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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4

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