Describe the clinical presentation and common complications of end stage renal disease Evaluate...
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Transcript of Describe the clinical presentation and common complications of end stage renal disease Evaluate...
Describe the clinical presentation and common complications of end stage renal disease
Evaluate treatments for a patient with anemia secondary to end stage renal disease
Evaluate treatments for a patient with hyperparathyroidism secondary to end stage renal disease
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Renin Synthesis
Renal FunctionsRenal Functions
Drugs!
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Susceptibility Factors
Initiation Factors Progression Factors
Advanced age Diabetes Mellitus Hyperglycemia
Reduced kidney mass, low birth weight
Hypertension Hypertension
Racial/ethnic minority Glomerulonephritis Proteinuria
Family history Obesity
Low income or education Smoking
Systemic inflammation
Dyslipidemia
Dipiro et al, 7th edition
Initiating Factors: Causes of ESRD in the USA
2006 ADR: USRDS
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Initiating Factors
CKDStage Description
GFR (mL/min/1.73 m2)
Metabolic Consequences
0 At increased risk 90 with CKD risk factors None
1Kidney damage with normal or GFR
90 None
2 Kidney damage with mild GFR 60-89 Parathyroid hormone level begins to
rise (GFR of 60 to 80).
3 Moderate GFR 30-59
Calcium absorption decreases (GFR below 50); onset of left ventricular hypertrophy and/or anemia (erythropoietin deficiency).
4 Severe GFR(Pre-ESRD) 15-29
Triglyceride concentration begins to rise; Hyperphosphatemia or metabolic acidosis develops; There is a tendency toward hyperkalemia.
5 Kidney failure <15 or dialysis Azotemia develops
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Sodium and Fluid Nocturia in CKD Stage 3 ESRD patients do not produce much urine, and become
volume overloaded ↑ blood pressure
Typical fluid allowance for patients on dialysis is 700 to 1000 mL/day, plus urine output
Hyperkalemia (Stage 4)
Metabolic Acidosis (Stage 4) Failure of kidney to excrete acid anions (particularly phosphate and sulphate) Sodium bicarbonate or sodium citrate (citrate is rapidly
metabolized to bicarbonate), typically in a daily dose of 0.5 to 1 meq/kg per day
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Patients with CKD 4-5 have many reasons to be anemic Reduced RBC lifespan in uremia Decreased EPO production Water soluble vitamins dialyzed RBC destroyed in hemodialysis (~25 mL/HD) Chronic inflammation/infection Platelet dysfunction (GI bleeds) Hyperparathyroidism
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Reduced oxygen delivery to tissues Decrease in Hgb compensated by increased cardiac output Progressive cardiac damage and progressive renal damage1
Increased mortality risk2
Reduced quality of life (QOL)3
FatigueDiminished exercise capacityReduced cognitive function
Left ventricular hypertrophy (LVH)4
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1. Silverberg et al. Blood Purif. 2003;21:124-130. 2. Collins et al. Semin Nephrol. 2000;20:345-349; 3. The US Recombinant Human Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial. 2003;16:101-105.
© 2005 The Johns Hopkins University School of Medicine.
For Adults with ≥ Stage 3 CKD: Assess Hemoglobin level If anemia (HgB ≤ 12)- Before treating with an erythropoiesis
stimulating agent, you must first: Check for bleeds…platelet dysfunction in uremia RBC indices/CBC Ensure adequate RBC co-factors
Water soluble vitamins Iron stores – iron is the “fuel” for erythropoiesis
Medical evaluation of comorbid conditions
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Laboratory Test Recommended Values Iron Deficiency
TSAT ≥ 20% Decreased
Serum Ferritin ≥ 200 ng/mL for HD patients
Decreased
Serum Iron Males: 65–175 µg/dLFemales: 50–170 µg/dL
Decreased
TIBC 250–425 µg/dL Increased
Reticulocytes 0.5%–1.5% of RBCs Decreased
*K/DOQI guidelines. TIBC = total iron-binding capacity; TSAT = transferrin saturation.Burtis et al. Tietz Textbook of Clinical Chemistry, 1998. Carey et al (eds). The Washington Manual of Medical Therapeutics, 1998. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis. 2001;37:S182-238.
Iron Preparation Tablet Size (mg) Elemental Iron Content (mg)
Ave Monthly Wholesale Cost
Ferrous sulfate 325 65 $2.29
Ferrous gluconate 325 35 $5.08
Ferrous fumarate 325 108 $1.63
Polysaccharide iron complex
150 150 $7.12 for 150mg
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Iron Compound FDA- approved indication Warnings
Iron Dextran Patients with iron deficiency in whom oral iron is unsatisfactory
Black box warning: anaphylactic reactions. Test dose required.
Iron Gluconate Adult and pediatric HD patients age 6 years and older receiving ESA therapy
Iron Sucrose HD patients with CKD receiving ESA therapyNondialysis-CKD patients receiving or notreceiving ESA therapy
Ferumoxytol Treatment of iron deficiency anemia in adult patients with CKD
ESRD population: patients come in three times a week for small doses of iron
Iron sucrose and iron gluconate are used in similar total doses per course of treatment, generally 1 gram per course Ferric gluconate: 125 mg x 8 consecutive dialysis sessions Iron sucrose: 100 mg x 10 consecutive dialysis sessions
Ferumoxytol 510 mg IV x 2 (doses separated by 3-8 days)
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Epoetin alfa (Epogen® Procrit ®) 50-100 units/kg 2-3 times weekly (IV or SC)
Darbepoetin alfa (Aranesp®) 0.45 mcg/kg once weekly (IV or SC)
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Epoetin Darbepoetin
Volume Overload Iron Overload Transfusion reactions Short supply Hyperkalemia Need for hospitalization Transplant issues
The frequency of hemoglobin testing should be at least monthly
It takes 2 weeks to see the effect of dose changes ESA doses should be decreased, but not necessarily
held, when a downward adjustment of Hb level is needed Withholding ESA may result in prolonged loss of
erythropoietic precursors Could lead to periodic cycling of Hb levels ≥ & ≤ target Hb
range
NKF KDOQI Guidelines. 2006.
Give IV or SC? S.C. administration of ESA produces more predictable &
sustained response than IV. IV can be more convenient, since it can be given at
dialysis
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IV Dosing
TIME
CO
NC
SC dosing
NKF-KDOQI 2000Hb 11-12 g/dLUpdated in 2006 11-13 g/dL
Medicare10-12 g/dL
FDA11-12 g/dL6/24/11: 10-11 g/dL for dialysis patients for non-HD CKD only use to avoid blood transfusions (start when Hb < 10)
Normal Hb valuesMale: 13-18 g/dLFemale: 12-16 g/dL
Normal Hb valuesMale: 13-18 g/dLFemale: 12-16 g/dL
Event Darbepoetin(n=734)
Epoetin(n=576)
Hypertension 30% 26%
Infection 27% 30%
Hypotension 27% 24%
Myalgia 26% 26%
Diarrhea 21% 22%
Nausea 21% 24%
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Most common adverse events occurring in controlled clinical trials(incidence >=20%)
Amgen Inc. Data on file.
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
Moe S, et al. Kidney Int 69: 1945, 2006
The parathyroid secretes parathyroid hormone We measure this as intact PTH (iPTH)
The parathyroid regulates calcium (and phosphate) in the body
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↑ Parathyroid hormone
↑ Bone resorption ↑ Production of active
vitamin D to increase GI absorption of calcium
Decreased loss of calcium in the
urine, ↑ Phosphate excretion
Functions of the Parathyroid
Low levels of calcium in the blood
Increased expression of parathyroid hormone Low calcium levels (through the calcium sensing receptor on the
parathyroid cells) High phosphorus (mechanism unknown)
Decreased expression of the parathyroid hormone High calcium levels 1, 25(OH)2D (activated vitamin D)
(inhibits PTH mRNA synthesis by binding to a Vitamin D receptor on the parathyroid tissue)
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Renal Dysfunction
Reduced phosphate excretion
Decreased activation of vitamin D3
Decreased calcium levels
Increased PTH secretion
Increased calcium reabsorption
Decreased phosphate reabsorption
Increased activation of vitamin D3
Increased bone resorption
Increased calcium
Increased phosphorus
Vascular Calcification
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Langman et al. htt
p://ww
w.m
edscape.org/viewarticle/554012
Parathyroid develops hyperplasia (abnormal enlargement) – becomes less sensitive to calcium levels- permanently stuck in the on position
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Abnormal mineral metabolism Phosphorus, iPTH Calcium, Vitamin D
Vascular calcification Arterial stiffness Increase in pulse pressure Impaired LV function and LVH
Heart Failure ± Ischemic heart disease
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Surrogate Measures of disease progression: Phosphorus, Calcium, iPTH, Ca x P product
Remember: Corrected calcium = Measured calcium + 0.8(4.0-albumin)
1. Decrease serum phosphorus (Goal: 3.5-5.5 mg/dl)• Limiting dietary phosphorus intake• Phosphate binders
2. Supplement vitamin D• 1α,25-dihydroxyvitamin D3
3. Reduce parathyroid hormone activity• Calcimimetic
MOA: Cations which bind anionic dietary phosphate to form insoluble complexes which are excreted in the feces
Ca2+
La3+
Mg2+
Al3+
1. Calcium-containing phosphate binders• Calcium acetate• Calcium carbonate
2. Non-calcium-containing phosphate binders• Sevelamer• Lanthanum• Other
Calcium acetate (PhosLo®) 667 mg [169 mg elemental Ca] capsules Starting dose: 2 tabs with each meal Titrate q2-3wks to serum phosphorus < 5.5 mg/dl SE’s: Constipation, hypercalcemia
Calcium carbonate (Tums®) 1250 mg [500 mg elemental Ca] tabs Same starting dose, titration schedule, and SE’s as above Over-the-counter
What about calcium citrate? (Citracal®) Contraindicated Citrate increases Al absorption Al eliminated by the kidneys
Sevelamer (Renvela®/Renagel®) 400 & 800 mg tablets Starting dose dependent upon serum phosphorus level
o 5.5 < phosphorus < 7.5 mg/dl: 800 mg PO TIDo 7.5 mg/dl < phosphorus < 9 mg/dl: 1200-1600 mg PO TIDo > 9 mg/dl: 1600 mg PO TID
Non-systemically absorbed cationic polymeroDrug interactions…oMechanistically similar to bile acid sequestrantoOther meds should be given at least 1 hour before or 3 hours after
sevelamero LDL-lowering effect
Does not contain Ca, Mg, or Al Do NOT crush
oOral suspension available
Lanthanum (Fosrenol®) Trivalent natural element 500, 750, & 1000 mg chewable tablets Starting dose: 1500 mg/day divided and taken with meals Increase dose by 750 mg/day q2-3 wks until serum
phosphorus < 5.5 mg/dl SE’s: N/V, abdominal pain
Magnesium phosphate binders Mg is eliminated by the kidney Contain Al Maalox ®, Mylanta ®
Aluminum phosphate binders Contain Al Acute situations only (2-3 doses) Amphojel®
Bioactivation of vitamin D3 requires hydroxylation step performed in the kidney
Reduced during renal dysfunction
Administer ACTIVE vitamin D analogues to CKD-MBD patients to increase calcium absorption
Calcitriol (Rocaltrol® PO, Calcijex® IV) Paricalcitol (Zemplar® PO and IV) Doxercalciferol (Hectorol® PO and IV)
Specific dosing and titration of vitamin D analogues depends on stage of CKD and iPTH levels
PO and IV dosing regimens differ Titrate to resolution of hyperparathyroidism No differences in mortality and resolution of
hyperparathyroidism among these agents
IV pulse dosing of active vitamin D analogues more effectively downregulates PTH secretion than PO therapy
PO increases the GI absorption of calcium (and phosphorus) more so than IV
Remember to individualize therapy! Serum calcium, phosphorus and iPTH levels must
be measured regularly throughout treatment [Ca] x [P] < 55
Cinacalcet (Sensipar®) Calcimimetic which increases the
sensitivity of calcium-sensing receptors on the parathyroid gland
Calcium-sensing receptors are predominantly responsible for increasing PTH secretion when Ca is low
Effect is a reduction in PTH secretion as well as a decrease in serum calcium and phosphorus levels
Safe for use in hypercalcemia and hyperphosphatemia
30, 60, & 90 mg tablets Starting dose: 30 mg PO once daily Titrate every 3 to 4 weeks in the order of 60, 90,
120, and 180 mg PO once daily as necessary to achieve iPTH levels of 150-300 pg/ml
SE’s: Hypocalcemia, N/V Do not initiate if serum Ca < 8.4 mg/dl Take with food to minimize GI SE’s
Drug interactions Strong CYP2D6 inhibitor CYP3A4 substrate
Patients receiving cinacalcet and physiologic doses of active vitamin D together are more likely to achieve [Ca] x [P] < 55 and goal iPTH levels than those receiving supraphysiologic doses of active vitamin D alone*
Impact of cinacalcet on cardiovascular events and overall mortality not as clear
*Chertow GM, et al. Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. Clin J Am Soc Nephrol. 2006; 1(2): 305-12.
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Encephalopathy Treat with HD
Peripheral neuropathy Looks like diabetic neuropathy Be sure patient has adequate water-
soluble vitamins Restless Legs Syndrome (25-50%
HD pts) Non-pharmacologic therapy Carbidopa/Levodopa doses of
25/100 Pramipexole
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Typical drugs don’t work well Antihistamines Anti-epileptics Lubriderm Tanning Bed
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Taste changes, NV, anorexia Delayed GI emptying
Compounded in diabetics Treatment of gastroparesis
Metoclopramide 5 mg orally 30 minutes before meals