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CHRONIC KIDNEY DISEASE

Chronic Kidney Disease (CKD) is defined as a reduction in the glomerular filtration rate (GFR)
and/or urinary abnormalities or structural abnormalities of the renal tract. CKD also has different level of
severity classified from 1 to 5 depending upon the level of GFR.

Renin-angiotensin-aldosterone system (RAAS)

- Has a critical role in the progression of CKD. Most of the renal effects of this system are through
regulating intra-glomerular pressures and salt and water balance. Renin is an enzyme which is
formed and stored in the juxtaglomerular apparatus and released in response to decreased
afferent intra-arterial pressures, decreased glomerular ultrafiltrate sodium levels and
sympathetic nervous system activation.
- In patients with CKD, intra-renal pressures are often low and sympathetic overactivity is common:
these factors lead to increased renin secretion. This can occur with normal or elevated systemic
blood pressure.
- Renin promotes cleavage of the protein angiotensinogen, which is produced by the liver, to
produce angiotensin I.
- Angiotensin I – is converted to angiotensin II by angiotensin-converting enzyme (ACE).
- Angiotensin II – has two major physiological effects; (1) Acts o the zona glomerulosa of the
adrenal cortex to promote production of the mineralocorticoid hormone aldosterone, with
resultant increased distal tubular salt and water reabsorption. Furthermore, it promotes ADH
release, which increases proximal tubular sodium reabsorption and promotes thirst. In
combination, these lead to salt and fluid retention, high intravascular volumes, hypertension, and
edema; (2) it is a direct vasoconstrictor and promotes systemic and renal hypertension.
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Classification of Chronic Kidney Disease

STAGE OF GLOMERULAR FILTRATION RATE DESCRIPTION
CKD
1 ≥90 Ml/min + proteinuria/haematuria Kidney damage with normal or increased GFR
or structural damage but other evidence of kidney damage.
2 60-90 Ml/min + Slight decrease in GFR with other evidence of
proteinuria/haematuria or structural kidney disease
damage
3a 45-59 Ml/min Moderate reduction in GFR.
3b 30-44 Ml/min With or without evidence of other kidney
disease
4 13-29 Ml/min Severe reduction in GFR
5 <15 Ml/min Kidney failure

Significance of CKD
- CKD indicates the possibility of progression to end-stage renal disease, and a strong association
with accelerated cardiovascular disease.
- Cardiovascular risk increases with the severity of CKD but is detectable at all levels.
- Risk factors: smoking, cholesterol and blood pressure.
- Cardiovascular disease found in CKD is more likely to be related to small vessel disease initiated
by endothelial dysfunction rather than atherosclerotic disease.
- Progression to more advanced stages of CKD may occur, particularly if the blood pressure is
inadequately controlled and there is significant proteinuria.

Measurement of renal function

1. Serum Creatinine
- is related to renal function, it is also dependent upon the rate of production of creatinine by the
patient.
- Creatinine is freely filtered by the glomerulus, so when muscle mass is stable any change in serum
creatinine levels reflects a change in its renal clearance. Consequently, measurement of serum
creatinine can be utilized to give an estimate of the kidney function.
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2. MDRD glomerular filtration rate equation

- More accurate than serum creatinine alone as an estimator of kidney function; however, it has
not been validated in the elderly, those with creatinine levels within the normal range or
transplant recipients.

3. Creatinine clearance
- It is a measurement of the volume of the blood that is cleared of creatinine with time.
- Measurements of creatinine clearance require accurate collection of 24 h urine samples with
serum creatinine sample midway through this period.
- This is time-consuming, inconvenient and prone to inaccuracy and is now rarely use in practice.

4. Cockroft-Gault equation
- Uses weight, sex and age to estimate creatinine clearance and was derived using average
population data.

𝐹 [140 𝐴𝑔𝑒 (𝑦𝑒𝑎𝑟𝑠)]𝑥 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)

𝐶𝑙𝑐𝑟 =
𝜇𝑚𝑜𝑙
𝑆𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 ( )
𝐿

F = 1.04 (female) or 1.23 (males)

Treatment

GOALS OF TREATMENT
1. Avoid conditions that might worsen renal failure
- Example: Reduced renal blood flow, Hypotension, Hypertension, Nephrotoxins including drugs,
Renal Artery disease and Obstruction (prostatic hypertrophy)

2. Treat the secondary complications of CKD (renal anemia and bone disease)
3. Relieve symptoms
4. Implement regular dialysis treatment and/or transplantation at the most appropriate time.
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Reversal or arrest of primary disease

- CKD rarely has a readily reversible component, in contrast to acute renal failure. However, it is
sometimes possible to identify a disease specific factor that is contributing to declining renal
function and remove it.

1. Hypertension
- Optimum control of blood pressure is one of the most important therapeutic measures since
there is a vicious cycle of events whereby hypertension causes damage to the intrarenal
vasculature resulting in thickening and hyalinization of the walls of arterioles and small vessels.
This damage effectively reduces renal perfusion, contributing to stimulation of the RAAS.
Arteriolar vasoconstriction, sodium and water retention result, which in turn exacerbates
hypertension.

Calcium Channel Blockers (CCBs)

- For patients WITHOUT proteinuria, CCBs are the agents of choice.
- They produce vasodilatation principally by reducing Ca2+ influx into vascular muscle cells.
- Promote sodium excretion in hypertension associated with fluid overload
- Verapamil and Diltiazem (non-dihydropyridine CCBs) block conduction across the atrioventricular
node and should not be used in conjunction with beta-blockers.
- Nifedipine and Amlodipine produce less cardiac depression and differentially dilate afferent
arterioles in the kidney.
- Can produce headache, facial flushing and edema. The edema is not related to salt or water
retention; hence, the lack of response to diuretic therapy.

Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs)
- The role of ACE inhibitors in hypertensive patients with renal insufficiency is complicated, the
current evidence base supports the principle that all diabetic patients with
micro/macroalbuminuria and CKD should be treated with ACE inhibitors or ARBs regardless of
blood pressure.
- There is also evidence that in non-diabetic patients with proteinuria, the use of these drugs can
reduce proteinuria and thus reduce progression of CKD.
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- ACE inhibitors – reduce circulating angiotensin II

- ARBs – block binding to the angiotensin II receptor, which results in vasodilation and reduced
sodium retention.
- ACE inhibitors and ARBs preferentially protect the glomerulus over and above their effect as
systemic hypertensive agents, through decreasing efferent glomerular arteriolar vasoconstriction
and therefore intra-glomerular hypertension and hyperfiltration.
- For long-term management, it is usually preferable to use an agent with a duration of action that
permits once-daily dosing.
- It has been reported that ACE inhibitors may reduce thirst, which may be useful in those patients
who tend to fluid overload because of excessive drinking. ACE inhibitors are potassium sparing
and therefore serum potassium should be monitored carefully. A low-potassium diet may be
necessary.
- ARBs have properties similar to ACE inhibitors with the advantage that, since they do not inhibit
the breakdown of kinins such as bradykinin, they do not cause the dry cough associated with ACE
inhibitors. There is interest in the potential use of dual blockade of the RAAS using ACE inhibitors
and ARBs to produce more complete blockade of angiotensin II. However, evidence to date as
shown no added benefit and some evidence of adverse renal outcomes.

Diuretics
- Are of use in patients with salt and volume overload, which is usually indicated by the presence
of edema. This type of hypertension may be particularly difficult to treat.
- The choice of agent is generally limited to LOOP DIURETIC.
- Potassium sparing diuretics – usually contraindicated owing to the risks of developing
hyperkalemia.
- Thiazides – become ineffective as renal failure progress. Ineffective at low GFR and may
accumulate, causing an increased incidence of side effects with notable exception of metolazone.
- In combination with ACE inhibitors, Spironoloactone – significantly reduce proteinuria; however,
the combination of these agents clearly raises the risk of significant hyperkalemia and care must
be taken (Bianchi el al., 2015). The combination should be avoided when the EGFR falls to
<30ml/min.
- Loop diuretics – need to be filtered to exert an action, progressively higher doses are required as
CKD worsens. Patients who do not respond to oral loop diuretic therapy alone may benefit from
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concomitant administration of metolazone, which acts synergistically to produce a profound

diuresis. Care must be taken to avoid hypovolemia and electrolyte disturbances such as
hypokalemia and hyponatremia.

Beta-blockers
- Commonly used in the treatment of hypertension in CKD.
- They exhibit a range of actions including a reduction of renin production. Consequently, beta-
blockers gave a particular role in the rational therapy of hypertension without fluid overload.
- Beta-blockers can reduce cardiac output, cause peripheral vasoconstriction and exacerbate
peripheral vascular disease.
- It is advisable to use the more cardioselective beta-blockers atenolol or metoprolol.
- Atenolol – is excreted renally and consequently should require dosage adjustment in renal failure.
Effective and tolerated well and renal patients at standard doses.
- Metoprolol – theoretically a better choice since it is cleared by the liver and needs no dosage
adjustment, although small initial doses are advised in renal failure since there may be increased
sensitivity to its hypotensive effects.

Selective α1-blockers
- Produce a variety of actions that may be of benefit in hypertension associated with CKD.
Sympathetic adrenergic activity can lead to sodium retention.
- To produce improvements in insulin sensitivity, adverse lipid profiles and obstruction caused by
hypertrophy of the prostate, all of which might be associated with some forms of CKD.
- These agents are used less commonly since there is some evidence that, in comparison to other
antihypertensives, use is associated with adverse cardiovascular outcomes, especially the
development of heart failure.

Vasodilators
- Hydralazine and minoxidil – have been used to treat hypertension in CKD with varying degrees
of success but are usually only used when other measures inadequately control blood pressure.
- The sensitivity of patients to these drugs is often increased in renal failure, so, if used, therapy
should be initiated with small doses.
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Centrally acting drugs

- Methyldopa and Clonidine – not commonly used as antihypertensives in CKD because of their
adverse side effect profiles.
- They are used in renal failure, initial doses should be small because of increased sensitivity to their
effects.

Spironolactone
- Potassium sparing diuretic spironolactone is an aldosterone receptor antagonist, reduces
proteinuria.
- Additionally, effective in combination with either an ACE inhibitor or an ARB but not as triple
therapy.

Statins
- Have beneficial effects on endothelial function, improving renal perfusion while reducing
abnormal permeability to plasma proteins.
- Not indicated for delaying the progression of CKD but are currently used for conventional
indications only in such patients.

Renal transplantation
- Transformed the outlook for many patients with end stage renal disease.
- The clinical outcomes of renal transplantation are now excellent.
- Important consideration is that renal transplantation is the treatment of choice for patients with
end stage renal disease who are fit to receive renal transplant.

Implementation of regular dialysis treatment

- End stage renal failure is the point at which the patient will die without the institution of renal
replacement by dialysis or transplantation.
- Principle of dialysis: the patient’s blood and a dialysis solution are positioned on opposing sides
of a semi-permeable membrane across which exchange of metabolites occur.
- The two main types of dialysis used in CKD are hemodialysis and peritoneal dialysis.
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PATIENT COUNSELLING
OVERVIEW

Chronic Kidney Disease (CKD), also called kidney failure or renal failure, is a condition in which the
kidneys lose some of their ability to remove waste products and excess fluid from the bloodstream. A
waste products and fluids build up in the body, other body systems are affected, which can be harmful to
your health.
The most common caused of CKD are diabetes and high blood pressure. In the early stages of CKD,
there are no symptoms. The disease can progress to complete kidney failure, also called end-stage
renal/kidney disease. This occurs when kidney function has worsened to the point that dialysis or kidney
transplantation is required to maintain good health and even life.
The main goal of treatment is to prevent progression of CKD to complete kidney failure. The best
way to do this is to diagnose CKD early and control the underlying cause.

Retrieved from: https://www.uptodate.com/contents/chronic-kidney-disease-beyond-the-basics (December 16, 2017)

GUIDELINES FOR CKD

1. National Kidney Foundation
2. Official Journal of the International Society of Nephrology: Kidney International Supplements:
KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and
Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

References:
• Walker, R & Whittlesea, C. (2012). Clinical Pharmacy and Therapeutics 5th edition
• UpToDate.com
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Observed Structured Clinical Evaluation (OSCE)

Drug and Disease Management 3 (Phar15)

B.S. Pharmacy Major in Clinical Pharmacy

Submitted by:
Charmaine Joyce M. Matias
5BCLPH

Submitted to:
Asst. Prof. Peter F. Quilala, MD, RPh

December 2018