1993; 296-301.

Question 9

  1. How do you calculate Fractional excretion of sodium (FeNa) and Fractional excretion of urea (FeUrea)?
    The fractional excretion of sodium (FENa) and urea (FEUrea) measures the percent of filtered sodium and urea, respectively, that is excreted in the urine.FENa = ((UrineNa * PlasmaCr) / (PlasmaNa * UrineCr)) * 100FEUrea = ((UUrea * PCr) / (PUrea * UCr)) * 100Calculate FeNA online
    Calculate FeUrea online
  2. When would you use FeUrea over FeNa?In pre-renal acute renal failure, there is significant reabsorption of filtered Na, resulting in a low urine sodium and fractional excretion of sodium. When patients are exposed to diuretics, there will be renal wasting of Na despite hypovolemia. In this setting, the FEUrea has been shown to be a more reliable discriminator between the pre-renal state and acute tubular necrosis.
  3. What values of FeNa and FeUrea suggests prerenal azotemia as a cause of elevated creatinine?An FeNa <1% and FeUrea <35% in the setting of acute renal failure suggest a pre-renal state as the etiology.


Carvounis CP, Nisar S, Guro-Razuman S. Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int. 2002 Dec;62(6):2223-9.

Question 10

A 74 year male was last noted to have a creatinine of 86 micromol/L 2 days prior to presentation. On presentation, his creatinine is 186 micromol/L and his potassium is 7.6 mmol/L.

Is this degree of hyperkalemia expected in this case of acute renal failure?

Name 4 conditions which may present with acute renal failure and severe hyperkalemia (higher than generally expected in acute renal failure). Hint: think of intracellular sources of potassium.

When patients develop acute renal failure, they often have a suddenly reduced capacity to excrete potassium and other solutes via the kidney. However, it generally takes time for potassium levels to rise as ongoing potassium intake overwhelms excretory capacity. When one sees a sudden and significant rise in potassium very soon after the onset of acute renal failure, one should consider the possibility of a unifying explanation for acute renal failure and a large potassium load.

This can be seen in conditions such as:

  • Hemolysis
  • Rhabdomyolysis
  • GI bleed
  • Tumor lysis syndrome

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