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PHAM 422 (Pharmacotherapy III)
Module IV (Nephrology)
Chronic Kidney Disease
Dr. S. Mahmood Alqallaf
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Introduction
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Objectives
• List the risk factors for development and progression of
Chronic Kidney Disease (CKD).
• Explain the mechanisms associated with progression of
CKD.
• Outline the desired outcomes for treatment of CKD.
• Develop a therapeutic approach to slow progression of
CKD, including lifestyle modifications and pharmacologic
therapies.
• Identify specific consequences associated with CKD.
• Design an appropriate therapeutic approach for specific
consequences associated with CKD.
• Recommend appropriate monitoring plan to assess
effectiveness of pharmacotherapy & specific
consequences.
• Educate patients with CKD about the disease state, the
specific consequences, lifestyle modifications, and
pharmacologic therapies used for treatment of CKD.
• “CKD is progressive, irreversible kidney damage
characterized by decreased estimated glomerular
filtration rate (eGFR) or evidence of kidney damage for
at least 3 months.”
• Progression of kidney disease to end-stage renal
disease (ESRD) generally occurs over months - years.
• The kidney has three main functions:
Excretory (excrete fluid, electrolytes, and solutes)
Metabolic (metabolize vitamin D and some drugs)
Endocrine (produce erythropoietin).
• When the number of nephrons decrease, these
functions are affected.
Pathophysiology
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Risk Factors • As mentioned earlier many factors cause the initial

1. Susceptibility factors: not
directly proven to cause CKD.
• These factors are generally
not modifiable.
2. Initiation factors: directly
cause CKD.
• These factors are modifiable
by pharmacologic therapy.
3. Progression factors: result
in a faster decline in kidney
function and worsening of CKD.
• These factors may also be
modified by pharmacologic
therapy or lifestyle
modifications to slow the
progression of CKD.
Susceptibility
• Advanced age
• Racial/ethnic minority
• Family history of kidney disease
• Low income or education
• Systemic inflammation
• Dyslipidemia
Initiation
• Diabetes mellitus
• Hypertension
• Autoimmune disease
• Polycystic kidney disease
• Drug toxicity
• Urinary tract abnormalities
(infections, obstruction, stones)
Progression
• Poor control of diabetes
• Uncontrolled Hypertension
• Proteinuria
• Tobacco smoking
damage to the kidney.
• Regardless of the initial cause of kidney damage, the
result is a decrease in the number of functioning
nephrons.
• This will result in hypertrophy of the remaining
nephrons to increase glomerular filtration and tubular
function, both reabsorption and secretion, in an
attempt to compensate for the loss of kidney function.
• Initially, these adaptive changes preserve many of the
clinical parameters of kidney function.
• However, as time progresses, angiotensin II is
required to maintain the hyperfiltration state of the
functioning nephrons.
• The vasoconstrictor effect of Ag II will cause an
increase in the pressure in the glomerular capillaries.

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• Increased glomerular capillary pressure expands the

pores in the glomerular basement membrane, altering
the size-selective barrier and allowing proteins to be
filtered through the glomerulus.
• Proteinuria increases nephron loss through various
mechanisms.
• Filtered proteins are reabsorbed in the renal tubules,
which activates the tubular cells to produce Clinical Presentation &
inflammatory and vasoactive cytokines.
• These cytokines cause interstitial damage and
Diagnosis
scarring in the renal tubules, leading to damage and
loss of more nephrons.
• Ultimately, the process leads to progressive loss of
nephrons to the point where the number of remaining
functioning nephrons is too small to maintain clinical
stability, and kidney function declines.

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• CKD is often asymptomatic Markers of structural

kidney abnormalities:
• Assessment for CKD relies on appropriate screening
• Albuminuria (30 mg/24 Staging of CKD
strategies in all patients with risk factors for developing hours or more)
CKD. • Albumin : creatinine ratio
• Assessment for CKD includes SCr, urinalysis, BP, of more than 30 mg/g
serum electrolytes, and/or imaging studies. • Hematuria or casts in urine
• A key part of CKD assessment is analysis for sediment
proteinuria (the primary marker of structural kidney • Electrolyte and other
abnormalities caused by
damage) even in patients with normal GFR. renal tubular disorders
• GFR is the main marker for the staging of CKD • Abnormalities detected by
• A patient is classified to have ESRD when the GFR is histology or imaging.
below 15 mL/min/1.73 m2 (<0.14 mL/s/m2) and either • Functional abnormalities
chronic dialysis or kidney transplantation is needed to are indicated by GFR less
than 60 mL/min/1.73m2
sustain life. (0.58 mL/s/m2).

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The decline in kidney function is associated with

a number of complications:

• Hypertension
• Fluid and electrolyte disorders Non-pharmacological
• Anemia treatment
• Metabolic bone disease

• The expected life expectancy of patients with

ESRD is only 25% of the general population

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• Restrict protein to 0.8 g/kg/day if GFR is less than 30

mL/min/1.73 m2. This has been shown to slow the
progression of kidney disease.

• Limiting salt intake to ˂ 2 g (90 mmol) of sodium per

day (equivalent to 5 g NaCl) will help to control BP and
reduce water retention in CKD.

• Encourage smoking cessation to slow progression of

Pharmacological Treatment
CKD and reduce the risk of CVD.

• Encourage exercise at least 30 minutes 5x / week and

achievement of a body mass index (BMI) of 20 - 25
kg/m2.

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Treatment goals General Approach to Treatment

• The best approach for the management of CKD is to
1. Slow progression of CKD to prevent cardiovascular prevent it via keeping the initial risk factors (such as
events and the CKD complications hypertension & DM) under strict control.

2. Delay the need for dialysis or kidney transplant as • Once the CKD occurred, the management strategy
would be to control its complications in addition to
long as possible strict control of the initial risk factors to slow the
progression of the CKD
3. Manage complications.
• Complications of the CKD:
1. Anemia
2. Metabolic bone disease
3. Fluid and electrolyte disorders
4. Hypertension

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1. Anemia of CKD
• The kidney produces 90% of the hormone
erythropoietin (EPO), which stimulates RBCs
production.
• Reduction in the number of functioning nephrons
decreases renal production of EPO, which is the
primary cause of anemia in patients with CKD.
• The development of anemia of CKD results in
decreased oxygen delivery and utilization, leading to
increased cardiac output and left ventricular
hypertrophy which increase the cardiovascular risk
and mortality in CKD.
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• When iron supplements alone is not sufficient to
increase Hgb level, ESAs (Erythropoiesis Stimulating
Agents) are necessary to replace erythropoietin.
• ESAs (e.g. Epoetin alfa & Darbepoetin alfa) are
synthetic formulations of EPO produced by
recombinant human DNA technology.
• Use of ESAs increases the iron demand for RBC
production leading to iron deficiency, requiring iron
supplements to correct and maintain adequate iron
stores to promote RBC production.
• All ESAs are equivalent in their efficacy and have a
similar adverse-effect profile.
• S.C. administration of ESA is preferred over IV
because it produces a more predictable and sustained
response & because lower doses less frequently need
to be given.
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Treatment
• In general, calcium, phosphorus, and PTH levels should
be maintained in the normal range for all stages of CKD.
This might be difficult in patients on dialysis, so close to
normal levels should be maintained.
Phosphate-Binding Agents
• Used when dietary restriction is not sufficient
• Calcium carbonate and calcium acetate can correct
hypocalcemia and bind phosphate.
• Calcium-containing phosphate binders also aid in the
correction of metabolic acidosis, another complication of
kidney failure.
• Calcium citrate is usually not used because the citrate salt
can increase aluminum absorption.
• Aluminum preparations should only be considered for
short term use (up to 4 weeks) in patients with severely
elevated phosphorus due to the risk for aluminum toxicity.
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Treatment
• The first-line treatment for anemia of CKD involves
replacement of iron stores with iron supplements.
• Oral iron supplements (200 mg elemental iron daily in
divided doses) are the first-line treatment for patients
not receiving hemodialysis.
• When oral iron is not effective to increase iron stores
or for patients receiving hemodialysis, IV iron should
be administered
• Injectable iron (iron dextran or iron sucrose) can be
given after routine testing of the iron store or in smaller
maintenance doses of iron weekly or with each
dialysis session
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2. CKD-Related Mineral and Bone Disorder
• Disorders of mineral and bone metabolism (CKD-MBD)
are common in CKD patients and include abnormalities
in PTH, calcium, phosphorus, vitamin D, and bone
turnover.
• Calcium-phosphorus homeostasis is mediated through
many hormones and their effects on bone, GIT, kidneys,
and the parathyroid gland.
• As kidney function declines, phosphate elimination
decreases resulting in hyperphosphatemia and a
decrease in serum calcium concentration.
• Hypocalcemia stimulates secretion of PTH causing
hyperparathyroidism.
• As renal function declines, serum calcium balance can
be maintained only at the expense of increased bone
resorption, leading to alterations in structural integrity of
bone and other consequences.
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Vitamin D Therapy
• In CKD, a decrease in renal metabolism of vit. D
decreases concentration of the activated form of vit. D,
calcitriol (1,25-dihydroxy vit. D) and its precursor 25-
hydroxy vit. D.
• Vit. D deficiency becomes evident as early as Stage 2
and leads to a rise in PTH levels
• Exogenous vit. D (e.g. Ergocalciferol & cholecalciferol)
act directly on the PT gland to decrease PTH secretion
Calcimimetics e.g. Cinacalcet
• This increases the sensitivity of receptors on the PT
gland to serum calcium levels to reduce PTH secretion,
but has no effect on GIT absorption of calcium or
phosphorus, and may even lower serum calcium levels.
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3. Electrolyte & Acid–Base Imbalance
• In CKD, reduction in the number of functioning
nephrons decrease glomerular filtration regulation of
electrolytes (Na+ & K+) and acid secretion.
Treatment
• Patients should be advised to refrain from adding salt
to their diet
• Fluid restriction is generally unnecessary as long as
sodium intake is controlled.
• Diuretic therapy is often necessary to prevent volume
overload
• Loop diuretics are most frequently used to increase
sodium and water excretion.
• Thiazide diuretics alone may not be effective in
reducing fluid retention.
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4. Proteinuria & Hypertension in CKD
• Poor control of BP accelerates progression and also
carries adverse cardiovascular risk.
• Target BP should be 130/80 mmHg, or 120/75 mmHg if
significant proteinuria and/or diabetes is present.
Treatment
• If proteinuria is present, ACE inhibitors are the first-line
treatment, as they reduce proteinuria in addition to their
antihypertensive effects in both diabetic and non-
diabetic renal disease.
• ARBs can be used as alternative, with similar effects on
proteinuria and prevention of progression.
• Initiate therapy with the lowest recommended dose and
increase dose until albuminuria is reduced by 30% -
50% or side effects occurs
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Renal Replacement Therapy
• Patients who progress to ESKD require RRT.
• The modalities used for RRT are hemodialysis,
peritoneal dialysis, and kidney transplantation.
• Complications associated with dialysis include:
hypotension, muscle cramps, hypersensitivity,
thrombosis, access infection and aluminium toxicity.
• Long-term complications include increase in
cardiovascular disease, bone disease and dialysis
amyloid.
• Kidney transplantation is the preferred method of RRT,
due to improved patient survival. However, organ
availability limits the number of patients who can
receive a kidney transplant in addition to complications
of immunosuppression.
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• Patients who develop hyperkalemia should restrict
dietary intake of potassium to 50 - 80 mEq (50–80
mmol) per day.
• Diuretics, sodium polystyrene sulfonate (K+ binding
agent), and fludrocortisone are useful in the
management of hyperkalemia in patients with CKD.
• Acute hyperkalemia that results in cardiac
abnormalities can be managed with calcium, insulin
and dextrose.
• Metabolic Acidosis can be managed with sodium
bicarbonate or citrate preparations
• Calcium carbonate and calcium acetate, used to bind
phosphorus might also aid in managing the metabolic
acidosis
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• Combined ACE inhibitors and ARBs have a synergistic
effect on proteinuria. Use both cautiously if necessary
to reduce proteinuria to < 1 g/24 hours.
• Non-dihydropyridine CCBs are 2nd line anti-proteinuric
drugs when ACEI or ARBs are contraindicated or not
tolerated & can be added to ACEi or ARBs (if needed).
• Dihydropyridine CCBs (e.g., amlodipine) should not be
used alone but can be added to ACEi or ARBs.
• Patients with CKD often need three or more agents to
achieve BP control.
• In stages 4 and 5 CKD, salt and water retention may
be significant factors in hypertension and can be
managed with loop diuretics, e.g. furosemide in
addition to salt & water restriction.
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Hemodialysis
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Thank You

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