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Chronic Kidney Disease:
Management of Complications
Pharmacotherapy II
Second Semester
2017
References
 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work
Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation
and Management of Chronic Kidney Disease. Kidney inter., Suppl.
2013; 3: 1-150.
 Kidney Disease: Improving Global Outcomes (KDIGO) Anemia
Work Group. KDIGO Clinical Practice Guideline for Anemia in
Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.
 KDIGO Clinical Practice Guidelines for the Diagnosis, Evaluation,
Prevention, and Treatment of Chronic Kidney Disease-Mineral and
Bone Disorder (CKD-MBD)
CKD complications
 Complications begin to develop as kidney disease progresses, most
often when patients reach to eGFR is <60 mL/minute/1.73 m2
(G3a-G5).
 Among these complications are:
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fluid and electrolyte abnormalities,
anemia,
hyperphosphatemia,
hyperparathyroidism,
metabolic acidosis,
cardiovascular complications,
poor nutritional status.
 Often, these complications go unrecognized or are inadequately
managed during the earlier stages of CKD, leading to poor
outcomes by the time a patient is in need of dialysis therapy.
Metabolic Effects of Progressive Kidney Disease
Cardiovascular
Hypertension
Congestive heart failure
Pericarditis
Atherosclerosis
Arrhythmias
Metastatic calcifications
Dermatologic
Altered pigmentation
Pruritus
Endocrine
Calcium-phosphorous imbalances
Hyperparathyroidism
Metabolic bone disease
Altered thyroid function
Altered carbohydrate metabolism
Hypophyseal-gonadal dysfunction
Decreased insulin metabolism
Erythropoietin deficiency
Fluid, Electrolyte, and Acid-Base
Effects
Fluid retention
Hyperkalemia
Hypermagnesemia
Hyperphosphatemia
Hypocalcemia
Metabolic acidosis
Gastrointestinal
Anorexia
Nausea, vomiting
Delayed gastric emptying
GI bleeding
Ulcers
Hematologic
Anemia
Bleeding complications
Immune suppression
Musculoskeletal
Renal bone disease
Amyloidosis
Neurologic
Lethargy
Depressed sensorium
Tremor
Asterixis
Muscular irritability and cramps (i.e., restless legs syndrome)
Seizures
Motor weakness
Peripheral neuropathy
Coma
Psychological
Depression
Anxiety
Psychosis
Miscellaneous
Reduced exercise tolerance
1) Fluid And Electrolyte Abnormalities:
Sodium and Water
 Patient with CKD or ESKD maintain sodium balance but are
volume expanded
 the most common manifestation of increased intravascular volume
is systemic hypertension
 The goal in managing sodium and water balance is to maintain a
normal serum sodium concentration while preventing fluid
overload or volume depletion (i.e., maintaining hemodynamic
stability).
 By achieving these goals, the risk of developing hypertension
secondary to volume overload is also reduced, although
hypertension is already present in many patients at G3 and G4.
secondary to the defect in urinary
concentrating ability
as the result of an increase
in FeNa
= plasma
Management
 The ability of the kidney to adjust to abrupt changes in sodium
intake is greatly diminished in patients with ESKD.
 Sodium restriction beyond a no-added-salt diet should not be
recommended except in the face of hypertension or
edema.(2-4 g/day).
 Saline-containing IV solutions should be used cautiously in patients
with CKD because the kidney’s ability to excrete a salt load is
impaired and such patients are prone to volume overload
 Fluid restriction is generally unnecessary provided sodium intake
is controlled, although fluid intake between dialysis sessions is
generally limited for hemodialysis patients (avoid < 2 L/d)
(depends on urine output).
 Diuretic therapy is often necessary to control edema or blood pressure.
 Loop diuretics, particularly when administered by continuous infusion, increase
urine volume and renal sodium excretion.
 Thiazide diuretics are ineffective in patients with a GFR below 30 mL/min. The
possible exception is use of the thiazide-like diuretic, metolazone, which may
retain its effect at reduced eGFRs.
 As kidney failure progresses, manifestations of excess fluid accumulation
develop that are resistant to more conventional interventions, and dialysis will
be required to control volume status.
2) Potassium Homeostasis (Hyperkalemia):
 Hyperkalemia can result from a combination of factors, including:
 diminished renal potassium excretion,
 redistribution of potassium into the extracellular fluid owing to metabolic
acidosis,
 excessive potassium intake.
 Rare if GRF >15 without an endogenous or exogenous load of
potassium.
 Hyperkalemia is defined as a serum potassium concentration greater than
5.5 mEq/L.
 It can be further classified according to its severity:
 mild hyperkalemia (serum potassium 5.5 to 6 mEq/L);
 moderate hyperkalemia (6.1 to 6.9 mEq/L);
 severe hyperkalemia (>7 mEq/L).
 The chronic goal is to maintain potassium concentrations of
approximately 4.5 to 5.5 mEq/L
Hyperkalemia – Clincal presentation
 Frequently asymptomatic; however, the patient may complain of heart
palpitations or skipped heartbeats.
 The earliest ECG change (serum potassium 5.5 to 6 mEq/l) is peaked T
waves.
 The sequence of change with further increases is:
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prolongation of the PR interval ,
widening of the QRS complex,
loss of the P wave,
merging of the QRS complex with the T wave resulting in a sine-wave
pattern.
 Hyperkalemic ECG changes are uncommon at potassium concentrations
of <7 mEq/L, but occur regularly at concentrations >8 mEq/L.
 Ventricular arrhythmias or cardiac arrest may ensue if no
effort to lower serum potassium
Hyperkalemia - Management
 Generally, treatment is unnecessary if the potassium concentration is <6.5
mEq/L and there are no ECG changes.
 If potassium concentrations rise above 6.5 mEq/L, and especially if they are
accompanied by neuromuscular symptoms or changes in the ECG, treatment
should be instituted.
 Chronic management involves prevention of hyperkalemia by:
 limiting potassium intake to 50 to 80 mEq/day
 Homework: what constitutes a low potassium diet?
 avoiding the use of agents that could elevate potassium levels.
 Homework: what are these agents?
 Constipation in patients with CKD can interfere with colonic
potassium excretion; therefore a good bowel regimen is
important.
 Homework: What is good bowel regimen?
Grains
Foods prepared with white flour (eg, pasta, bread), white rice
Beverages
Non-dairy creamer, fruit punch, drink mixes (eg, Kool-Aid), tea (<2 cups or 16 ounces
per day), coffee (<1 cup or 8 ounces per day)
Sweets
Angel or yellow cake, pies without chocolate or high-potassium fruit, cookies without
nuts or chocolate
Fruits
Apples (1), apple juice, applesauce, apricots (canned), blackberries, blueberries,
cherries, cranberries, fruit cocktail (drained), grapes, grape juice, grapefruit (½),
mandarin oranges, peaches (½ fresh or ½ cup canned), pears (1 small fresh or ½ cup
canned), pineapple and juice, plums (1 whole), raspberries, strawberries, tangerine (1
whole), watermelon (1 cup)
Vegetables
Alfalfa sprouts, asparagus (6 spears), green or wax beans, cabbage (cooked), carrots
(cooked), cauliflower, celery (1 stalk), corn (½ fresh ear or ½ cup), cucumber, eggplant,
kale, lettuce, mushrooms (fresh), okra, onions, parsley, green peas, green peppers,
radish, rhubarb, water chestnuts (canned, drained), watercress, spinach (raw, 1 cup),
squash (yellow), zucchini
Proteins
Chicken, turkey (3 ounces), tuna, eggs, baloney, shrimp, sunflower or pumpkin seeds (1
ounce), raw walnuts, almonds, cashews, or peanuts (all 1 ounce), flax seeds (2
tablespoons ground), unsalted peanut butter (1 tablespoon)
Dairy
products
Cheddar or Swiss cheese (1 ounce), cottage cheese (½ cup)
HW: low-potassium diet
These foods have a low level of potassium (less than 250 mg potassium per serving on average). You can eat
these low-potassium foods, but be sure to watch your portion size since potassium can quickly add up if you eat
a large portion. Unless noted, one serving is ½ cup (4 ounces)
Agents that can cause hyperkalemia.
 Medication that interferes with urinary excretion:
 ACE inhibitors and angiotensin receptor blockers
 Potassium-sparing diuretics (e.g. amiloride and spironolactone)
 NSAIDs such as ibuprofen, naproxen, or celecoxib
 The calcineurin
inhibitor immunosuppressants cyclosporine and tacrolimus
 The antibiotic trimethoprim
 The antiparasitic drug pentamidine
 In constipation use: potassium-binding resins such as sodium
polystyrene sulfonate (Kayexalate)
Hyperkalemia - Management
 Acute management involves:
 reversal of cardiac effects with calcium
administration (antagonize membrane effects of
potassium)
 reduction of serum potassium which can be achieved
by shifting potassium intracellularly with
administration of:
 glucose and insulin,
 β-adrenergic agonists,
 alkali therapy (if metabolic acidosis is a
contributing factor)
 Removing excess potassium from the
body
 Loop or thiazide diuretics
 exchange resins to remove potassium
 dialysis using a low-potassium dialysate bath
Therapeutic alternatives for the management of hyperkalemia
3) Metabolic Acidosis:
 A clinically significant metabolic acidosis is commonly seen when the GFR drops below
20-30ml/min.
 The major factors responsible for development of metabolic acidosis in
advanced kidney disease:
 Reduced bicarbonate reabsorption
 impaired production of ammonia by the kidneys
 Consequences of metabolic acidosis include:
 renal bone disease (bone buffering of some of the excess hydrogen ions is associated with
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the release of calcium and phosphate from bone, i.e. promoting bone resorption),
Fatigue and decreased exercise tolerance,
reduced cardiac contractility,
increased vascular irritability ,
protein catabolism (Uremic acidosis can increase skeletal muscle breakdown and diminish
albumin synthesis)
 The goals of therapy for patients with CKD are:
 to normalize the pH of the blood (pH of approximately 7.35 to 7.45)
 maintain the serum bicarbonate within the normal range (22 to 28 mEq/L).
Metabolic acidosis - Management
 Asymptomatic patients with mild acidosis (bicarbonate of 12 to 20
mEq/L; pH of 7.2 to 7.4) generally do not require emergent therapy and
gradual correction over days to weeks is appropriate.
 When plasma bicarbonate ↓< 20 mEq/L, give NaHCO3 orally
 Each 650-mg tablet of sodium bicarbonate provides 8 mEq of sodium and 8 mEq of
bicarbonate.
 Dose (mEq)= 0.5 x WT x (24 – Serum bicarbonate)
 The calculated amount of bicarbonate replacement therapy (in milliequivalents [or in mmols])
should be administered over several days to prevent volume overload from excessive sodium
intake.
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Should be administered over several days to avoid volume overload from Na.
Daily dose should not exceed 0.5 mEq/kg/day and should be given in divided doses
GI distress from carbon dioxide production
Homework: what are Bicitra and Polycitra and what are their uses.
 Patients with severe acidosis (serum bicarbonate <8 mEq/L; pH <7.2)
may require IV therapy
 Bicitra contain 1 mEq/mL (1 mmol/mL) of sodium and the
equivalent of 1 mEq/mL (1 mmol/mL) of bicarbonate as sodium
citrate/citric acid. Citrate is metabolized in the liver to
bicarbonate, and citric acid is metabolized to CO2 and water.
 Polycitra, which contains potassium citrate (1 mEq/mL [1
mmol/mL] of sodium, 1 mEq/mL [1 mmol/mL] of potassium, and
2 mEq/mL [2 mmol/mL] of bicarbonate) should not be used in
patients with severe CKD because of the risk of
hyperkalemia.
Other Electrolyte and Metabolic Disturbances of CKD
 Hypermagnesemia
 is due to decreased elimination of magnesium by the kidney.
 Magnesium is eliminated by the kidney to the extent required to achieve
normal serum magnesium concentrations (1.7 to 2.2 mg/dL) until eGFR is
<30 mL/minute/1.73 m2.
 Serum magnesium concentrations <5 mEq/L rarely cause symptoms.
 Higher concs can lead to nausea, vomiting, lethargy, confusion, and
diminished tendon reflexes,
 Severe hypermagnesemia may depress cardiac conduction.
 The risk of hypermagnesemia can be reduced by
 avoiding magnesium-containing antacids and laxatives
 use of magnesium-free dialysate in patients with stage 5 CKD requiring dialysis.
Other Electrolyte and Metabolic Disturbances of CKD
 Hyperphosphatemia
 is a result of decreased phosphorus elimination by the kidneys
 patients should reduce dietary phosphorus to 800 to 1,000
mg/day while maintaining adequate nutritional needs.
 Phosphorus-containing laxatives and enemas should also be avoided.
 Hyperphosphatemia is associated with low serum calcium
concentrations.
 Asymptomatic Hyperuricemia.
 Happen due to diminished urinary excretion of uric acid.
 In the absence of a history of gout or urate nephropathy, asymptomatic
hyperuricemia does not require treatment.
4) Anemia:
 Anemia appears as early as G3 stage
 Usually is normochromic & normocytic
 The primary cause of anemia in patient with CKD or ESKD is
erythropoietin (EPO) deficiency.
 Other factors include:
 decreased lifespan of red blood cells secondary to uremia,
 blood loss from frequent phlebotomy and HD, GI bleeding,
 severe hyperparathyroidism, protein malnutrition, severe infections, and
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inflammatory conditions
uremic toxins may inhibit the production of EPO, the bone marrow response
to EPO, and the synthesis of heme.
iron deficiency  microcytic hypochromic pattern
vitamin B12 & folate deficiency, occurs more frequently in dialyzed patients
since folic acid is removed by dialysis (rare in other stages of CKD) 
macrocytic anemia
Aluminum intoxication (RBCs are typically microcytic). The major source is
aluminium-containing antacids.
Definition and identification of anemia in CKD
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The recommended thresholds for diagnosis and evaluation of anemia should not be interpreted as being
thresholds for treatment of anemia but simply for the identification of this complication. Practice preferences
with respect to treatment strategies should be directed according to local resources.
Evaluation of anemia in people with CKD
 To identify anemia in people with CKD measure Hb concentration:
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when clinically indicated in people with GFR<60 ml/min/1.73 m2 (GFR categories G1-G2);
at least annually in people with GFR 30-59 ml/min/1.73 m2 (GFR categories G3a-G3b);
at least twice per year in people with GFR <30 ml/min/1.73 m2 (GFR categories G4-G5).
at least every 3 months in patients with CKD 5HD and CKD 5PD
Anemia - Clinical presentation and diagnosis
 Pallor and fatigue are the earliest clinical signs, with other manifestations
(exertional dyspnea, dizziness, headache) developing as anemia worsens
progressively with declining kidney function
 A significant consequence of anemia is development of left ventricular
hypertrophy (LVH), further contributing to cardiovascular complications and
mortality in patients with CKD  CHF, angina
 Early and aggressive treatment of anemia of CKD before the development
of stage 5 CKD is important.
• A more complete and regular workup for anemia of CKD is recommended for patients
with an eGFR of <60 mL/minute/1.73 m2. This workup includes:
• monitoring of hemoglobin and hematocrit,
• assessment of iron indices with correction if iron deficiency is present,
• evaluation for sources of blood loss, such as bleeding from the GI tract.
Laboratory tests in the evaluation of anemia
MCV=(Hct/RBC Count)
MCHC=(Hgb/Hct)
MCH=(Hgb/RBC Count)
% Transferrin saturation = (Serum iron/TIBC) x 100
RBC Distribution Width = (Standard deviation of MCV ÷ mean MCV) × 100
Anemia – Goals of therapy
 The desired outcomes of anemia management are:
 to increase oxygen-carrying capacity,
 decrease signs and symptoms of anemia,
 improve the patient’s quality of life,
 decrease the need for blood transfusions.
 Achievement of these goals requires a combination of an ESA and
iron supplementation to promote and maintain erythropoiesis.
 Hb is the preferred monitoring parameter for red blood cell
production because, unlike Hct, its concentration is not affected by
blood storage conditions and instrumentation used for analysis.
Parameter
Hb
KDOQI
KDIGO
ND-CKD and
PD-CKD
HD-CKD
ND-CKDa
HD and PD-CKDa
Hb 11–12 g/dL
Hb 11–12 g/dL
If Hb ≥10 g/dL, do not
initiate an ESA
Do not use ESAs
to exceed Hb of
13 g/dL
Do not use ESAs to
exceed Hb of 13 g/dL
Use ESAs to avoid
drop in Hb to <9
g/dL by starting
ESA when Hb is
between 9 and 10
g/dL
If Hb <10 g/dL,
consider rate of fall of
Hb, prior response to
iron, risk of needing a
transfusion, risk of ESA
therapy, and presence
of anemia symptoms
before initiating an ESA
Do not use ESAs to
maintain Hb above
11.5 g/dL
Do not use ESAs to
maintain Hb above
11.5 g/dL
TSatb (goal during
ESA therapy)
>20% (>0.20)
>20% (>0.20)
>30% (>0.30)
>30% (>0.30)
Serum ferritinb (goal
during ESA therapy)
>100 ng/mL
>200 ng/mL
>500 ng/mL
>500 ng/mL
a The
KDIGO expert panel considered the quality of the evidence to be low or very low.
b If TSat and serum ferritin are below suggested levels, consider iron supplementation if goal is to increase Hb and/or
decrease ESA dose. Note: Serum ferritin is an acute-phase reactant—use clinical judgment when above 500 ng/mL.
Target Hemoglobin and Use of ESAs
 Initiation of ESA therapy should be considered in all CKD patients
when Hb is between 9 and 10 g/dL and in nondialysis patients
when the following additional criteria are met:
 (a) the rate of Hb decline indicates the likelihood of requiring a RBC
transfusion and
 (b) reducing the risk of alloimmunization and/or other RBCtransfusion-related risks is a goal.
 According to the labeling for the available ESAs, the ESA dose
should be decreased or interrupted when Hb is above 10 g/dL in
CKD patients not receiving dialysis or above 11 g/dL in patients
receiving dialysis. This is in contrast to the KDOQI and more recent
KDIGO recommendations.
New KDIGO guidelines
The 2012 KDIGO guidelines
 suggested that ESAs not be started among adult non-dialysis CKD patients with Hgb concentrations
≥10 g/dL.
 For non-dialysis CKD patient with Hgb <10 g/dL, the decision to start ESAs should be
individualized based upon:
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the rate of fall in Hgb concentration,
prior response to iron therapy,
risk of needing a transfusion,
the risks related to ESA therapy
the presence of symptoms.
 Among dialysis patients, KDIGO suggests initiating ESAs when the Hgb concentration is below 10
g/dL.
 The KDIGO 2012 guidelines suggest that ESAs should generally not be used to
maintain Hgb concentrations above 11.5 g/dL, but that individualization of therapy
will be necessary as some patients may have improvements in quality of life at Hgb
≥11.5 g/dL and will be prepared to accept the risks . The KDIGO guidelines
recommended that ESAs not be used to maintain Hgb ≥13 g/dL.
 The 2012 KDIGO guidelines recommended that ESAs be used with great caution if at all in
CKD patients with active malignancy, especially if cure is anticipated , or with a
history of stroke or a history of malignancy.
Iron Status
 Iron supplementation is required by most CKD patients receiving
an ESA because of the increased iron demand that results from
stimulation of red blood cell production. As CKD worsens, a
progressive decline in Hb despite ESA therapy may be observed.
 Iron indices that should be monitored include:
 TSat, an indicator of iron immediately available for delivery to the
bone marrow
 (Transferrin is the carrier protein for iron and, as a protein, may be affected by
nutritional status)
 serum ferritin, an indirect measure of storage iron.
 Serum ferritin is an acute-phase reactant, meaning it may be elevated under
certain inflammatory conditions and give a false indication of storage iron.
 The content of hemoglobin in reticulocytes (CHr) is also
recommended as a parameter to assess iron status in hemodialysis
patients, although it is not commonly used in clinical practice..
Anemia - Management
 Nonpharmacologic Therapy
 Nonpharmacologic therapy for anemia of CKD includes maintaining adequate dietary
intake of iron as well as folate and B12.
 Patients on hemodialysis or peritoneal dialysis should be routinely supplemented with
water-soluble vitamins (vitamins B, C, and folic acid) as these vitamins are often
depleted with dialysis therapy.
 A relatively small amount of dietary iron, approximately 1 to 2 mg (or approximately
10%), is absorbed each day, primarily in the duodenum. Although there is some
debate as to whether GI absorption of iron is significantly altered in patients with
severe CKD, it is clear that oral intake from dietary sources alone is insufficient to
meet the increased iron requirements from initiation of ESA therapy.
 Pharmacologic Therapy
 Pharmacologic therapy for anemia of CKD is based on a foundation of ESA therapy
to correct erythropoietin deficiency and iron supplementation to correct and prevent
iron deficiency caused by ongoing blood loss and increased iron demands associated
with the initiation of erythropoietic therapy.
 Iron supplementation is first-line therapy for anemia of CKD if iron deficiency is
diagnosed, and for some patients the target Hb may be achieved without concomitant
ESA therapy. For most individuals with advanced CKD, however, combined therapy
with iron and an ESA is required.
Anemia - Management
1) Iron (Parenteral and Oral Form)
 Anemia therapy in patients with CKD requires effective use of iron
agents, guided by appropriate testing of iron status. Efficacy of iron
therapy appears not to be limited to patients with evidence of iron
deficiency.
 Thus, the goals of iron therapy are:
 to avoid storage iron depletion,
 prevent iron-deficient erythropoiesis,
 achieve and maintain target Hgb levels
 Iron status tests should be performed as follows:
 Every month during initial ESA treatment
 At least every 3 months during stable ESA treatment or in patients
with HD-CKD not treated with an ESA
Iron preparations - Oral
Oral ferrous sulphate (glutamate, fumarate)
 200mg/day of elemental iron taken on empty stomach in 2-3 doses
 Patients should be advised to take oral iron on an empty stomach to maximize
absorption, unless side effects prevent this strategy.
 In case of GI complaints:
 oral iron can be taken with small snack /or
 ferrous sulphate solution, iron polysaccharide complex or sustained-release
preparation may be used but with the latter two bioavailability is the problem
 Patients should be counseled on potential drug interactions with oral iron (e.g.,
antacids, quinolones) and GI side effects (e.g., nausea, abdominal pain, diarrhea,
constipation, dark stools).
 Food and CaCO3 delay iron absorption  iron should be taken 1 hr before or 2 hr
after CaCO3
 Noncompliance with therapy is a primary cause of therapeutic failure with oral iron.
Oral Iron Preparations
Iron Product
Common Agents and Available Elemental Iron per
Units
Unit
Ferrous sulfate
Fer-In-Sol (75 mg/0.6 mL)
75 mg
Feosol (200 mg)
65 mg
Ferrous sulfate, various preparations 65 mg
(325 mg)
Slow FE (160 mg)
50 mg
Ferrous fumarate Ferrous fumarate, various preparations 99 mg
(300 mg)
Femiron (63 mg)
20 mg
Nephro-Fer (350 mg)
115 mg
Vitron-C (65-125 mg)
65 mg
Ferrous gluconate Ferrous gluconate, various (325 mg) 36 mg
Fergon (240 mg)
27 mg
Polysaccharide iron Niferex (50 mg)
50 mg
Hytinic (150 mg)
150 mg
Heme iron
Proferrin-ES (12 mg)
12 mg
polypeptide
Number of
Units Per Daya
2–3
3–4
3–4
4
2
10
2
3
5
6
4
1–2
17
Differences between iron products
 The ferrous form of
iron is absorbed three
times more readily
than the ferric form.
 Although ferrous
sulfate, ferrous
gluconate, and ferrous
fumarate are absorbed
almost equally, each
contains a different
amount of elemental
iron.
Iron-drug interactions
Iron preparation - Parenteral
Parenteral iron therapy: The IV iron preparations currently available are:
 iron dextran (INFeD and Dexferrum),
 ferric gluconate (Ferrlecit),
 iron sucrose (Venofer).
 Ferumoxytol (Feraheme
)
 Iron dextran
 100mg during each HD session by IV push over 2 min for 10 session  50 mg each week
during dialysis for 10 weeks
 ADR:
 Arthralgias, myalgias, serum sickness-like syndrome, hypotension.
 A one-time dose of 25mg in adults should be administered IV before initiating therapy
to detect small risk of anaphylaxis
 ferric gluconate and iron sucrose and ferumoxytol have less ADR  no need for test
dose
 Administration of IV iron also introduces a risk of iron overload. (How can this be
prevented and treated?)
Parenteral Iron Preparations
Iron Compounds
FDA-Approved
FDA-Approved Dosing
Indications
Patients with iron
IV push: 100 mg over 2 min (25deficiency in whom oral mg test dose required)
iron is unsatisfactory
Iron Dextran
(INFeD, Watson
Pharma Inc.,
Morrisontown, NJ,
and DexFerrum,
American Regent,
Inc.. Shirley, NY)b
Sodium ferric
Adult and pediatric HD
gluconate (Ferrlecit, patients age 6 years and
Sanofi-Aventis,
older receiving ESA
Dagenham, Essex,
therapy
c
England)
a Small
Warnings
Black box
(risk of
anaphylacti
c reactions)
IV push (adult): 125 mg over General
10 min
IV infusion (adult): 125 mg in
100 mL of 0.9% NaCl over 60
min
IV infusion (pediatric): 1.5
mg/kg in 25 mL of 0.9% NaCl
over 60 min; maximum dose 125
mg
Dose
Rangesa
25–1,000
mg
62.5–1,000
mg
dosing ranges (e.g., 25–150 mg per week) generally used for maintenance
regimens. Larger doses (e.g., 1 g) should be administered in divided doses.
b Supplied in 2-mL single-dose vials containing 50 mg of elemental iron per mL.
c Available in colorless glass ampules containing 62.5 mg elemental iron (12.5 mg/mL).
Parenteral Iron Preparations-cont’d
Iron Compounds
Iron sucrose
(Venofer, American
Regent, Inc., Shirley,
NY)d
Ferumoxytol
(Feraheme, AMAG
Pharmaceuticals,
Lexington, MA)e
d Supplied
FDA-Approved
Indications
Adult and pediatric HD
patients age 2 years and
older
FDA-Approved Dosing
Warnings
IV push: 100 mg over 2–5 min
General
IV infusion: 100 mg in maximum
of 100 mL of 0.9% NaCl over 15
min
Adult and pediatric ND- IV push: 200 mg over 2–5 min on 5
CKD patients age 2 years different occasions within 14-day
and older
period
Adult and pediatric HD IV infusion: 2 infusions, 14
patients age 2 years and
days apart, of 300 mg in a
older
maximum of 250 mL of 0.9% NaCl
over 1.5 h, followed by 1 infusion,
14 days later, of 400 mg in a
maximum of 250 mL of 0.9% NaCl
over 2.5 h
Adult patients with ironIV: 510 mg (17 mL) as a single General
deficiency anemia
dose, followed by a second 510
associated with chronic
mg dose 3–8 days after the
kidney disease
initial dose (rate of 1 mL or 30
mg/second)
Dose
Rangesa
25–1,000
mg
510 mg
in 5-mL single-dose vials containing 100 mg elemental iron (20 mg/mL).
e Supplied as a 17-mL single-use vial containing 510 mg elemental iron (30 mg/mL).
Dosing and admiration of iron
 If oral therapy is initiated, the recommended dose is 200 mg of elemental iron per
day. With numerous oral agents to choose from, the best option is one that provides
adequate elemental iron with the fewest number of dosage units required per day.
 KDIGO guidelines suggest a 1- to 3-month trial of oral therapy in the nondialysis
CKD population.
 For the hemodialysis population, administration of 1 g of IV iron is recommended to
initially replete patients with an absolute iron deficiency. :
 Typical repletion dosing regimens for IV iron are 100 mg as iron sucrose or
iron dextran over 10 dialysis sessions,
 or 125 mg of sodium ferric gluconate over 8 dialysis sessions (see Table 29-10).
 Ferumoxytol is administered as 510 mg at a rate not to exceed 30 mg/s (1 mL/s) with a
second dose given within 3 to 8 days, a higher dose and administration rate compared with
other available IV iron formulations.
 Without ongoing iron supplementation, many patients quickly become iron
deficient. To prevent iron deficiency, maintenance doses of IV iron are administered
in hemodialysis patients (e.g., iron sucrose or iron dextran 25 to 100 mg/wk;
sodium ferric gluconate 62.5 to 125 mg/wk) based on evidence of improved Hb and
lower ESA doses with these regimens.
According to the labeling for the available
ESAs, the ESA dose should be
decreased or interrupted when Hb is
above 10 g/dL in CKD patients not
receiving dialysis or above 11 g/dL in
patients receiving dialysis
Anemia – Management (cont’d)
2) Folic Acid 1 mg/day
3) Blood Transfusion
 Is no longer the main therapy due to risk of iron overload, infections,
suppression of erythropoietin.
 Only use in case of persistent anemia, severe symptoms and substantial
blood loss(acute bleeding).
4) Erythropoiesis-Stimulating Agent (ESA)
 The erythropoietin deficiency evident in patients with CKD can be
corrected by the exogenous administration of erythropoiesisstimulating agents. Two such agents are currently available:
 Epoetin alfa (recombinant human erythropoietin [rHuEPO - Epogen™ or
Procrit™])
 Darbepoetin alfa (Aranesp™), a unique molecule that stimulates erythropoiesis
with a longer half-life than rHuEPO
Dosing and administration of ESA
 Recommended starting doses of ESA are listed inTable 29-11. Less
frequent dosing ofepoetin alfa (e.g., every 1 to 2 weeks) is
effective and may be preferred for stage 3 and 4 CKD patients since
these patients are seen in the outpatient clinical setting on a relatively
infrequent basis.Subcutaneous dosing is also more convenient in this
population and in peritoneal dialysis patients who do not have
regular IV access. Conversion tables for patients who are to be
switched from epoetin alfa (units per week) to darbepoetin
alfa(micrograms per week) are available in the labeling information for
darbepoetin.
 When starting an ESA, Hb levels should be monitored at least
weekly until stable and then at least monthly. Dose adjustments
should be made based on Hb response with consideration of data on risks
associated with higher Hb levels and rate of rise in Hb. An acceptable
rate of increase in Hb is 1 to 2 g/dL (10 to 20 g/L; 0.62 to 1.24
mmol/L) per month.
Dosing and administration of ESA
 As a general rule, ESA doses should not be increased more frequently than every 4 weeks,
although decreases in dose may occur more frequently in response to a rapid rate of rise in Hb.
 Based on labeling for ESAs, the dose should be reduced by at least 25% if the Hb increases by
more than 1 g/dL (10 g/L; 0.62 mmol/L) in a 2-week period.
 The dose should be reduced or temporarily discontinued if the Hb level approaches or
exceeds 11 g/dL (110 g/L; 6.83 mmol/L) in dialysis patients (all ESAs) or 10 g/dL (100 g/L; 6.21
mmol/L) in patients with CKD not requiring dialysis.
 KDIGO recommendations advocate a decrease in dose as opposed to withholding the ESA
when a decrease in Hb concentration is desired. A 25% increase in dose may be considered if the Hb
has not increased by 1 g/dL (10 g/L; 0.62 mmol/L) after 4 weeks of ESA treatment and if no
causes of resistance to the ESA have been identified.
 For patients who do not respond adequately over a 12-week escalation period, an increase in
ESA dose is unlikely to improve response and may increase risks. Initial hyporesponsiveness to
ESAs should be considered when there is no increase in Hb from baseline after the first month of
appropriate weight-based dosing. Acquired ESA hyporesponsiveness may be suspected when patients
previously on a stable ESA dose require two increases in ESA doses up to 50% beyond the stable
dose.
 in these situations repeat escalations in ESA dose beyond double the initial weight-based dose
should be avoided.
 The lowest dose of ESA should be used to maintain a Hb level sufficient to reduce the need
for RBC transfusions. Figure 29-6 provides an approach to management of anemia using ESAs and
iron therapy in patients with CKD.
Anemia – Management (cont’d)
 Improvement of anemia with erythropoiesis-stimulating agents is
associated with some clinical benefits. These include:






improvements in quality of life
increased energy levels
greater capacity for work and exercise
restored sexual function
improved appetite and participation in social activities
reduced depression and fatigue
 Human ERYthropoetin-Epoetin Alfa
 SC administration is preferred because lower doses can be administered less
frequently and cost is lower than with IV administration
 Based on the half-life of epoetin alfa (8.5 hours IV, 24.4 hours SC), the total
weekly dose is usually divided into smaller doses, administered one to three
times per week with SC administration and three times per week for IV
administration in patients on HD
Anemia – Management (cont’d)
 ESA: Darbepoetin alfa:
 The newer erthropoietic agent, has a longer half life and prolonged biological
activity therefore, doses are administered less frequently, starting at once a
week or every other week when administered IV or SC.
 Starting dose in patients not previously receiving epoietin-alpha therapy is
0.45 mcg/kg IV or SC once weekly.
 For patients previously receiving epoietin alpha: conversion doses is listed in
table (2-3 x/week  weekly, weekly every other week)
 Extended dosage interval – up to 4 weeks shown to be successful
 In dialysis and nondialysis patients with CKD receiving ESA therapy, the
selected Hgb target should generally be in the range of 11.0 to 12.0 g/dL
and not be greater than 13g/dL.
 favors subcutaneous administration in non-hemodialysis-CKD patients
and intravenous (IV) administration in HD (hemodialysis)-CKD patients
Estimated starting dose schedule of darbepoetin alfa according to the
previous rHuEPO regimen in patients with CKD.
ADR of ESA
The most common causes of resistance are iron deficiency,
acute illness, catheter insertion, hypoalbuminemia, elevated
C-reactive protein, chronic bleeding, aluminum toxicity,
malnutrition, hyperparathyroidism, cancer and
chemotherapy, AIDS, inflammation, and infection.
According to the labeling for the available
ESAs, the ESA dose should be
decreased or interrupted when Hb is
above 10 g/dL in CKD patients not
receiving dialysis or above 11 g/dL in
patients receiving dialysis
ESA
 Causes of ESA resistance:
 Fe deficiency
 Inflammation ↓Fe delivery
to BM response
 AL toxicity
 Folate and vit B 12
Deficiency
 Hyperparathyrodism
 Possibly ACEIs
 Before patient starts EPA
following tests should be
done:
 RBC indices
 Hct or Hgb
 Reticulocyte count
 Iron parameter
 Occult blood in the stool
Peginesatide (withdrawn)
 Peptides that mimic the action of erythropoietin may eliminate the need
for recombinant EPO in renal failure.
 Peginesatide is a synthetic peptide that activates the EPO receptor.
Peginesatide stimulates erythroid colony growth, reticulocyte count and
hematocrit in animal models, but, because its amino acid sequence is
unrelated to erythropoietin, does not cross react with erythropoietin
antibodies.
 March 2012 The US Food and Drug Administration has approved
peginesatide for intravenous or subcutaneous administration to treat
anemia in adult dialysis patients with CKD but not in CKD patients who
are not on dialysis
 February 2013  Peginesatide has been withdrawn from the market due
to serious hypersensitivity reactions reported in approximately 0.2
percent of patients following the first dose of intravenous administration
with death occurring in 0.02 percent of patients.
Evaluation of therapeutic outcomes
 Iron status should be assessed at least every 3 months in patients receiving
a stable ESA regimen or for those hemodialysis patients not treated with
an ESA to detect iron deficiency as a cause for anemia. Iron status should be
monitored more frequently (e.g., every month) when initiating or
increasing the ESA dose, following a course of IV iron, or when other
factors put the patient at risk for iron loss (e.g., bleeding).
 For all ESAs, the initial dose and subsequent adjustments should be
determined by the patient’s Hb level and the observed rate of increase in Hb.
 In patients with anemia not treated with an ESA, Hb levels should be
monitored at least every 3 months in stage 3 to 5 CKD patients not
requiring hemodialysis and at least monthly in hemodialysis patients.
 Hb should be monitored at least monthly (weekly preferred) in patients
started on ESA therapy until the Hb is stable. Once Hb is stable, the
recommended frequency of monitoring is monthly in dialysis patients and
every 3 months in nondialysis CKD patients (see Fig. 29-6).
Key points for the management of anemia in CKD patients
1.
2.
3.
4.
5.
Work-up for anemia in CKD should include assessment of secondary
causes including iron deficiency.
Iron replacement is often effective in anemia of CKD as initial therapy
and routes of administration (intravenous or oral) will be determined
by clinicians, patient preferences, and local available resources.
ESA therapy is not recommended in those with active malignancy, or
recent history of malignancy.
In most people with CKD, ESAs should not be used to intentionally
increase the Hb concentration above 11.5 g/dl (115 g/l)
For pediatric patients, the selection of Hb concentration at which ESA
therapy is initiated should be individualized after taking into account
the potential benefits (e.g., improvement in QOL, school attendance/
performance, and avoidance of transfusion) and potential harms.
Case: Anemia in CKD
Note:
Refer to the case in the previous lecture
CKD-Mineral and Bone Disorder (MBD)
 CKD-MBD is a systemic
disorder of mineral and bone
metabolism due to CKD
manifested by either one or a
combination of the following:
 Abnormalities of calcium,
phosphorus, PTH, or vitamin
D metabolism
 Abnormalities in bone
turnover, mineralization,
volume, linear growth, or
strength
 Vascular or other soft tissue
calcification
6) Secondary Hyperparathyroidism and Renal
Osteodystrophy (mineral and bone disorders)
 Calcium and phosphorus homeostasis is mediated through the effects of four
hormones on bone, the GI tract, kidney, and parathyroid gland.
 These hormones include PTH, the precursor form of vitamin D known as 25hydroxyvitamin D (25-OHD), active vitamin D or 1,25-dihydroxyvitamin D
(calcitriol), and fibroblast growth factor-23 (FGF-23).
Homeostatic mechanisms to maintain serum Ca concentration
Renal Osteodystrophy
Renal osteodystrophy is an alteration of bone morphology in patients with
CKD. It is one measure of the skeletal component of the systemic disorder of
CKD-MBD that is quantifiable by histomorphometry of bone biopsy.
It can be classified as follows:
Turnover
High
Normal
Low
Mineralization
Normal
Abnormal
Volume
High
Normal
Low
Slide courtesy of Susan Ott
2ry Hyperparathyroidism and Renal Osteodystrophy
 As kidney disease progresses renal activation of vitamin D is impaired, which reduces gut
absorption of calcium. Low blood calcium concentration stimulates secretion of PTH  As renal
function declines, serum calcium balance can be maintained only at the expense of increased
bone resorption, ultimately resulting in renal osteodystrophy.
Pathogenesis of 2ry Hyperparathyroidism and Renal Osteodystrophy:
Renal Osteodystrophy:
 Secondary hyperparathyrodism can cause complication such as:
 osteitis fibrosa cystica (high bone formation rate - bones turn soft and







become deformed)
Osteomalacia (softening of the bones)
adynamic bone disease (under active bone)
altered lipid metabolism,
altered insulin secretion,
resistance to erythropietic therapy,
impaired neurological and immune function
increased mortality.
 Renal osteodystrophy progresses insidiously for several years before the
onset of symptoms such as bone pain and fractures, when symptoms
appear, the disease is not easily amenable to treatment.
Lab findings and monitoring
Corrected calcium (mg/dL) = measured total Ca
(mg/dL) + 0.8 (4.0 - serum albumin [g/dL]),
There are no substantial differences between
KDOQI and KDIGO with regard to
recommendations for serum calcium (corrected for
serum albumin) and phosphorus. Both KDOQI and
KDIGO recommend maintaining serum
phosphorus within the normal range for stage 3 to
4 CKD patients and lowering phosphorus toward
the normal range for dialysis patients. KDIGO
recommends that the corrected serum calcium be
maintained within the normal range for all CKD
patients; however, KDOQI recommends a more
conservative range in stage 5 CKD patients based
on an increased risk of soft-tissue and vascular
calcifications. The most appropriate strategy is to
evaluate trends in corrected calcium to predict if
hypercalcemia is a concern that warrants changes in
therapy.
KDIGO did not specify a particular PTH target, but
rather advocated looking at trends in serum PTH to
make treatment decisions.
Recommended Frequency of Monitoring Calcium, Phosphorus, PTH , and 25
OHD by Stage of CKD (KDIGO Guidelines)
CKD
Stage
Calcium and Phosphorus
PTH
KDOQI
KDIGO
KDOQI
KDIGO
Annually
Every 6–12
months
Annually
Baseline, and
If PTH above
then based on target
level and CKD
progression
Every 3
months
Every 3–6
months
Every 3
months
Every 6–12
months
Monthly
Every 1–3
months
Every 3
months
Every 3–6
months
3
4
5
25-Hydroxyvitamin D
KDOQI
KDIGO
Baseline level;
correct
deficiencies as
in general
population
Not measured
The KDIGO guidelines also recommend monitoring bone-specific alkaline phosphatase
annually in stage 4 and 5 CKD patients.
The frequency of monitoring these parameters may increase once a diagnosis of CKDMDB is made and further information is needed to assess the patient's response to
treatment and to guide decisions about changes in therapy.
Monitoring
 In addition to monitoring for biochemical abnormalities that define CKD-
MBD, evaluation of bone architecture is also necessary in some cases.
 The gold standard test for diagnosing bone manifestations of CKD-MBD is a
bone biopsy for histologic analysis; however, this is an invasive test that is
not easily performed. KDOQI and KDIGO guidelines recommend bone
biopsy only in patients in whom the etiology of symptoms is not clear or in
individuals with more unique biochemical abnormalities.
 This includes patients experiencing unexplained fractures, persistent
hypercalcemia, and possible aluminum toxicity. If aluminum concentrations are
elevated (60 to 200 mcg/L, a deferoxamine test should be done.
 KDIGO also suggests a bone biopsy be considered in CKD patients prior to
beginning treatment with bisphosphonates since adynamic bone disease is a
contraindication to the use of these agents.
Monitoring
 Bone biopsy findings are described on the basis of turnover rate,
mineralization, and volume.
 Bone mineral density testing is not generally recommended in
patients with advanced CKD since this test has not been shown to
predict fracture risk and does not indicate the type of ROD.
Monitoring
 Abnormalities in mineral metabolism are highly associated with
vascular and soft-tissue calcifications, known risk factors for
mortality; therefore, diagnostic testing for calcifications should be
considered in the evaluation for CKD-MBD.
 Electron-beam computed tomography (EBCT) is a noninvasive
and sensitive method available for detecting cardiovascular
calcifications and has been used clinically and in studies in the CKD
population.
 Other methods advocated include:
 lateral abdominal radiographs to detect vascular calcification
 echocardiogram to detect valvular calcification.
 KDIGO suggests these tests are reasonable alternatives to EBCT based on the
sensitivity to detect calcifications and lower cost.
Management of Renal Osteodystrophy:
 The optimal approach for treating secondary hyperparathyroidism
and mineral metabolism abnormalities in predialysis patients with
stage 3, 4, and 5 CKD is unclear.
 The current management of secondary hyperparathyroidism in
patients with stage 3 to 5 CKD not yet on dialysis principally
involves the administration of some combination of:
 dietary phosphate restriction,
 phosphate binders (either calcium or non-calcium containing binders),
 vitamin D analogues,
 calcium supplementation and/or (possibly)
 a calcimimetic (NOT currently approved for patients with CKD not
yet undergoing dialysis).
1) Dietary Phosphate Restriction
 In general, serum phosphorus should be lowered toward near normal
levels.
 KDIGO recommends normal levels for all stages of CKD, whereas
K/DOQI allows a more liberal phosphorus management in stage 5 of 3.5
to 5.5 mg/dL.
 Dietary phosphorus restriction can prevent hyperphosphatemia and
maintain target phosphorus concentrations.
 Dietary phosphorus should not exceed 800 to 1,000 mg/day.
 Predominate sources of phosphorus are protein rich foods, which
presents a challenge in tailoring a diet that lowers dietary phosphorus intake
while providing adequate nutrition.
 However, efforts should be made to distinguish between organic (e.g., plant
seeds, nuts, legumes, and meats) and inorganic phosphorus (e.g.,
preservatives and additive salts found in processed foods) sources. Inorganic
phosphorus sources are absorbed to a greater extent than organic phosphorus
(90% vs.50%, respectively) and should be minimized in the diet.
 1) Dietary Phosphate Restriction (cont’d)
 Dark carbonated beverages are a common culprit for elevated
phosphorus levels; their consumption should be discouraged, and the
beverages should be removed from vending machines in dialysis clinics.
 Although phosphorus is removed to some extent by dialysis, neither
HD nor PD removes adequate amounts to warrant complete
liberalization of phosphorus in the diet (diet phosphate can be
increased up to 1200 mg/day)
 Regular dietary counseling by a kidney specialist dietitian is
necessary to reinforce the importance of phosphorus restriction and
other dietary recommendations.
2) Phosphate Binding Agent:
 A significant reduction of serum phosphorus is difficult to achieve with
dietary intervention alone, particularly in patients with more advanced
kidney disease (eGFR<30 mL/minute/1.73 m2).
 In these patients, the use of phosphate binding agents is also necessary.
 These agents decrease phosphorus absorption from the gut and should
be administered with meals to maximize this effect
(A) Oral calcium compounds are first-line agents for controlling
both serum phosphorus and calcium concentration, elemental calcium
should not exceed 1500 mg/day.
 Correction of hypocalcemia is an added beneficial effect of the calcium-containing
preparations;
 Before initiating Ca therapy and during it, the Ca-P product (Ca x P) should be
determined. If >55, patient is at risk for Ca deposition in soft tissues and patient
should be switched to other binders.
 A “corrected” serum calcium and the “Ca-P product” should be determined before
therapy is started and at regular intervals thereafter. (Note: KDIGO guidelines is
different – check the next slide)
 Comment on Ca×P product
 Traditionally, the calculated calcium–phosphorus product(Ca×P) value
is used as an indication as to when calcium and phosphate may
precipitate and deposit into soft tissue, leading to calcific uremic
arteriolopathy (CUA). CUA, or calciphylaxis, is characterized by
calcification of the arterioles and small arteries with intimal
proliferation and endovascular fibrosis and manifests visually as
necrosis of the skin.
 K/DOQI guidelines set a target goal of the Ca×P to be less than 55
mg2/dL2, whereas a Ca×P greater than 60 to 70 mg2/dL2 suggests an
increased risk of CUA.
 However, KDIGO suggests the Ca×P provides no additional clinical
information than the individual values of calcium and phosphorus and
is not recommended for guiding therapy.
Phosphate-Binding Agents Used for the Treatment of
Hyperphosphatemia in CKD Patients
Compound
Content (mg)
500, 750,
1,000,
1,250
1,250
1,500
667
Dose Titrationa
Starting Doses Comments
Increase or decrease
by 500 mg per meal
(200 mg elemental
calcium)
Sevelamer carbonate Renvela
*Available as tablet
and powder for oral
suspension
800
Increase or decrease
by 800 mg per meal
0.5–1 g
(elemental
calcium) three
times a day with
meals
0.5–1 g
(elemental
calcium) three
times a day with
meals
800–1,600 mg
three times a day
with meals
Sevelamer
Hydrochloride
Lanthanum
carbonate
Renagel
400, 800
Fosrenol
500, 750, 1,000
Increase or decrease
by 1 tablet per meal
Increase or decrease
by 750 mg per day
Compound
Trade Name
Calcium carbonate
(40% elemental
calcium)
Tums
Oscal-500
Caltrate 600
Calcium acetate
(25% elemental
calcium)
PhosLo
Aluminum hydroxide Alterna GEL
600 mg/5 mL
Increase or decrease
by 667 mg per meal
(168 mg elemental
calcium)
–
Same as Renvela
750–1,500 mg
daily in divided
doses with meals
300–600 mg three
times a day with
meals
First-line agent; dissolution characteristics and
phosphate binding may vary from product to
product
Approximately 39 mg phosphorus bound per 1 g
calcium carbonate
First-line agent; comparable efficacy to calcium
carbonate with half the dose of elemental calcium
Approximately 45 mg phosphorus bound per 1 g
calcium acetate
By prescription only
First-line agent; lowers low-density lipoprotein
cholesterol
More expensive than calcium products; consider
in patients at risk for extraskeletal calcification
Associated with a lower risk of acidosis and GI
adverse events than Renagel.
Same as Renvela, plus acidosis
First-line agent; Available as chewable tablets
Not a first line agent; do not use concurrently
with citrate-containing products
Reserve for short-term use (4 weeks) in patients
with hyperphosphatemia not responding to other
binders
3) Vitamine D Therapy: (what are its benefits?)
 Calcium (less than 9.5 mg/dL) and phosphorus (less than 4.6 mg/dL) must be controlled
before Vitamin D therapy is initiated.
 Ergocalciferol
 In stage 3 and 4 If the 25-hydryoxyvitamin D level is less than 30 ng/mL, a vitamin D precursor (e.g.,
ergocalciferol) is recommended
 To prevent vitamin D insufficiency, doses of 600 to 800 units per day of ergocalciferol are
recommended
 Calcitriol, (1,25-Dihydroxyvitamine D3)
 Has been used for the management of secondary hyperparathyroidism
 Directly suppresses PTH synthesis and secretion and appears to upregulate vitamin D receptors which
ultimately may reduce parathyroid hyperplasia.
 If hypercalcemia develops, the decision to withhold therapy orto switch to a vitamin D analog.
 The comparative effects of the different active oral vitamin D analogs in predialysis
patients with CKD have not been established. As a result, any one of the available active
oral agents (calcitriol, alfacalcidol, doxercalciferol, or paricalcitol) may be
administered.
Available Vitamin D Agents
Generic Name
Trade Name
Form of Vitamin
D
Dosage Range
Dosage
Forms
Frequency of
Administration
400–50,000 IU
PO
Daily (doses of 400–2000 IU)
Vitamin D precursor
Ergocalciferol
Vitamin D2
D2
Cholecalciferol
Vitamin D3
D3
Weekly or monthly for higher
doses (50,000 IU)
Active vitamin D
Calcitriol
Calcijex
0.5–5 mcg
IV
Three times per week
Rocaltrol
0.25–5 mcg
PO
Daily, every other day, or three
times per week
1–4 mcg
PO
Daily or three times per week
2.5–15 mcg
IV
Three times per week
5–20 mcg
PO
Daily or three times per week
2–8 mcg
IV
Three times per week
Vitamin D analogs
Paricalcitol
Doxercalciferol
Zemplar
Hectorol
= 1-hydroxyvitamin D2
4) Calcimimetics:
 Acts on Ca-sensing receptor on the surface of chief cell of PT gland to mimic effect of
extracellular ionized Ca & increase sensitivity of Ca-sensing receptor to Ca  decrease PTH
secretion within hours after administration.
 The calcimimetic cinacalcet (Sensipar): is the first agent in this class to be approved by the FDA.
 demonstrated efficacy in lowering PTH concentrations and Ca-P product in patients on HD with sHPT
and a higher proportion of patients achieved recommended targets for PTH, calcium, phosphorus, and
Ca-P product.
 No data are found on survival rates for patients receiving cinacalcet versus those treated with vitamin D.
 Cinacalcet, however, offers an additional choice of agent to lower PTH when vitamin D cannot be
increased because of elevated calcium, phosphorus, or calcium-phosphorus product.
 Initiated at a dose of 30 mg daily with dosage titrations occurring every 2 to 4 weeks to 60, 90, 120 or a
maximum of 180 mg daily to achieve target iPTH levels. (given with meals)
 Because cinacalcet lowers serum calcium and may cause hypocalcemia, this agent should
not be started if the serum calcium is less than the lower limit of normal, approximately 8.4
mg/dL
 Serum calcium and phosphorous levels should be drawn within 1 week after initiation or dosage increase,
and plasma PTH levels drawn within 4 weeks after initiation of therapy or dosage adjustment.
 Cinacalcet is metabolized by the liver, specifically by the cytochrome P450 isoenzymes CYP3A4,
CYP2D6, and CYP1A2  drug interactions
 Cinacalcet is also a potent inhibitor of the enzyme CYP2D6.
Stepped approach for the management of renal osteodystrophy
Step 1
 The initial focus in managing sHPT should be the management of
hyperphosphatemia.
 Among patients with hyperphosphatemia  restricting dietary phosphate
intake.
Step 2
 Among patients with hyperphosphatemia despite dietary phosphorus restriction
after two to four months  administration of phosphate binders
 For patients with an initial serum calcium levels less than 9.5 mg/dL (<2.37
mmol/L), a calcium containing phosphate binder should be administered as long as
hypercalcemia does not develop.
 For patients with an initial serum calcium level greater than 9.5 mg/dL (<2.37
mmol/L), a non-calcium based phosphate binder rather than a calcium-containing
phosphate binder. Either sevelamer or lanthanum carbonate can be given in this
setting.
 Treatment with ergocalciferol should be initiated if vitamin D deficiency exists,
as demonstrated by a 25(OH)-vitamin D (calcidiol) level of less than 30 ng/mL.
 If elevated PTH levels remain despite ergocalciferol and phosphate binder
therapy over a six-month period  administering a low dose active oral vitamin
D analog.
 If the serum level of corrected total calcium exceeds 10.2 mg/dL (2.54
mmol/L)  ergocalciferol therapy and all forms of vitamin D therapy should
be discontinued
Step 3
 Decide whether phosphate binder therapy is sufficient or whether a vitamin D
analogue should be added. This is based upon calcium, phosphate, and PTH
levels that are measured when administering optimal phosphate binder therapy.
Step 4
 Among predialysis patients with sHPT, the use of cinacalcet is controversial.
Some experts and the KDIGO working group recommend NOT giving
cinacalcet given the paucity of data concerning efficacy and safety in predialysis
patients with CKD.
Case: Renal Osteodystrophy
New! Feb 2017
 The US Food and Drug Administration (FDA) has approved the
novel calcimimetic etelcalcetide (Parsabiv, Amgen) for the
treatment of secondary hyperparathyroidism in adults on
hemodialysis.
 Etelcalcetide reduces the PTH level by binding to and activating the
calcium-sensing receptor on the parathyroid gland. It offers an
advantage over the current standard calcimimetic treatment,
cinacalcet (Sensipar, Amgen), in that it can be administered
intravenously by the dialysis healthcare team at the end of each
hemodialysis session.
6) Hyperlipidemia:
 Treatment with a statin should not be initiated in patients with type
2 diabetes on maintenance hemodialysis who do not have a specific
cardiovascular indication for treatment (Strong evidence) – see
next slide.
 Lipid profile should be reassessed at least annually and 2 to 3
months after changing treatment.
 HMG-CoA reductase inhibitors may have some other advantages
that may help to reduce kidney disease progression in addition to
lipid reduction, such as: reduction of monocyte infiltration,
mesangial cell proliferation, mesangial matrix expansion, and
tubulointerstitial inflammation and fibrosis
 New phosphate-binding agent sevelamer hydrochloride appears to
lower lipid levels by mechanisms similar to those of bile acid
sequestrants.
KDIGO
 Management of dyslipidemia in patients with CKD has been guided by
recommendations from the National Cholesterol Education Program and the
KDOQI guidelines for dyslipidemia. Based on evidence of risk reduction and the
benefits of lipid-lowering therapy in the general population, the consensus was
that CKD patients should be treated aggressively to an LDL cholesterol goal
below 100 mg/dL.
 However, the KDIGO guidelines for lipid management in CKD published in
2013 do not support this goal since clinical trials have not proven
the strategy of targeting a specific LDL level to be beneficial.
 KDIGO recommends that a lipid profile be done for all adults with CKD to include
LDL, HDL, and triglycerides. Follow up lipid levels are not recommended unless the
information may alter management (e.g., assessing adherence to therapy or assessing
cardiovascular risk in a patient <50 years of age and not currently on a statin).
Patients should also be evaluated for other conditions that are known to cause
dyslipidemias (e.g., liver disease).
 KDIGO acknowledges that reduction in the risk of adverse
cardiovascular events in patients with CKD has only been
demonstrated with regimens that include a statin or statin plus
ezetimibe combination and recommendations focus on these agents for
individuals at risk of cardiovascular events.
KDIGO
 Based on the available evidence, the KDIGO guidelines for lipid management in
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
CKD recommend treatment with a statin in adults aged 50 and older
with stage 1 to 5 CKD (not on dialysis).
The statin/ezetimibe combination may also be an option in patients in this
age group in stage 3 to 5 CKD (not on dialysis).
KDIGO only recommends statins in adults aged 18 to 49 years with stage
1 to 5 CKD (not on dialysis) who have one or more of the following: known
coronary disease, diabetes mellitus, prior ischemic stroke, and an estimated 10year incidence of coronary death or nonfatal myocardial infarction >10%.
It is not recommended that statins or statin/ezetimibe be initiated
in patients with stage 5 CKD on dialysis; however, therapy with these
agents may be continued if patients were receiving these medications at the time
of dialysis initiation.
Due to the risk of adverse events with statins and absence of safety data in
patients with stage 3 to 5 CKD, KDIGO recommends using statins at doses
shown to be beneficial in randomized studies conducted in this population (e.g.,
atorvastatin 20 mg, fluvastatin 80 mg, rosuvastatin 10 mg,
simvastatin 20 mg).

Atorvastatin treatment in patients with type 2
diabetes on maintenance hemodialysis treatment
does not improve cardiovascular outcomes.
(Strong evidence)

Results from a 4-year study evaluating
the effect of atorvastatin therapy on
cardiac mortality in more than 1,200
hemodialysis patients with type 2
diabetes showed no significant benefit in
the composite end point compared with
the placebo group. 124 In fact, there was a
significantly greater relative risk of fatal
stroke in the atorvastatin-treated
patients. These findings do not support
initiation of statin therapy in ESRD
patients, especially those with type 2
diabetes
Avoiding agents that increase the blood levels of statins
 A number of medications may interact with the metabolism of
statins and thereby increase statin blood levels.
 Medications known to increase statin blood levels should either be
avoided, or, if necessary, the statin should be reduced or stopped.
 While this is true for all patients, it is especially true for patients
with CKD Stages 4-5, since some statin levels tend to be high in
Stage 4-5 CKD patients.
 It is even more critical for interactions to be avoided among kidney
transplant patients receiving cyclosporine (and possibly tacrolimus),
since cyclosporine often increases statin levels through mechanisms
that may be exacerbated by the addition of a third interacting agent.
7) Hypertension:
 The pathogenesis of
hypertension in patient with
CKD is multifactorial.
8) Anorexia & Malnutrition
 Limited data defining CKD stage where malnutrition develops
 Malnutrition is common in patients with advanced chronic renal disease because of: a
lower food intake (principally due to anorexia), decreased intestinal absorption
and digestion, and metabolic acidosis
 Studies have shown a strong correlation between malnutrition and death in maintenance
dialysis patients
 It is desirable to monitor the nutritional status of patients with chronic kidney disease.
NKF K/DOQI guidelines: evaluate for signs of malnutrition when GFR < 60
mL/min/1.73 m2
 A low plasma concentration of albumin and/or creatinine (which varies with
muscle mass as well as GFR) may be indicative of malnutrition.
 Nutrition assessment
 dietary protein
 calorie intake
 serum albumin
 urine protein
Malnutrition:
 Protein-energy malnutrition is common in patients with stage 4 or
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5 CKD
Daily protein intake should be 1.2g/kg for patient undergoing
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 3035 kcal/kg for patients older than 60 years.
Water-soluble vitamins should be supplemented to replace
dialysis-induced loss
L-carnitine is not recommended for patients with ESKD unless
the disorders for which it has shown benefit (eg:
hpertriglyceridemia, hypercholesterimia, and anemia) do not
respond to standard therapies.
9) Other complications
Self reading:
 Management of other complications:
 Uremic bleeding
 Pericarditis
 Uremic neuropathy
 Thyroid dysfunction
 Reference: UpToDate:
 Overview of the management of chronic kidney disease in
adults
Prescribing in people with CKD
Prescribing in people with CKD