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Clinical Pharmacy
Chapter 10
Chronic Kidney Disease
Rowa’ Al-Ramahi
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DEFINITION
• Chronic kidney disease (CKD) is a progressive loss of
function over several months to years, characterized by
gradual replacement of normal kidney architecture with
interstitial fibrosis.
• CKD is categorized by the level of kidney function, based
on glomerular filtration rate (GFR), into stages 1 to 5,
with each increasing number indicating a more advanced
stage of the disease, as defined by a declining GFR.
This classification system from the National Kidney
Foundation’s Kidney Dialysis Outcomes and Quality
Initiative (K/DOQI) also accounts for structural evidence
of kidney damage.
• CKD stage 5, previously referred to as end-stage renal
disease (ESRD), occurs when the GFR falls below 15
mL/min per 1.73 m2 body surface area. The patient with
stage 5 CKD requiring chronic dialysis or renal
transplantation for relief of uremic symptoms is said to
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have ESRD.
PATHOPHYSIOLOGY
• Susceptibility factors increase the risk for kidney disease
but do not directly cause kidney damage. Susceptibility
factors include advanced age, reduced kidney mass and
low birth weight, racial or ethnic minority, family history,
low income or education, systemic inflammation, and
dyslipidemia.
• Initiation factors initiate kidney damage and can be
modified by drug therapy. Initiation factors include
diabetes mellitus, hypertension, autoimmune disease,
polycystic kidney disease, and drug toxicity.
• Progression factors hasten decline in kidney function
after initiation of kidney damage. Progression factors
include glycemia in diabetics, hypertension, proteinuria,
and smoking.
• Most progressive nephropathies share a final common
pathway to irreversible renal parenchymal damage and
ESRD. Key pathway elements are loss of nephron mass,
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glomerular capillary hypertension, and proteinuria.
CLINICAL PRESENTATION
• CKD development and progression is insidious. Patients
with stage 1 or 2 CKD usually do not have symptoms or
metabolic derangements seen with stages 3 to 5, such
as
anemia,
secondary
hyperparathyroidism,
cardiovascular disease, malnutrition, and fluid and
electrolyte abnormalities that are more common as
kidney function deteriorates.
• Uremic symptoms (fatigue, weakness, shortness of
breath, mental confusion, nausea, vomiting, bleeding,
and anorexia) are generally absent in stages 1 and 2,
minimal during stages 3 and 4, and common in patients
with stage 5 CKD who may also experience itching, cold
intolerance, weight gain, and peripheral neuropathies.
DESIRED OUTCOME
• The goal is to delay the progression of CKD, minimizing
the development or severity of complications.
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TREATMENT: PROGRESSION-MODIFYING
THERAPIES
NONPHARMACOLOGIC THERAPY
• A low-protein diet (0.6 to 0.75 g/kg/day) can delay
progression of CKD in patients with or without diabetes,
although the benefit is relatively small.
PHARMACOLOGIC THERAPY
Hyperglycemia
• Intensive therapy in patients with type 1 and type 2
diabetes reduces microvascular complications, including
nephropathy. Intensive therapy can include insulin or oral
drugs and involves blood sugar testing at least three
times daily.
• The progression of CKD can be limited by optimal
control of hyperglycemia and hypertension
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• Hypertension
• Adequate blood pressure control can reduce the rate of
decline in GFR and albuminuria in patients with or without
diabetes.
• Antihypertensive therapy should be initiated in diabetic or
nondiabetic CKD patients with an ACEI or an ARB.
Nondihydropyridine CCBs are generally used as secondline antiproteinuric drugs when ACEIs or angiotensin II
receptor blockers are not tolerated.
• ACEI clearance is reduced in CKD, therefore treatment
should begin with the lowest possible dose followed by
gradual titration to achieve target blood pressure and,
secondarily, to minimize proteinuria. No individual ACEI is
superior to another.
• GFR typically decreases 25% to 30% within 3 to 7 days
after starting ACEIs because this class reduces
intraglomerular pressure. Sustained increases in the serum
creatinine by more than 30% after starting ACEIs may be
due to the ACEI and discontinuation should be strongly
considered. Serum potassium should also be monitored
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after initiating or increasing the dose of an ACEI.
Supportive Therapies
• Dietary protein restriction, lipid-lowering medications,
smoking cessation, and anemia management may help
slow the rate of CKD progression.
• The primary goal of lipid-lowering therapies in CKD is to
decrease the risk for progressive atherosclerotic
cardiovascular disease.
• A secondary goal is to reduce proteinuria and renal
function decline seen with administration of statins.
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TREATMENT: MANAGEMENT OF COMPLICATIONS
• Progression of CKD to ESRD can occur over years to
decades, with the mechanism of kidney damage
dependent on the etiology of the disease; however, the
consequences and complications of marked reductions
in kidney function are fairly uniform irrespective of the
underlying etiology.
• No single toxin is responsible for all of the signs and
symptoms of uremia observed in stage 4 or 5 CKD.
Toxins accumulate as a result of increased secretion,
decreased clearance secondary to reduced metabolism
within the kidney, and/or decreased renal clearance of
by-products of protein metabolism.
• The overall goal of therapy is to optimize the patient’s
duration and quality of life. Patients who reach CKD
stage 4 almost inevitably progress to ESRD, requiring
dialysis to sustain life.
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FLUID AND ELECTROLYTE ABNORMALITIES
• Serum sodium concentration is generally maintained by an
increase in fractional excretion of sodium, resulting in a
volume-expanded state. The most common manifestation of
increased intravascular volume is systemic hypertension.
• The kidney’s ability to adjust to abrupt changes in sodium
intake is diminished in patients with ESRD. Sodium
restriction beyond a no-added salt diet is not recommended
unless hypertension or edema is present. A negative sodium
balance can decrease renal perfusion and cause a further
decline in GFR.
• Diuretic therapy or dialysis may be necessary to control
edema or blood pressure.
• Loop diuretics, particularly when administered by continuous
infusion, increase urine volume and renal sodium excretion.
Although thiazide diuretics are ineffective when creatinine
clearance is less than 30 mL/min, adding them to loop
diuretics can enhance excretion of sodium and water.
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POTASSIUM HOMEOSTASIS
• Serum potassium concentration is usually maintained in
the normal range until the GFR is less than 20 mL/min
per 1.73 m2, when mild hyperkalemia is likely to develop.
• The definitive treatment of severe hyperkalemia in ESRD
is hemodialysis. Temporary measures include calcium
gluconate, insulin and glucose, nebulized albuterol,
and sodium polystyrene sulfonate.
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ANEMIA
• The primary cause of anemia in patients with CKD or ESRD
is erythropoietin deficiency. Other contributing factors include
decreased lifespan of red blood cells, blood loss, and iron
deficiency.
• Iron supplementation is necessary to replete iron stores.
Parenteral iron therapy improves response to erythropoietic
therapy and reduces the dose required to achieve and
maintain target indices. In contrast, oral therapy is often
inadequate.
• Adverse effects of IV iron include allergic reactions,
hypotension, dizziness, dyspnea, headaches, lower back
pain, arthralgia, syncope, and arthritis. Some of these
reactions can be minimized by decreasing the dose or rate
of infusion. Sodium ferric gluconate and iron sucrose have
better safety records than iron dextran. Iron dextran requires
a test dose to reduce the risk of anaphylactic reactions.
• SC administration of epoetin alfa is preferred because IV
access is not required, and the SC dose that maintains
target indices is 15%-50% lower than the IV.
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• Darbepoetin alfa has a longer half-life than epoetin alfa and
prolonged biologic activity. Doses are administered less
frequently, starting at once a week IV or SC.
• Erythropoietic agents are well tolerated. Hypertension is the
most common adverse event.
Evaluation of Therapeutic Outcomes
• Iron indices (transferrin saturation [TSat]; ferritin) should be
evaluated before initiating an erythropoietic agent. To avoid
errors, clinicians should wait at least 2 weeks after a loading
dose of IV iron to reassess them.
• For monitoring purposes, hemoglobin is preferred to hematocrit
because the latter fluctuates with volume status. The target
hemoglobin is 12 g/dL.
• After an erythropoietic agent is initiated, hemoglobin response
is typically delayed. Steady-state levels do not occur until after
the life span of a red blood cell (mean 2 m; range 1-4 m). To
avoid making premature dosing changes, clinicians should
evaluate response over several weeks.
• Patients should be monitored for potential complications, such
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as hypertension, which should be treated before starting
erythropoietic agent.
SECONDARY HYPERPARATHYROIDISM
AND RENAL OSTEODYSTROPHY
Pathophysiology and Clinical Presentation
• As kidney disease progresses, renal activation of vitamin D
is impaired, which reduces gut absorption of calcium. Low
blood calcium concentration stimulates secretion of
parathyroid hormone (PTH). As renal function declines,
serum calcium balance can be maintained only at the
expense of increased bone resorption, ultimately resulting in
renal osteodystrophy.
• Secondary hyperparathyroidism can cause altered lipid
metabolism, altered insulin secretin, resistance to
erythropoietic therapy, impaired neurologic and immune
functions, and increased mortality.
• ROD progresses insidiously for several years before the
onset of symptoms such as bone pain and fractures. Skeletal
complications include osteitis fibrosa cystica (high bone
turnover), osteomalacia (low bone turnover) and adynamic
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bone disease. When ROD symptoms appear, the disease
not easily amenable to treatment.
Treatment
• Preventive measures should be initiated in patients in
early stages of CKD to improve outcomes by the time
they reach stage 5 CKD or ESRD.
• Dietary phosphorus restriction (800 to 1,000 mg/day)
should be first-line intervention for stage 3 or higher
CKD.
• By the time ESRD develops, most patients require a
combination of phosphate-binding agents, vitamin D, and
calcimimetic therapy to achieve K/DOQI goals.
Phosphate-Binding Agents
• Phosphate-binding
agents
decrease
phosphorus
absorption from the gut and are first-line agents for
controlling both serum phosphorus and calcium
concentrations.
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• K/DOQI guidelines recommend that elemental calcium
from calcium containing binders should not exceed 1,500
mg/day and the total daily intake from all sources should
not exceed 2,000 mg. This may necessitate combination
of calcium- and noncalcium-containing products (e.g.,
sevelamer HCL, lanthanum carbonate).
• Adverse effects of calcium-containing phosphate
binders, as well as sevelamer and lanthanum, include
constipation, diarrhea, nausea, vomiting, and abdominal
pain. The risk of hypercalcemia is also a concern. To
avoid potential drug interactions, phosphate binders
should be administered 1 hour before or 3 hours after
other oral medications.
Vitamin D Therapy
• Calcium (less than 9.5 mg/dL) and phosphorus (less
than 4.6 mg/dL) must be controlled before vitamin D
therapy is initiated. Calcitriol , 1,25-dihydroxyvitamin D
3 , directly suppresses PTH synthesis and secretion and
upregulates vitamin D receptors, which ultimately may
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reduce parathyroid hyperplasia.
• The newer vitamin D analogs paricalcitol and
doxercalciferol may be associated with less
hypercalcemia and, for paricalcitol, hyperphosphatemia.
Vitamin D therapy, regardless of agent, is associated
with decreased mortality.
Calcimimetics
• Cinacalcet reduces PTH secretion by increasing the
sensitivity of the calcium-sensing receptor. The most
common adverse events are nausea and vomiting.
• The most effective way to use cinacalcet with other
therapies has not been decided.
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METABOLIC ACIDOSIS
• A clinically significant metabolic acidosis is commonly
seen when the GFR drops below 20 to 30 mL/min (stage
4 CKD). The goals of therapy in CKD are to normalize
the blood pH (7.35 to 7.45) and serum bicarbonate (22 to
26 mEq/L). Consequences of metabolic acidosis include
renal bone disease, reduced cardiac contractility,
predisposition to arrhythmias, and protein catabolism.
• Oral alkalinizing salts (e.g., sodium bicarbonate, Shohl
solution, and Bicitra= CITRIC ACID / SODIUM CITRATE)
can be used in patients with stage 4 or 5 CKD. Polycitra ,
which contains potassium citrate, should not be used in
patients with severe CKD because hyperkalemia may
result.
• Metabolic acidosis in patients undergoing dialysis can
often be managed by using higher concentrations of
bicarbonate or acetate in the dialysate.
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HYPERTENSION
• The pathogenesis of hypertension in patients with CKD
is multifactorial and includes fluid retention, increased
sympathetic activity, an endogenous digitalis-like
substance, elevated levels of endothelin-1, erythropoietin
use, hyperparathyroidism, and structural arterial
changes.
• In early stage CKD, the target blood pressure for
cardiovascular risk reduction is 130/80 mm Hg. The
K/DOQI guidelines propose a predialysis blood pressure
of less than 140/90 mm Hg and a postdialysis blood
pressure of less than 130/80 mm Hg.
• Salt (2 to 3 g/day) and fluid intake should be restricted.
• Most patients with ESRD require three or more
antihypertensive agents to achieve target blood
pressure. As with less advanced CKD ACEIs, ARBs, and
dihydropyridine calcium channel blockers are the
preferred agents.
• Blood pressure should be monitored at each visit, and at
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home when feasible.
HYPERLIPIDEMIA
• The prevalence of hyperlipidemia increases as renal
function declines. Hyperlipidemia should be managed
aggressively in patients with ESRD to a low-density
lipoprotein cholesterol goal of less than 100 mg/dL.
Statins are the drugs of first choice. Although well
tolerated by otherwise healthy patients, statins have the
potential to cause myotoxic effects when administered in
patients with hepatic disease or with interacting drugs
such as azole antibiotics, cyclosporine, gemfibrozil, and
niacin.
• In patients with ESRD, lipid profile should be reassessed
at least annually and 2 to 3 months after changing
treatment.
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OTHER SECONDARY COMPLICATIONS
Pruritus
Nutritional Status
• Protein-energy malnutrition is common in patients with
stage 4 or 5 CKD. Daily protein intake should be 1.2 g/kg
for patients undergoin hemodialysis and 1.2 to 1.3 g/kg
for those undergoing peritoneal dialysis.
• Daily energy intake should be 35 kcal/kg for patients
undergoing any type of dialysis. The intake should be
lowered to 30 to 35 kcal/kg for patients older than 60
years.
• Vitamins A and E are elevated in ESRD whereas watersoluble vitamins should be supplemented to replace
dialysis-induced loss.
Uremic Bleeding
• Nondialytic therapies that may temporarily shorten
increased bleeding time include cryoprecipitate, and
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estrogens.
What makes me weak?
My fears.
What keeps me standing? My faith.
What sustains my mind?
My quest for knowledge.
What teaches me all lessons?
My mistakes.
What empowers me?
My God & Me.
What if I can't go on?
Not an option.
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