Assessment of renal function and drug handling

Question 1

What is the measurement of renal function based on?

Answer 1

The rate of filtration of glomerulus capillaries into the Bowman’s capsule so the volume of fluid per unit of time.

Question 2

State the four functions of the kidney.

Answer 2

Excretory (waste products and fluid)
Endocrine (renin, erythropoietin, prostaglandins production)
Regulatory (bp, blood pH, fluid and composition)
Metabolism (Vitamin D)

Question 3

What factors contribute to which to which functions are compromised in CKD?

Answer 3

Stage of CKD, later the stage the more likely the function will be impaired and complications will arise
There is an extent of inter-person variability, of which functions are affected and to what extent

Question 4

What is the main purpose of monitoring renal function as a toxic parameter?

Answer 4

When renal function is impaired, in relation to its excretory role, the ability of the kidney to clear the blood of waste products including drug molecules is reduced, meaning that drug concentrations can accumulate to toxic amounts. Therefore in renal impairment some drugs, especially if highly renally cleared, should be dose reduced to compensate for the reduced clearance.

Question 5

Aside from dose reducing in renal impairment, what other drug considerations should be made?

Answer 5

Avoiding nephrotoxic drugs
Temporarily withholding the drug - sick day rules
Potentially switching to an alternative drug that you do not have to dose reduce (Linagliptin for example)

Question 6

What type of test of renal function is usually conducted in hospital?

Answer 6

Usually plasma tests rather than urine tests, even if the patient does not have known renal impairment either chronic or acutely, it provides a good indication of the patient’s renal function.

Plasma tests include:
Creatinine
Urine
eGFR

Question 7

What is creatinine?

Answer 7

Creatinine is a waste product of protein metabolism that is freely excreted by the kidneys.

Question 8

What is the purpose of measuring creatinine in assessment of the patient’s baseline renal function?

Answer 8

As creatinine is freely excreted by the kidney, a build up of serum creatinine can be used to indicate the renal impairment.

Question 9

Why is creatinine clearance used?

Answer 9

A rise in serum creatinine can be influenced by other factors not just renal impairment therefore using creatinine clearance takes this into account when calculating renal function.

Question 10

What are some of the other factors that cause a rise in serum creatinine?

Answer 10

Some factors that can lead to higher creatinine levels (making your eGFR level appear lower than it might really be) include:

Eating large amounts of cooked meats
Taking creatine supplements
Recent high intensity exercise
High muscle mass (very muscular body frame, bodybuilder)
Taking medications such as cimetidine, cobicistat, dolutegravir, fenofibrate, ritonavir, or trimethoprim

Question 11

What are some of the other factors that cause a decrease in serum creatinine?

Answer 11

Some factors that can lead to lower creatinine levels (making your eGFR level appear higher than it might really be) include:

Following a vegan or vegetarian diet
Low muscle mass
Pregnancy
History of an amputation or muscle wasting disease
Severe liver disease (cirrhosis)

Question 12

What are the two methods of calculating serum creatinine levels?

Answer 12

Either by a 24 hour urine collection or
Cockcroft and Gault equation to estimate creatinine clearance

Both provide the Creatinine clearance in mL/min

Question 13

What are the limitations of the 24 hour urine collection?

Answer 13

Time delay
Questionable accuracy

Question 14

What test of calculating CrCl is used in practice?

Answer 14

Cockcroft and Gault which estimates CrCl

Question 15

What is the equation for Cockcroft and Gault and the 24 hour urine collection?

Answer 15

Cockcroft and Gault:
(1.23 or 1.04) x (140 - Age) x Weight (kg) / Plasma creatinine (umol/L)

24 hour urine collection:
Urine creatinine (umol/L) x Volume (mL) / plasma creatinine (umol/L) x Time

Question 16

What are some of the limitations of using the Cockcroft and Gault equation?

Answer 16

Assuming average population data - in terms of age, biological sex and weight
Not appropriate for children or in pregnancy
Assuming renal function is stable

Question 17

What is considered normal creatinine and creatinine clearance?

Answer 17

Although not used to determine extent of renal impairment and classify CKD stages, it provides a baseline renal function.

Normal creatinine is between 55-125 umol/l
Normal creatinine clearance is about 120 mL/min

Question 18

What are the two methods of calculating the eGFR?

Answer 18

Either using the:
CKI-EPI (most recommended)
MD-RD

Using similar factors such as age, ethnicity, gender and serum creatinine and produces a similar value to CrCl.

Question 19

What are the limitations of using the MDRD formula which resulted in preference to the CKI-EPI?

Answer 19

Was found to be overestimating renal function in elderly patients in addition to being less accurate when the eGFR was below 60mL/min/1.73m2

Question 20

What are some of the limitations of using eGFR calculations?

Answer 20

Again assuming average population data and not appropriate for children and pregnant women.

Question 21

Is a black ethnic multiplier still used in the eGFR?

Answer 21

NICE 2021- multiplier of 1.159x was removed as a definite recommendation from the eGFR equation.

Studies regarding eGFR in America found that patients with a black ethnic origin were found to have an increased creatinine level and therefore a multiplier should be added to the equation to reflect this.
However repeated studies in the UK and Europe did not find the same conclusions and therefore suggested that the studies in the US could be more in relation to other factors such as socio-economic factors and could be disproportionate for all patients within this ethnic group.
It was removed from the equation by NICE in 2021 due to debate surrounding it, it was not concluded one way or the other.

Question 22

What are the different stages of renal impairment according to eGFR?

Answer 22

Stage 1: normal eGFR ≥ 90 mL/min per 1.73 m2 (no higher value will be stated)
Stage 2: eGFR between 60 to 89 mL/min per 1.73 m2
Stage 3: eGFR between 30 to 59 mL/min per 1.73 m2
Stage 4: eGFR between 15 to 29 mL/min per 1.73 m2
Stage 5: eGFR of < 15 mL/min per 1.73 m2 or end-stage renal disease

Question 23

What does the 1.73m2 stand for in the eGFR units?

Answer 23

It is the normalised body surface taken from average population data.
For it to be specific to the patient this can be converted to:
GFR (absolute) = eGFR x (individual BSA / 1.73)

Question 24

What is urea?

Answer 24

Urea is a nitrogenous breakdown product of protein metabolism from ammonia, that is freely excreted from the kidneys.
Again renal impairment will result in a raise in serum urea levels.

Question 25

What is the reference range for urea and above which level is it classed as uraemia?

Answer 25

Reference range: 1.7 - 6.7 mmol/L
Uraemia: > 15 mmol/L

Question 26

Aside from renal function what are some of the other factors that cause a raise in serum urea level?

Answer 26

Dehydration
Muscle injury
Infection
Haemorrhage
Excess protein intake

Therefore should not be used in isolation

Question 27

When serum levels of urea rise what are the clinical presentations?

Answer 27

Nausea and vomiting
Fatigue
Anorexia
Weight loss
Muscle cramps
Pruritus

Question 28

What is the osmolality urine test?

Answer 28

It checks for the concentration of particles within the urine. The higher the particle concentration, the higher the osmolality.

Question 29

What is the specific gravity urine test?

Answer 29

Measure of the solute concentration within the urine, again the higher the solute concentration the higher the gravity.

Both osmolality and specific gravity urine tests are assessments of the concentration of the urine, CKD patients are unable to maintain the dilutions and concentrations of their urine appropriately.

Question 30

When may you carry out an MSU or haematuria test?

Answer 30

To identify the cause of the renal impairment.
Haematuria*
Mid stream urine - identification of UTIs

Question 31

What is the purpose of albumin monitoring in the urine?

Answer 31

Albumin is a plasma protein, present in the blood but is not excreted by the kidneys. Therefore testing for the presence of albumin within the urine can be indicative of kidney disease, especially within diabetic patients.

Question 32

What is the ACR threshold values?

Answer 32

Interventions should be initiated such as ACE inhibitors and closely monitoring renal function.
In non-diabetics >70mg/mmol
In diabetics >2.5mg/mmol in males and >3.5mg/mmol in females

Question 33

What does the ACR ratio predict?

Answer 33

If patients present with an ACR above their threshold respectively, it indicates the increased likelihood of CKD progression, AKI development, CVD events and general increased risk of mortality.

Question 34

In relation to ACR and GFR, when is increased risk of adverse effects more likely?

Answer 34

As the ACR increases (greater than 30mg/mmol is considered severely increased) and GFR decreases, the increased probability of adverse outcomes is the highest (CKD progression, AKI, CVD etc)

Question 35

What are the specific classifications of renal disease according to ACR and GFR?

Answer 35

GFR: mL/min/1.73m2
Stage 1: normal eGFR ≥ 90 G1
Stage 2: eGFR between 60 to 89 G2
Stage 3: eGFR between 45 to 59 G3a
Stage 3: eGFR between 30 to 44 G3b
Stage 4: eGFR between 15 to 29 G4
Stage 5: eGFR of < 15 G5

ACR: mg/mmol
< 3 Normal to mildly increased
3-30 Moderately increased
> 30 Severely increased

Question 36

How does renal impairment affect drug absorption?

Answer 36

Due to the build of urea, known as uraemia when the concentration is 15mmol/L this impairs drug absorption due to cause diarrhoea and vomiting, in addition to gastrointestinal oedema.

There is also reduced calcium absorption due to lack of Vitamin D activation.

Hyperphosphatemia due to reduced renal phosphate excretion, results in the therapeutic use of drugs such as calcium carbonate which is a phosphate binder, decreasing concentrations. However use of calcium carbonate also reduces the absorption of some other drug molecules.

Question 37

How does renal impairment affect drug distribution?

Answer 37

In CKD patients there are changes within the hydration status, due to fluid accumulation affecting the distribution of water soluble drugs.

High levels of urea competes with drugs for binding sites such as protein and tissue binding.

Question 38

Provide some examples of drugs that you would have to monitor due to changes in distribution in CKD patients.

Answer 38

As mentioned high levels of urea compete with drugs for protein and tissue binding. An example of a drug that is highly protein bound is Phenytoin - 90% protein (albumin) bound, with only the free drug having a therapeutic effect. Increased competition for albumin binding with urea, increases the fraction of unbound Phenytoin, increasing the serum levels possibly resulting in possibly toxic accumulation.
Furthermore, regardless of increased urea competing, hypoalbuminemia can occur due to increased excretion within the urine, reducing plasma levels, further increasing the fraction of unbound albumin.
In both instances the ACR and urea level would need to be monitored closely and the Phenytoin dose titrated accordingly or potentially switch to another medication.

Urea also competes with Digoxin for free tissue binding, when serum levels of urea arise in CKD, this increases the serum Digoxin levels meaning that it must be closely monitored and dose reduced appropriately.

Question 39

How does renal impairment affect drug metabolism?

Answer 39

Less Vitamin D is metabolised into its active form due to the reduced capability of the kidney to perform the second hydroxylation. This results in reduced calcium absorption from the gut and the kidneys.
Also less insulin metabolism therefore this may alter the requirements for Diabetics that rely on insulin therapy.
There is also less activation of pharmacologically active metabolites such as nor-pethidine. Nor-pethidine is responsible for CNS excitation and can cause epileptic seizures- which is more likely in accumulation.

Question 40

Which is more appropriate for pain management Morphine or Oxycodone?

Answer 40

Oxycodone is used in preference to Morphine due to being less renally excreted in comparison to the Morphine metabolites which can accumulate resulting in toxicity.

Question 41

How does renal impairment affect drug excretion?

Answer 41

Dose modification is required for:
Drugs highly renally eliminated to avoid toxicity associated with accumulation
The total daily dose should be reduced, either reducing the dose or increasing the dosing interval

However this is drug dependent - not every drug will be reduced by the same extent or in the same way

No dose adjustments are required for loading doses- as this is just to ensure the correct distribution to the site of action, it is only the maintenance

Question 42

What dose adjustments need to be made for loading and maintenance doses?

Answer 42

No dose adjustments are required for loading doses- as this is just to ensure the correct distribution to the site of action.
However the maintenance doses do need to then be adjusted to avoid accumulation.

Question 43

What are the ideal drugs to use in renal impairment?

Answer 43

Have a wide therapeutic index
Undergoes liver elimination - so it is not affected by changes in renal function Unaffected by changes in distribution factors such as fluid balance, tissue or protein binding
Not be nephrotoxic - however may need to be used due to co-morbidity or long term reno-protective benefit (ACE inhibitors/ARBs - monitor closely)

In end stage renal patients, not worried about nephrotoxic causing further decline, as it is already very damage, more worried about toxic accumulation

Question 44

What reference sources can be used for renal impairment patients?

Answer 44

BNF or BNFc - CrCl or eGFR
emc - CrCl or eGFR
Renal drug handbook - monographs were lead by specialist Pharmacists

As advice can vary between the sources it is appropriate to gather a range of information before reaching a clinical decision.

Question 45

What are the units for Creatinine Clearance and eGFR?

Answer 45

CrCl: mL/min
eGFR: mL/min/1.73m2

Question 46

When should IBW be used?

Answer 46

In calculating the creatinine clearance for obese patients (when the BMI is greater than 30).

Question 47

When should actual body weight be used?

Answer 47

When a patient’s actual body weight is below their ideal body weight - this is crucial for medicines such as DOACs.

Question 48

What is the appropriate management is a patient is borderline between doses?

Answer 48

Look at the context whether their renal function is projecting to improve or decline to help inform your decision.
In addition to assessment of what the drug is being used for, for example antibiotics.