IPHA Slides Final Version 7.31 Khanedit · 2015-09-23 · 9/23/2015 4 Anemia of Chronic Kidney...

9/23/2015

1

The Pharmacist’s Role in the Management of Chronic Kidney

DiseaseAyesha Khan, PharmD, BCPS

Lalita Prasad‐Reddy, PharmD, MS, BCPS, BCACPAssistant Professors of Pharmacy Practice

Chicago State University‐College of Pharmacy

Disclosures/Conflict of Interest

• Drs. Prasad‐Reddy and Khan declare no conflicts of interest, real or apparent, and no financial interests in any company, product or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria.

ObjectivesPharmacists

• Compare and contrast different methods to evaluate kidney function.

• Discuss the pathogenesis of anemia and CKD, and evaluate the available options for treatment as they pertain to clinical guidelines.

• Discuss the pathogenesis of renal osteodystrophy, and given a patient case, recommend an appropriate treatment plan.

• Discuss the dosing of medications in patients with CKD, and identify different pharmacokinetic and pharmacodynamic characteristics that may present.

At the conclusion of this program, the pharmacist will be able to:

Pre‐Test Questions

True/False. Hypertension is the leading cause of chronic kidney disease (CKD) in the United States.

True/False. Creatinine clearance is the most effective way to measure kidney function.

True/False. Patients with CKD have an decreased risk of osteoporosis due to decreased calcium excretion from the tubules.

True/False. Patients with CKD have a 2 – 4 fold increase of cardiovascular disease when compared to the general population.

Methods to Evaluate Kidney Function

5

Audience Poll

Select the correct statement regarding GFR and creatinine clearance(CrCl):

A. GFR can be measured indirectly by assessing various filtration markers

B. Measurement of CrCl is one method used to estimate GFR

C. Creatinine is secreted by the proximal tubule and filtered by the glomerulus

D. CrCl exceeds actual GFRE. All of the above

9/23/2015

2

Glomerular Filtration Rate (GFR)

National Kidney Disease Education Program (NKDEP). (September, 2014) Renal Hemodynamics Animation [Video file]. Retrieved from https://www.youtube.com/watch?v=J2YaULhMx5g&feature=youtu.be

CKD StagingStage Description GFR (mL/min/1.73 m2)

1 Normal or increased GFR ≥ 90

2 Mildly decreased GFR 60‐89

3a Mild to moderately decreased GFR 45‐59

3b Moderately decreased GFR 30‐44

4 Severely decreased GFR 15‐29

5 Kidney failure < 15 (or dialysis)

• GFR ≥ 90 considered normal in otherwise healthy persons• GFR between 60‐89 may be normal for geriatric persons• GFR between 60‐89 for 3 or more months PLUS kidney damage indicator

for early kidney disease• GFR <60 for 3 or more months is considered CKD

• Complications include CKD‐MBD & anemia

KDIGO. Summary of recommendation statements. Kidney Int 2013; 3 (Suppl):5.

CKD Staging

Evaluation of GFR

• Indicator of overall kidney function

• How is it measured?

• Filtration markers

• Achieves stable plasma concentration

• Inert

• Freely filtered by glomeruli

• Not reabsorbed, secreted or metabolized

• Gold standard: inulin, iothalamate, iohexol

• Endogenous markers: serum creatinine, serum urea, serum cystatin C

Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol. 2009;20(11):2305‐2312.

• Secreted by proximal tubule & filtered by glomerulus clearance exceeds GFR

• Isolated use to assess renal function is not advised

• Metformin and SCr controversy

• Inverse relation between GFR and SCr is nonlinear

• Risk of CV disease and CKD complications increase when GFR falls below 60

Ann Intern Med 1999;130:461‐470

Serum Creatinine (SCr)

Factors Affecting SCr

• Demographics

• Aging

• Female gender

• Ethnicity

• AA , Hispanic , Asian

• Body Habitus

• Muscular

• Malnourished/amputation

• Medications

• Cimetidine, trimethoprim, probenecid, K‐sparing diuretics

Levey AS. Assessing the effectiveness of therapy to prevent the progression of renal disease. Am J Kidney Dis. 1993;22(1):207‐214.

MDRD (4 variable) 2009

GFR estimation methodsCockroft‐Gault 1973

Jelliffe 1973

Salazar‐Corcoran 1988

MDRD (6 variable) 1999

CKD‐EPI 2009

Schwartz (“bedside”) 2009

9/23/2015

3

Equations for Estimating GFR

Equation Comments

Jelliffe(1973)

CrCl (ml/min * 1.73m2) = 98 – 16 (age‐20/20)

SCr: Multiply CrCl by 0.9 if female

• Letter to the Editor publication• Replaces height/weight parameters with

BSA• For stable renal function only

Salazar‐Corcoran(1988)

CrCl (males)= (137‐age) x [(0.285 x weight) + 12.1 x height)]/ 51 x SCr

CrCl (females)= (146‐age) x [(0.287 x weight) + (9.74 x height)]/ 60 x SCr

• Designed to estimate CrCl in obesity (BMI >30m2)

• Superior to original Cockroft‐Gault and Jelliffe methods (TBW)

• Both the Jelliffe and Salazar‐Corocoran equations has since fallen out of favor

Jelliffe RW, Jelliffe SM. A computer program for estimation of creatinine clearance from unstable serum creatinine levels, age, sex, and weight. Mathematical Biosciences. 1972;14(1‐2):17‐24.Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat‐free bodymass. Am J Med. 1988;84(6):1053‐60.

Equation Comments

Cockroft‐Gault(CG) (1973)

CrCl = (140‐ age) x (weight)72 x SCr

Multiply CrC by 0.85 if female

• Gold‐standard• 249 males with stable renal function• Utilized ABW, suggest correction with

ascites or obesity• Adjustments in obesity (40%)

Modification of Diet in Renal Disease (MDRD) (1999,2009)

IDMS calibrated assays:GFR= 175 x SCr‐1.154 x age‐0.203 x (0.742 if female) x (1.21 if AA)

Non‐IDMS assays:GFR= 186 x SCr‐1.154 x age‐0.203 x (0.742 if female) x (1.21 if AA)

• 6‐variable equation simplified in 2 variations to reflect lab methods

• 1628 patients with CKD and GFR from 5‐90

• More accurate than CG when using TBW• Not validated for drug dosing• Validated in GFR <60 only

Chronic Kidney Disease EpidemiologyCollaboration (CKD‐ EPI)(2009)

GFR = 141 x min (Scr/k, 1)α x max (Scr/k, 1)

‐1.209 x 0.993Age x 1.018[female] x 1.159 [black]

• F/u to MDRD equation to improve accuracy with GFR >60

• Validated retrospectively in 8,254 patients from 10 studies

• Renal failure patients excluded• 45% women, 87% non‐black patients


Cockroft DW, GaultMH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):3141.Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604‐12

Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247‐54.

Cockroft‐Gault (CG) and MDRD Limitations• Require stable kidney function and steady‐state SCr concentrations

• Use cautiously in the critically ill, those with AKI, and requiring RRT

• SCr rounding in elderly patients

• Rounding to 1.0 mg/dL may underestimate actual renal function resulting in under‐dosing

• Obesity

• May lead to increased renal plasma flow and GFR

• 2009 MDRD study

• Included 999 overweight patients (BMI 26‐30 kg/m2) and 1039 obese patients (BMI >30kg/m2)

• Tended to underestimate measured GFR

• Use of adjusted body weight has been validated in aminoglycoside dosing

• Use of lean body weight recommended by some experts

PaiMP, Paloucek FP. The origin of the "ideal" body weight equations. Ann Pharmacother. 2000;34(9):1066‐9.

Cockroft‐Gault Equation

• Used in pharmacokinetic studies

• Estimates used for drug dosage recommendations

• NKDEP recommend using either CG or MDRD for drug dosing

• Simple mathematical formulation and bedside applicability

National Kidney Disease Education Program. Chronic Kidney Disease and Drug Dosing: Information for Providers. Available at http://www.nkdep.nih.gov/.../CKD_DrugDosing_508.pdf. Updated April 18, 2015. Accessed July 13, 2015.


• Current recommendations:

• The National Kidney Disease Education Program (NKDEP), National Kidney Foundation (NFK) and American Society of Nephrology (ASN) all recommend estimating GFR from SCr

• MDRD & Cockcroft‐Gault equation

• Incorporate multiple factors to reduce limitation with SCr alone

• CKD‐EPI: replaces MDRD equation

• Most labs report GFR estimates using MDRD

• NKF now recommends using CKD‐EPI

National Kidney Foundation. Frequently Asked Questions about GFR Estimates. Available at http://www.kidney.org/sites/default/files/docs/12‐10‐4004_kbb_faqs_aboutgfr‐1.pdf. Accessed July 13, 2015.National Kidney Disease Education Program. Chronic Kidney Disease and Drug Dosing: Information for Providers. Available at http://www.nkdep.nih.gov/.../CKD_DrugDosing_508.pdf. Updated April 18, 2015. Accessed July 13, 2015.

Considerations

• Role of the FDA

• The 1998 FDA guidance on PK studies recommend use of creatinine clearance for renal dose adjustments

• Recommendations to include both CG derived creatinine clearance and equations based on eGFR

• Unlikely to impact medications with existing renal dose adjustments

• Clinical Considerations

• Renal function is a mosaic representation

• Pharmacist/clinical should consider labs, clinical signs, symptoms in addition to renal function estimation equations

9/23/2015

4

Anemia of Chronic Kidney Disease

19

Anemia in CKD: Pathogenesis

• Common complication of CKD• Occurrence and severity varies with degree of renal dysfunction

• Hgb < 13.0 g/dL (men), < 12 g/dL (women)

• Compensatory mechanisms do not exist in patients with CKD

• Normochromic, normocytic anemia

Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach, Ninth Edition. 2014

Etiology of Anemia in CKD

• Multifactorial

• Erythropoietin deficiency

• Deficiencies in iron, folate, vitamin B

• Shortened life‐span of red blood cells

• Uremic complications

• Gastrointestinal bleeding, hemolysis

• Bone marrow suppression

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.


Anemia in CKD: Symptoms

• Hemoglobin should be measured in ALL individuals with CKD regardless of disease stage

• Symptoms • Complications

• Shortness of breath• Extremity tingling• Headaches• Chest pain• Tachycardia• General malaise

• Heart failure• Left ventricular hypertrophy• Angina• Increased hospitalizations• Decreased quality of life• Increased all‐cause mortality



Audience Poll

Which of the following should be avoided in patients with chronic kidney disease who present with anemia?

A. Erythropoietin stimulating agents

B. Oral iron therapy

C. Intravenous iron therapy

D. Red blood cell transfusions

Anemia in CKD: Treatment

• Erythropoiesis stimulating agents

• Epoetin alpha

• Darbopoetin alpha

• Iron therapy

• Red blood cell transfusions



9/23/2015

5

Erythropoiesis Stimulating Agents (ESAs)

Drug Initial Dosing

Epoetin – α (Procrit®)50‐100 units/kg

IV/SQ 3 times weekly

Darbopoetin – α

(Aranesp®)

0.45 mcg/kg/week

IV/SQ (~ 40 mcg)

Decrease dose by 25% if Hgb increases by > 1g/dL or is approaching 12 mg/dL

Reassess labs monthly –do not adjust doses more than once monthly


ESA’s Cont.

• Derived by recombinant DNA technology

• Extended T1/2 with Aransep®

• Subcutaneous vs. intravenous administration

• Onset of action

• Immediate reticulocyte demargination

• ~ 2 weeks before erythrocytes mature

• Hgbwill continue to increase for lifespan of RBC



ESA’s Adverse Effects

• Hypertension

• Seizures

• Vascular access thrombosis

• CV disease/Stroke

• Neutralizing antibodies

• Pure red cell aplasia (PRCA)

• Results in resistance to all ESA’s



How High is Too High: An Analysis of Clinical Trials Utilizing ESA’s

Trial Population Findings Findings

Normal Hematocrit Trial (1998)

• 1233 patients with CKD – HD with evidence of HF or CADwere randomized to partial treatment of anemia or full anemia correction utilizing epoetin

• Hematocrit targets were 42% for “full anemia correction” and 30% for “partial correction”

• 202 primary events of MI or death in full correction group compared to 164 events in partial correction – risk ratio 1.3 (0.9‐1.9)

• Trial was halted early

CHOIR Trial (Correction of Hemoglobin and Outcomes in Renal Insufficiency) – (2006)

• 1432 patients with CKD Stage 3 – 4 were randomized to Hgb targets full anemia correction or partial anemia correction

• Hemoglobin targets were 13.5 g/dL in patients randomized to full correction, and 11.3 g/dL in patients randomized to partial

• Patients randomized to the higher Hgbconcentration had an increase in the primary composite outcome of death, MI, hospitalization, stroke (HR 1.34, p = 0.03)

Meta‐Analysis of Trials (2010) • Abstract of aggregate data from reports of clinical trials

• Higher Hgb concentrations in CKD increases risk for stroke (RR 1.51), HTN (RR 1.67), vascular access thrombosis (RR 1.33), p <0.05 for all

• Higher Hgb concentrations in CKD increases risk for death (RR 1.09), serious cardiovascular events (RR 1.15), and ESRD (1.08), p> 0.05 for all

Clinical Practice Recommendations –Initiation of ESA’s

• In patients on dialysis, initiate ESA’s when Hgb is 9 – 10 g/dL

• In patients NOT on dialysis, decision to initiate ESA’s when Hb concentration < 10g/dL should be based upon an individualized approach

• In patients NOT on dialysis, do not initiate ESA’s if Hgb > 10 g/dL

• When considering ESA initiation, always recommend balancing the benefits of anemia‐related adverse effects and risk of RBC transfusion, with potential agent harm



General Recommendations for ESA’sNon‐Dialysis Dependent Patients on ESA’s Dialysis‐Dependent Patients on ESA’s

During initiation of phase of ESA’s, monitor Hgbconcentration at least monthly

During initiation of phase of ESA’s, monitor Hgbconcentration at least monthly

For CKD‐ND patients, during the maintenance phase of ESA therapy, monitor Hgb concentrations at least every 3 months

For CKD‐HD patients, during the maintenance phase of ESA therapy, measure Hgb concentration at least monthly

Utilize subcutaneous administration of ESA’s for CKD‐NDpatients

Utilize intravenous or subcutaneous administration of ESA’s for HD patients

Utilize subcutaneous administration of ESA’s for PD patients

ESAs should not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adultpatients with CKD

In all adult patients ESAs not be used to intentionally increase the Hb concentration above13 g/dl (130 g/l)

9/23/2015

6

What is the most common cause of resistance to erythropoiesis-

stimulating agents?

Iron Deficiency

Iron Therapy

• Etiology

• Blood loss

• Increased erythropoiesis stimulation

• GI blood loss

• Platelet dysfunction

• Interference of iron absorption

• Mechanical losses due to hemodialysis



Anemia in CKD: Oral vs. IV IronOral iron Intravenous Iron

Advantages Inexpensive, readily available, does not require intravenous access, relatively safe

Avoids concerns with medication adherence and absorption

Disadvantages Requires multiple daily doses, GI adverse effects, variable GI absorption, DDI

Potential for iron overload, serious adverse reactions, need for IV access

Potential candidates Trial of 1 – 3 months in patients with CKD assuming:• TSAT < 30%• Ferritin < 500 mg/dLPediatric patients NOT on HD

Patients on hemodialysis

Patients in Stage 3 – 5 CKD who do not meet criteria for oral agents

Formulation Typical Dosing Test Dose Clinical Pearls

Iron dextran 100 mg IV over 2 minutes Yes!!! • Requires in‐office observation at first dose

Sodium ferric gluconate/ferricgluconate

125 mg IV over 1 min, or dilutedover an hour

No • May be considered an alternative option in patients with sensitivity to dextran

Iron sucrose 100 mg IV over 2 – 5 minutes or diluted over 15 minutes

No • May be considered an alternative option in patients with sensitivity to dextran

Ferumoxytol 510 mg over 15 minutes No • Can affect accuracy of MRI• May be re‐administered 3 – 8 days after

initial infusion

Ferric carbohymaltose 750 mg over 7.5 minutes ordiluted over 15 minutes

No • Only indicated in patients with non‐dialysisdependent kidney disease

• Weight based dosing guides administration frequency

Intravenous Iron Products

Methods of Iron Dosing in CKDMaintenance Dosing

• Provides patients with small doses of iron administered at regular intervals to maintain iron status

• Intent is to avoid iron deficiency or decline iron test parameters

• May be associated with lower ESA doses and lower cumulative iron doses

• May result in lower infection risk

• May resemble more physiologic processes when compared to loading doses

• Requires frequent monitoring and supply costs

Loading Dosing

• Provides patients with periodic iron repletion to replenish stores when iron status indicate deficiency

• Critics suggest that total amount of iron administered may not be sufficient to maintain concentration of erythropoiesis in the long term

• May lead to periods of functional iron deficiency and fluctuations in hemoglobin concentrations

• “Rollercoasting” effect may occur


Management of the Complications of CKD:

Chronic Kidney Disease: Bone‐Mineral Disorder (CKD‐BMD)

9/23/2015

7

Chronic Kidney Disease‐Bone Mineral Disorder

Biochemical Abnormalities

Bone Deformities

Soft Tissue and Vascular Calcification

CKD‐BMD

Abnormalities in Bone Metabolism

• Secondary hyperparathyroidism

• Phosphate retention

• Decreased free calcium concentrations

• Decreased 1,25 dihydroxyvitamin D concentrations

• Increased fibroblast growth factor 23 concentrations

• Reduced expression of various substances

• Vitamin D receptors, calcium‐sensing receptors, fibroblast growth factor receptors, klothoin PTH glands

Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney International 2009; 76 (Suppl 113): S1–S130.

Reduced GFR

Decreased Phosphate Excretion

↑ Serum Phosphorous

↓ Serum Ca ↓Vit. D Activation↑ PTH

↑Ca Resorption from bone

Osteitis Fibrosa Cystica

Renal Osteodystrophy SimplifiedHyperphosphatemia

• Initial alteration is excretion of phosphate

• Secondary effects on PTH, Ca, and Vitamin D

• Increases calcium x phosphate concentration

• Treatment

• Dietary restriction to 900 mg/day

• Phosphate Binding Agents

• Bind dietary phosphorous in GI tract and are excreted in the feces minimizing absorption

• Choice of agent is based upon other therapies, DDI, adverse effects, patient preferences, cost, risk of hypercalcemia


Phosphate Binder Initial dose Considerations

Calcium carbonate (Tums®) 500 – 1000 with meals N/V/D, calcificationDDI, hypercalcemia, large pill burden, affected by gastric

pH

Calcium acetate (PhosLo®) 667 – 1334 with meals N/V/D, calcificationDDI, hypercalcemia, large pill burden, minimally affected

by pH

Aluminum hydroxide 600 – 1200 with meals Constipation, CNS toxicity, osteomalacia, utilize only forshort term

Sevelamer HCL (Renagel®) 800 – 1600 with meals Colonic obstruction, N/V, acidosis effected by gastric pH, large pill burden, $$$, efficacy > when compared to other

agents??

Lanthanum carbonate (Fosrenol®)

500 – 100 with meals Non‐toxic, No DII, $$$

Phosphate Binders


Vitamin D Therapy• Established role in mineral homeostasis

• Stimulates absorption of serum calcium

• Down regulates synthesis/release of iPTH

• Modulates immune function and inflammatory response• Increases osteoblast activity• Negative endocrine regulator of renin system

• Cardiovascular benefitsClinical Practice Recommendations Notes

Patients with CKD Stage 3 – 5 NOT on dialysis • In patients with elevated PTH levels, correct abnormalities in phosphate, calcium, and vitamin D deficiency

• Utilize native vitamin D

Patients with CKD Stage 3 ‐5 NOT on dialysis with persistent elevated PTH levels

• Once modifiable factors have been corrected, consider treatment with a vitamin D analog (calcitriol) if PTH levels are rising

Patients with CKD Stage 5 who are dialysis dependent

• Treat patients with calcitriol or another vitamin D analog• Stop or reduce treatment in the presence of hypercalcemia

9/23/2015

8

Vitamin D Therapy Calcitriol

• Most active form of Vitamin D (1,25 dihydroxyvitamin D)

• Utilized when PTH levels are high • Up regulates Vitamin D receptors reducing parathyroid hyperplasia

• Analogs available• Calcitriol, Doxecalciferol, Paricalcitiol

• No difference in efficacy between agents• Pharmacodynamic parameters guide usage


Calcitriol and AnalogsAgent Clinical Characteristics

Calcitriol • Same as endogenous vitamin D3• Affinity for both intestinal and parathyroid gland vitamin D receptors and has propensity to increase

serum calcium concentrations• Prodrug that must be activated in liver• High % of hypercalcemia and hyperphosphatemia

Doxercalciferol • Vitamin D analog that has less affinity for the intestinal receptors• Lower incidence of hypercalcemia when compared to calcitriol• More rapid suppression of PTH when compared to calcitriol• Prodrug that must be activated in liver

Paricalcitiol • Vitamin D analog that has less affinity for the intestinal receptors• Potential mortality benefit when compared to calcitriol• More rapid suppression of PTH when compared to calcitriol


Calcitriol and Analogs Calcitriol and Analogs

• Adverse Effects• Hypercalcemia• Hyperphosphatemia• Increased Ca X Phosphorous

ratio

• Monitoring • Serum concentrations prior to

initiation • Must be within normal range to

initiate therapy • “Regularly” while receiving

therapy

Paricalcitol

Doxer‐calciferol

Calcitrol

Risk of hypercalcemia among agents

Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney

International 2009; 76 (Suppl 113): S1–S130.

• Cinacalcet HCL (Sensipar®)• Attaches to calcium receptor on the PT gland and

increases sensitivity to serum calcium thereby reducing PTH

• Augments the signal caused by the binding of extracellular ionized calcium to CaR to increase intracellular calcium and decrease PTH release

PTHCa P

Ca xP

Treatment of Hyperparathyroidism in Dialysis Patients: Calcimimetics

Cinacalcet Prescribing Information. Amgen Pharmaceuticals. 2004

What Does the Data for Cinacalcet Say?

Trial Population Findings

Lindberg et al .(2005)

Phase 3 randomized, multicenter,double‐blind study

• Three‐hundred ninty five patients on either hemodialysis or peritoneal dialysis were randomized to receive either “traditional” therapy for hyperparathyroidism or “traditional” + cinacalcet

• Patients who received cinacalcet had greater reductions in their PTH levels, a greater proportion of patients had > 30% reduction in levels, and experienced significant reductions in serum calcium, phosphorous, and calcium phosphate ratios

Palmer et al. (2013) Metaanalysis of randomized trials evaluating effects of calcimimetictherapy on mortality and adverse events in patients with CKD

• Metanalysis of eighteen trials with 7,446 patients who were treated with cinacalcet compared with conventional treatment for hyperparathyroidism

• Cinacalcet had little or no effect on all‐cause mortality (relative risk, 0.97 [95% confidence interval, 0.89–1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16–2.87]), and prevented parathyroidectomy (0.49 [0.40–0.59]) and hypercalcemia (0.23 [0.05–0.97]), but increased hypocalcemia (6.98 [5.10–9.53]), nausea (2.02 [1.45–2.81]), and vomiting (1.97 [1.73–2.24]).

9/23/2015

9

Senispar® • Dosing: 30 mg daily, Max = 180 mg daily

• Potent inhibitor of CYP 2D6

• Adverse effects

• Nausea, vomiting

• Hypocalcemia (avoid initiation of corrected Ca < 8.4 mg/dL)

•Monitoring

• Calcium, phosphorous, Ca x P, iPTHCinacalcet Prescribing Information. Amgen Pharmaceuticals. 2004

Drug Dosing Considerations in CKD

Drug‐Related ADRs in CKD

• Approximately half of patients with an estimated GFR <60 ml/min are at risk for ADRs

• Risk Factors

• Non‐white ethnicity

• Older age

• ACEi/ARB use

• Diabetes

• Advanced CKD

Ginsberg JS, et al. J Am Soc Nephrol2014.

Rate of adverse drug events in ambulatory patients with CKD

N=267 Rate (per 100 patients)*

PATIENT REPORTED

Hypoglycemia 57.6

Falling/ severe dizziness 23.1

Nausea, vomiting ± diarrhea 21.1

Hyperkalemia 18.1

Confusion 16.9

DETECTED AT STUDY VISIT

Hypoglycemia 8.3

Hyperkalemia 8.3

Bradycardia 6.4

*Adjusted for sociodemographic, comorbid conditions, GFR, and number of medications

Adapted from Ginsberg JS, et al. J Am Soc Nephrol2014.

Medication Safety in CKD

Fink et al. KI 2009;76:1123–1125

PK and PD Considerations: CKD• Increased volume of distribution (Vd) in moderate to severe CKD & preexisting

CKD with AKI

• Decreased protein binding

• Increased tissue binding

• Alteration in body composition (i.e. fluid overload)

• Metabolite accumulation

• Questionable pharmacologic action

• May contribute to adverse drug reactions

• Non‐renal clearance

• CKD and AKI may effect activities of uptake and efflux transporters, and CYP enzymes

• Clinical dosing impact unknown

Matzke GR, Dowling T. Dosing concepts in renal dysfunction. In: Murphy JE (ed). Clinical Pharmacokinetics Pocket Reference, 5th edn. American Society of Health‐System Pharmacists: Bethesda, MD, 2011.MatzkeGR, Aronoff GR, Atkinson Jr AJ, et al. Drug dosing consideration in patients with acute and chronic kidney disease‐a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11);1122‐

37.

9/23/2015

10

PK and PD Considerations: CKD

• Loading dose (LD):

• Most guidelines do not recommend a LD

• Consider when:

• Drug with long half‐life

• Need to rapidly achieve steady‐state concentrations

• If Vd of drug significantly increased

• Modified LD:

LD= usual LD x [(patient’s Vd)/(normal Vd)]

Matzke GR, Dowling T. Dosing concepts in renal dysfunction. In: Murphy JE (ed). Clinical Pharmacokinetics Pocket Reference, 5th edn. American Society of Health‐System Pharmacists: Bethesda, MD, 2011

.MatzkeGR, Aronoff GR, Atkinson Jr AJ, et al. Drug dosing consideration in patients with acute and chronic kidney disease‐a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11);1122‐37.

PK and PD Considerations: CKD

• Maintenance dose:

• Simple proportional approach can be utilized

• Generally, prolonging dosing interval while maintaining same dose will result in similar troughs

• Serum Drug Monitoring

• Helps to optimize therapeutic regimens

• Delayed steady‐state (longer half‐life)

• Correction in renal failure

• phenytoin



PK and PD Considerations: HD• Drug‐related factors:

• Molecular weight or size

• Degree of protein binding

• Distribution volume

• Kidney Disease Program

• https://kdpnet.kdp.louisville.edu/drugbook/adult/



Assessment Question

A 52 year old male (60 kg) is being treated empirically for cellulitis with vancomycin 750 mg IV every 12 hours. Estimated CrCl is 45 ml/min. Steady‐state trough returns at 25 mcg/ml (goal: 10‐15 mcg/ml). What is the next appropriate step?

A. Decrease dose to 500mg, continue same interval

B. Decrease dose to 500mg, extend interval

C. Continue same dose, decrease interval

D.Continue same dose, extend interval

Drug Selection Considerations

ACEi/ARB in CKD• Effectively lower glomerular capillary pressure

• Protective in CKD, especially diabetes

• Decreased pressure in hypo‐perfused states

• Volume depletion, cirrhosis, congestive heart failure


9/23/2015

11

Prostaglandins in CKD• Dilate afferent arterioles preserve GFR

• NSAIDs block this protective action

• NSAIDs and RAAS‐inhibitors may result in afferent vasoconstriction and efferent dilation, respectively


Iodinated Contrast

• Leads to acute kidney injury

• Risk factors: CKD, diabetes, CHF, dehydration, concurrent nephrotoxic agents

• Minimize risk:

• Low or iso‐osmolar agents at lowest doses

• Avoid concurrent nephrotoxic agents

• Optimize volume status

• NO benefit of prophylactic hemofiltration/HD

KDIGO Guidelines on CKD Diagnosis and Management. Kidney Int. 2013.

IV Fluid Selection

Group A: NS 1 ml/kg/h starting @ 8 h pre‐ and continued ≥12h post‐procedure

Group B: NaHCO3 (166 mEq/L) 3 ml/kg/h 1h pre‐ and 1ml/kg/h for 6h post‐procedure

Group C: NaHCO3 3ml/kg bolus 20 mins pre + 1,500 mg tab/10kg + 100‐200 ml mineral water orally and 500 ml of mineral water post‐procedure

Klima T, et al. Euro Heart J, 2012.

RAAS Antagonists

• Expect a 10‐30% rise in SCr

• Hyperkalemia

• Practice recommendations:

• Assess eGFR and potassium 1 week after initiation or dose increase

• Discontinue/reduce dose if SCR increases > 30% or K+ >5.5 mEq/L

Ahmed AK, KamathNS, El Kossi M et al. The impact of stopping inhibitors of the renin angiotensin system in patients with advanced chronic kidney disease. Nephrol Dail Transplant 2010;25: 3977–3982.

KDIGO Guidelines on CKD Diagnosis and Management. Kidney Int. 2013.

Treatment Considerations in CKD Patients with UTI

Ampicillin* • Achieve good urine concentration

Cephalosporins* • Generally low urine concentrations• Exceptions: cefazolin and ceftriaxone, but not FDA approved for UTI

treatment

Carbapenems • <50% of active drug present in urine• Unknown efficacy for UTI in CKD patients

Quinolones* • Ciprofloxacin and levofloxacin achieve good urine concentrations

Nitrofurantoin • Low renal excretion, avoid if eGFR <50 ml/min

Trimethoprim* • Achieve good urine concentration

Aminoglycosides* • Achieve high urine concentrations• Nephrotoxic

*Requires dose adjustment in CKDAdapted from Gilbert DN, J Am Soc Nephrol. 2006

Antimicrobials & CKD

• Most require renal dose adjustments

• Common exceptions: Ceftriaxone, moxifloxacin, macrolides, doxycycline, clindamycin, linezolid

• Trimethoprim/ sulfamethoxazole

• May ↑SCr slightly due to ↓renal tubular creatinine excretion– no change in GFR.

• Distinguish from AKI due to drug allergic interstitial nephritis

• Hyperkalemia

• Imipenem/ cilastatin

• High seizure risk in CKD patients

• Consider carbapenem in CKD

• Limited dosing recommendations in HD and PD

• Review PK/PD of abx (AUC, MIC)

• Consult ID pharmacist

KDIGO Guidelines on CKD Diagnosis and Management. Kidney Int. 2013.MunarMY and Singh H. Am Fam Physician, 2007.

9/23/2015

12

Antimicrobials & CKD

• Example: long‐term amphotericin needed for a HD (receives TIW) patient who is unable to come to infusion center daily for amphotericin dose. Physician requests dose to be given on dialysis days.

• Recommendations per packet insert to dose daily

• Review PK/PD of abx

• Consult ID pharmacist

The Pharmacist’s Role in the Management of Chronic Kidney

DiseaseAyesha Khan, PharmD, BCPS

Lalita Prasad‐Reddy, PharmD, MS, BCPS, BCACPAssistant Professors of Pharmacy Practice

Chicago State University‐College of Pharmacy

Date post:	23-Jul-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

IPHA Slides Final Version 7.31 Khanedit · 2015-09-23 · 9/23/2015 4 Anemia of Chronic Kidney...

Documents