Handout#3 (CKD and CKD Complications) (1).pdf

PMD 703 PT1 Handout #5 Topic # 8: Chronic Kidney Disease (CKD) Learning Objectives Define the stages of chronic kidney disease (CKD) Recognize common risk factors for CKD and suggest preventive measures where appropriate Identify potential signs and symptoms exhibited by patients within each stage o...

PMD 703 PT1 Handout #5 Topic # 8: Chronic Kidney Disease (CKD) Learning Objectives Define the stages of chronic kidney disease (CKD) Recognize common risk factors for CKD and suggest preventive measures where appropriate Identify potential signs and symptoms exhibited by patients within each stage of CKD Recommend treatment options for slowing the progression of CKD in diabetic kidney disease Managing hypertension in CKD patients Definition of CKD Presence of kidney damage or reduced glomerular filtration rate (GFR) < 60 mL/min/1.73m2 for a period of 3 months or more Progressive decline over months to years For renal function to be diminished by 50% you must lose > 75% of kidney tissue (since there are 2 kidneys) Damage is typically irreversible; however, progression could be slowed down by proper management CKD staging Use eGFR not CrCl for determining CKD stage For adults ( ≥ 18 years old) o eGFR calculated with CKD-Epi Equation o NKF calculator online at https://www.kidney.org/professionals/kdoqi/gfr_calculator For pediatric (< 18 years old) use the eGFR calculated with the Modified-Schwartz Equation Comprehensive assessment of kidney function Kidney function stage Kidney damage stage A1 A2 A3 uACR < 30 uACR 30-300 uACR >300 G1 >90 Low Risk Moderate Risk High Risk G2 60-89 Low Risk Moderate Risk High Risk G3a 45-59 Moderate Risk High Risk Very High Risk G3b 30-44 High Risk Very High Risk Very High Risk G4 15-29 Very High Risk Very High Risk Very High Risk G5 65 years old) Racial/ ethnic minorities (Blacks, Hispanics, Native Americans) Reduced kidney mass or dysplastic kidney disease Low birth weight or congenital defects Family history of CKD History of AKI The most common causes of CKD Diabetes Mellitus (DM) Hypertension (HTN) Glomerulonephritis (GN) Polycystic kidney disease (PKD) Congenital anomalies of the kidney and urinary tract (CAKUT) Kidney stones, etc. Incidence of End Stage Kidney Disease (ESKD) Major primary causes of ESRD Patients ages 0-19 years old Patients ages ≥ 20 years old Diabetes 1 %* 45% Glomerulonephritis 34.3% 8.4% 5% n/a Hypertension 4.5%* 28.7% Others causes (CAKUT, Hydronephrosis, Stones…) 38.3% 2.3% Interstitial nephritis/ Pyelonephritis Key elements of irreversible kidney disease Loss of nephron mass o As a result of exposure to initiating factors (diabetes, hypertension, etc.) o Remaining nephrons may hypertrophy to compensate for loss of function Glomerular capillary hypertension o Result from nephron hypertrophy and may be mediated by angiotensin II Proteinuria (protein in urine) o Accelerates progressive loss of nephrons due to direct toxicity (albumin, immunoglobulins, other plasma proteins are toxic to renal tubular cells) Cellular damage occurs as a result of up-regulation of inflammatory and vasoactive cytokines Signs and Symptoms of CKD by Stage Stage (s) Clinical signs/Lab findings G1 and G2 G3 to G4 G5 Often none Symptoms Often none ✓ Elevated BUN ✓ Anemia ✓ Secondary Often none or mild symptoms (fatigue, hyperparathyroidism loss of appetite, etc..) ✓ Abnormal Ca and phosphorus levels ✓ Vitamin D deficiency Stage G3/ 4 clinical findings plus, ✓ Metabolic acidosis ✓ Hyperkalemia ✓ Fluid retention ✓ Microalbuminuria, Hypoalbuminemia Symptoms seen in G3/4 plus, ✓ Asterixis (tremors) ✓ Pruritis ✓ Dysgeusia ✓ Bleeding abnormalities ✓ Encephalopathy Treatment of CKD Prevention and treatment of complications of CKD The main goal in the management of patients with CKD Stages G1-3 is to slow the progression to dialysis dependent CKD (ESRD) For patients at CKD stages G4 and 5 the goals now include preparing the patient for dialysis Diabetic Kidney Disease (DKD) Diabetes is the most common cause of CKD in adults (at about 45%) Relative risk of diabetic nephropathy based on diabetes type o Type I diabetes: 40% o Type II diabetes: 50% o Other types of diabetic: 10% Prolonged hyperglycemia leads to vascular injury o Leading to hemodynamic changes causing increased glomerular permeability o Leading to albuminuria which is a hallmark of diabetic nephropathy o Leading to inflammation within the proximal tubule and fibrosis of kidney tissue o Ultimately leading to decreased GFR Management of DKD As discussed, earlier proteinuria (albuminuria) is a hallmark finding in patients with DKD In DKD the first goal is control the diabetes (blood sugar levels) Then to reduce the decrease protein excretion to protect kidneys from further damage Key medications used are: o ACEIs or ARBs (will be discussed later with hypertension meds) o Sodium glucose co-transporter (SGLT) -2 inhibitors o Finerenone Role of SGLT2 inhibitors Block the reabsorption of glucose and sodium in the proximal tubule of the nephron Approved as an antidiabetic medication but have now shown added benefit in slowing CKD progression Examples: o Dapagliflozin o Empagliflozin o Canagliflozin Role of SGLT2 inhibitors in CKD Mechanism of kidney protection in CKD o It is believed that they protect the kidney directly by reducing the glomerular hyperfiltration through the inhibition of sodium (along with glucose) reabsorption leading to natriuresis causing a feedback vasoconstriction and consequent decrease in intraglomerular pressure o This may also have an anti-inflammatory and anti-fibrotic effect on the glomeruli They require dose adjustment in individuals with diminished kidney function Image from: Kidney International (2018) 94, 26–39 Drug Dosage Adverse Events Dapagliflozin (Farxiga®) CKD with or without diabetes (adjunctive agent): 10 mg by mouth once daily Hypovolemia, genitourinary infections, euglycemic diabetic ketoacidosis, dyslipidemia Empagliflozin (Jardiance®) CKD with or without diabetes (adjunctive agent): 10 mg by mouth once daily Hypovolemia, genitourinary infections, euglycemic diabetic ketoacidosis, dyslipidemia Canagliflozin (Invokana®) DKD: 100mg by mouth once daily prior to first meal of day Hypovolemia, genitourinary infections, euglycemic diabetic ketoacidosis, dyslipidemia, bone fractures, risk of amputation Finerenone (Kerendia) A non-steroidal mineralocorticoid receptor inhibitor o Finerenone selectively blocks mineralocorticoid receptor–mediated sodium reabsorption and inhibits the overactivation of these receptors which is a hallmark of CKD o Reduces fibrosis and inflammation within the kidneys FDA approved for slowing CKD progression in diabetic patients o Dosed based on serum potassium levels o Adverse reaction: hyperkalemia, hypotension, hyponatremia Hypertension and CKD HTN is the second most common cause of CKD in adults (about 28.7%) Prevalence of HTN increases with increasing stage of CKD o At CKD Stage 3: > 75% of patients will show signs of hypertension o Diagnosed after 3+ elevated BP readings at the clinic or based on ABPM findings Hypertension is unique because it is both a risk factor (or causative factor) and complication of (or caused by) CKD Blood Pressure Goals in CKD: ACC/ AHA 2017 guidelines vs KDIGO 2021 Target ACC/AHA 2017 population For CKD BP < 130/80 mmHg patients For patient BP < 130/80 mmHg post-kidney transplant KDIGO 2021 *Systolic BP < 120 mmHg BP < 130/80 mmHg Non-Pharmacological Approach Life-style modifications Weight loss: maintain a BMI of 20-25kg/m2 Smoking cessation Dietary: reduce salt (Na) intake to < 2g/day Exercise: at least 30 minutes of moderate severity exercise 5 or more days a week. Reduce alcohol consumption Managing Hypertension in CKD The renin angiotensin aldosterone system (RAAS) plays a very important role in the regulation of blood pressure by the kidney Drugs that alter the RAAS are the 1st line (choice) medications in treating HTN in patients with CKD and HTN Drug classes for treating hypertension in CKD Angiotensin converting enzyme (ACE) inhibitors (1st Line) Angiotensin receptor blockers (ARBs) (1st Line) Calcium Channel Blockers (CCB)* Diuretics Beta-receptor Blockers Others - Aldosterone Receptor Antagonists, Alfa-receptor antagonists, Central Alfa-receptor agonists, Direct Vasodilators *Alternative 1st-line option when ACE inhibitors and ARBs are contraindicated Managing a patient with hypertension and CKD* 1st Line anti-hypertensive medication (ACEIs or ARBs) unless contraindicated If still not at goal BP, add another agent (the order is not as important to most clinicians), but you must consider patient related factors o Dihydropyridine CCB o Diuretic (Thiazides or loops depending on CrCl), see slides on diuretics o Beta-blocker (depending on heart rate) If still not at goal BP with the above, add the any of the following; o Aldosterone Receptor Antagonists, Alfa-receptor antagonists, Central Alfa-receptor agonists, or Direct Vasodilators It is common to see a CKD patient on 3 or more anti-hypertensive medication ACE Inhibitors (ACEi) Mechanism of action o Inhibits the angiotensin converting enzyme (ACE) facilitated conversion of angiotensin I to angiotensin II, leading to vasodilation and decreased aldosterone secretion and consequently decreased Na reabsorption (Review the RAAS) Side effects o Hypotension, Hyperkalemia, Dry Cough, Angioedema, Elevation of Scr* * This could be transient, but it might persist facilitating a switch to another antihypertensive drug class Examples of ACE Inhibitors Generic Lisinopril Brand(s) Prinvil, Zestril Qbrelis Enalapril Vasotec Epaned Ramipril Altace Benazepril Lotensin Captopril Capoten Formulation Daily dose range Frequency Oral tablet Oral solution (1mg/mL) 10 – 40 mg Once daily Oral tablet Oral solution (1mg/ mL) Oral tablet Oral tablet Oral tablet 2.5 – 40 mg 1 – 2 times daily 1.25 – 20 mg 10 – 40 mg 25 – 100 mg Once daily 1 -2 times 2 – 3 times daily Angiotensin Receptor blockers (ARBs) Mechanism of action: o Blocks angiotensin type-1 (AT I ) receptor antagonists, preventing the binding of angiotensin II to this receptor, leading to vasodilation and decreasing aldosterone secretion and consequently decreasing Na reabsorption Side effects: o Hypotension, Hyperkalemia, Angioedema, Elevation of Scr* * This could be transient, but it might persist facilitating a switch to another antihypertensive drug class Examples of ARBS GENERIC BRAND (S) FORMULATION TOTAL DAILY DOSE FREQUENCY Losartan Cozaar Oral tablet 25 – 100 mg 1-2 times daily Valsartan Diovan Oral tablet 80 – 320 mg Once daily Olmesartan Benicar Oral tablet 5 – 40 mg Once daily Irbesartan Avapro Oral tablet 150 – 300 mg Once daily Candesartan Atacand Oral tablet 8 – 32 mg Once daily Key facts facts on ACEi and ARBs Although side effects are similar, patient with cough secondary to ACEIs may tolerate ARBs Both protect against heart failure and proteinuria (in addition to their anti-hypertensive function) ACEIs and ARBs can increase SCr by up to 20-30% when first initiated so close monitoring is essential Both are contraindicated in pregnancy!!! The use of ACEI and ARBs together is not recommended Revisit your knowledge of the RAAS system Diuretic Use in CKD Diuretics are second line options for managing hypertension in CKD especially in the presence of fluid overload (edema) The two most important classes of diuretics used in CKD are o Thiazides (including thiazide-like) diuretics o Loop diuretics In patients with CrCl is 30mL/min or higher o Thiazides or thiazide-like diuretics are preferred In patients with CrCl < 30mL/min o Recommend loop diuretics o Thiazides are not recommended because they are not as effective in these patients Loop Diuretics Mechanism of action o Inhibits reabsorption of Na in the thick ascending limb of the loop of Henle by blocking the Na-K2Cl co-transporter, thus causing increased excretion of Na and water, with a corresponding reduction of blood pressure Key side effects o Orthostatic hypotension, Hypomagnesemia, Hypocalcemia, hematologic side effects, anaphylactic reactions Examples of Loop Diuretics Generic Brand (s) Formulation (s) Total daily dose for hypertension Frequency Furosemide Lasix Oral tablet IV 20 – 80 mg BID Bumetanide Bumex Oral tablet IV 0.5 – 2 mg BID Torsemide Demadex Oral tablet IV 2.5 – 10 mg Once a day Thiazide/ Thiazide-like Diuretics Mechanism of action: Inhibits Na reabsorption at the distal renal tubule resulting in increased excretion of sodium, chloride and water Key side effects: Hypotension, hyponatremia, hypokalemia, hypercalcemia, hypomagnesemia, photosensitivity Examples of Thiazide/ Thiazide-like diuretics Generic Brand (s) Daily dose Frequency Hydrochlorothiazide Microzide 12.5 – 50 mg Once daily Chlorothiazide Diuril 250 – 1000 mg Once daily - BID Chlorthalidone ------- 12.5 – 25 mg Once daily Metolazone* Zaroxolyn 2.5 – 20 mg Once daily *Thiazide-like Dihydropyridine (DHP) Calcium channel blockers (CCBs) Mechanism of action: o Reduces peripheral vascular resistance and lowers blood pressure by blocking Ca channels within the vascular smooth muscle, thus causing vasodilation of the peripheral arteries Key side effects: o Peripheral edema, Flushing, orthostatic hypotension Examples of DHP-CCBs Generic Brand (s) Total daily dose Frequency Amlodipine Norvasc Katerzia (1mg/ mL) 2.2 – 10 mg Once daily Nifedipine Nifedipine ER Procardia 10 – 60 mg TID Procardia XL 30 – 120 mg Once daily Beta-receptor Blockers Mechanism of action: o Block beta-1 adrenoreceptors located mainly in cardiac muscles reducing heart rate and blood pressure. Examples: Metoprolol, Labetalol, Carvedilol In addition to beta-1 receptor blockade, Carvedilol and Labetalol also have peripheral alpha-1 receptor blockade activity Key side effects: Bradycardia, bronchospasm, hypotension A few examples of Beta-receptor Blockers Generic Brand Formulation Total daily dose Frequency Metoprolol Tartrate Lopressor Oral tablet 25 – 200 mg BID IV solution (1mg/ mL) 2.5 - 5 mg Intermittent Metoprolol Succinate Toprol-XL Extended release tablet 50 – 400 mg Once daily Carvedilol Coreg Oral tablet 3.125 – 25 mg BID Coreg CR ER capsule 10 – 80 mg Once daily Trandate Oral tablet 100 – 1200 mg BID IV solution (5mg/mL) Max daily cumulative dose=300 mg IV boluses or continuous infusion Labetalol Alfa-receptor Antagonists Examples: Prazosin, Doxazosin Mechanism of action: o Inhibits postsynaptic alpha-1-adrenergic receptors which results in vasodilation of arterioles causing a decrease in peripheral vascular resistance and blood pressure Key side effects: Orthostatic hypotension, Palpitations Central Alfa-2-receptor Agonists Examples: Clonidine, Methyldopa Mechanism of action: o Stimulates alpha 2-adrenergic receptors in the CNS resulting in reduced sympathetic outflow leading to decreased peripheral vascular resistance, heart rate, and blood pressure Key (unique) side effects: Bradycardia, Drowsiness, Sedation Direct Vasodilators Examples: Hydralazine, Minoxidil Mechanism of action: o Act by directly relaxing peripheral arterial smooth muscle leading to vasodilation, decrease in peripheral vascular resistance and a reduction in blood pressure Key side effects: Tachycardia, Peripheral edema Topic # 9: Chronic Kidney Disease (CKD) – Part II Learning Objectives Review the functional physiology of the glomerulus Explain the characteristics of nephritic and nephrotic syndromes Interpret a typical urinalysis (spot test and urine chemistry) Recommend pharmacotherapeutic strategies for a given patient with glomerulonephritis Other Causes of CKD I. Glomerulonephritis II. Nephrolithiasis III. Polycystic kidney disease (PKD) IV. Recurrent urinary tract infections (UTIs) V. Congenital anomalies of the kidneys and urinary tract (CAKUT) Glomerulonephritis Refers to a broad group of diseases characterized by symptoms of damage to the glomerulus Common cause of renal failure in the pediatric population o Third most common cause in adults Could be idiopathic, secondary to infections or autoimmune diseases Examples Post-Streptococcal GN Membranoproliferative GN Lupus Nephritis IgA Nephropathy Henoch-Schonlein Pupura (HSP) Function of Glomerulus A “specialized” capillary Creates a selective barrier allowing and preventing the excretion of substances Main functional parts o Fenestrated endothelium o Basement membrane o Podocytes (especially their foot processes) Podocytes They form a very effective barrier preventing the filtration of large substances from passing through Glomerular Basement Membrane (GBM) The GBM gives the glomerulus a negative charge and enables it to repel negatively charged substances Glomerular Selectivity These properties determine if a substance will pass through the glomerular filter or not Molecular Size: less than ~50kDa pass easily Charge: (negatively charged substances poorly filtered) Protein binding: Protein substances are poorly filtered Urinalysis Spot Urine Test/ Dip-Stick o Quick and convenient for clinic setting o Does not accurately quantify analytes Urine Chemistry Laboratory analysis (quantitative) of: o Urine protein, Urine creatinine, Electrolytes, Ketones, Nitrites etc,… Some relevant urinalysis tests in nephrology Protein Normal is 0 or trace Albumin and low molecular wt. serum globulins Increases may be seen in kidney damage, DM, severe HTN, Nephrotic/nephritic syndromes Blood/Hemoglobin Normal is 0 or trace May be micro or gross hematuria, hemoglobinuria, or myoglobinuria Urine color might not always look different (as in microscopic hematuria) Renal biopsy For definitive diagnosis of specific disease Clinical Presentation of Glomerulonephritis Usually varies depending on primary cause: Nephritic symptoms o Hematuria o Hypertension o Others, low complement levels [C3, C4] (beyond the scope of this class) Nephrotic symptoms o Proteinuria o Hypoalbuminemia o Edema Management of Glomerulonephritis First-line is to treat underlying cause if identified (infections infection, lupus, hepatitis, etc,…) Then manage the symptoms … Hematuria Gross hematuria o Urine is “rust-colored, tea-colored, cola-colored” Management: o Usually transient o Resolves on its own when underlying cause is treated Hypertension First-line: o RAAS blocking agents - ACEIs or ARBs Second-line o DHP-CCBs and diuretics (if edema is also an issue) Nephrotic Range Proteinuria Spot urine tests are not a good quantitative tool for assessing proteinuria o Urine chemistry test is often needed to quantify proteinuria Nephrotic range proteinuria is defined as: o On a urine dipstick: 3+ or more o Urine protein excretion > 3.5 g per 24hours o Urine protein concentration > 300 mg/dL o Urine Protein-Creatinine ratio (uPCR) > 2000mg/g (or > 2) Management of Proteinuria Corticosteroids - for severe proteinuria (nephrotic range) o Prednisone o Prednisolone For sub-nephrotic proteinuria o ACEIs/ ARBs Edema Tends to be mild-moderate Usually peri-orbital, lower extremity Shifts with changing body positioning Management o Loop diuretics ( ex. Furosemide, etc,…) o Thiazides (ex. Hydrochlorothiazide, etc,…) o Non-pharmacological: Na restriction < 2g/ day Nephrolithiasis This is essentially “kidney stones” Pathophysiology is complex as there are various types and etiology Some causes of kidney stones include o Genetic/ congenital diseases (e.g. Oxaluria…) o Nephrocalciuria o Dehydration o Diet o Bacterial infections (UTIs) o Medications (like Bactrim, Indinavir, Topiramate, …) Treatment approaches Hydration (drinking water) Alkalization of urine o Citrate supplementation ▪ Sodium citrate, Potassium citrate, or Lime Dietary and lifestyle changes Thiazide diuretics – in severe cases Lithotripsy Polycystic Kidney Disease (PKD) Polycystic kidney disease (PKD) is a genetic disease characterized by the presence of fluid filled cysts in the kidney Accounts for around 2% of CKD cases There are 2 broad types of CKD: o Autosomal dominant polycystic kidney disease (ADPKD) o Autosomal recessive polycystic kidney disease (ARPKD) Treatment of ADPKD Treatment of symptoms o ACEI/ ARBs for hypertension o Pain relievers o Low sodium diet Reducing Cyst size o Tolvaptan (marketed for ADPKD as Jynarque®) for slowing the growth of the cysts Other Important Causes of CKD Recurrent urinary tract infections (UTIs) o This could lead to scarring of glomerular tissue o Treatment of UTIs will be covered in PT5 Congenital anomalies of the kidneys and urinary tract (CAKUT) o These are anatomical malformations to the kidneys, ureters, bladder, or urethra o No pharmacological treatment Topic # 10: Complications of Chronic Kidney Disease Learning Objectives Identify complications of CKD in a given patient Describe the subjective and objective findings supporting each complication Discuss the recommended guidelines for managing each complication List pharmacologic and non-pharmacologic options for managing each Recommend monitoring and follow-up parameters for each complication based on clinical guidelines Some Key Complications of CKD Hypertension (discussed previously) Anemia of CKD Mineral Bone Disease Electrolyte disorders Metabolic acidosis Hypoalbuminemia Anemia of CKD The Kidney Diseases Improving Global Outcomes (KDIGO) defines anemia as hemoglobin (Hb) < 13g/dL in adult males or Hb < 12g/dL in adult females A patient with anemia may be asymptomatic so a diagnosis often depends on laboratory tests Anemia is a common complication in CKD patients Prevalence: o 26% in patients with eGFR> 60ml/min/1.73m2 o 75% in patients with eGFR< 15ml/min/1.73m2 Associated with increased risk of cardiovascular disease (CVD) and mortality Signs and Symptoms of Anemia Fatigue Headache General malaise Shortness of breath Cold intolerance Chest pain Tingling in the extremities Tachycardia Proposed causes of Anemia in CKD Decreased production of erythropoietin from kidneys Chronic Inflammation o Over-expression of Hepcidin Blunted response to erythropoietin Iron deficiency Important Laboratory findings for assessing Anemia in CKD Complete blood count (CBC): must include Hb, Hematocrit (Hct), white blood cell (WBC) count (with differential), and platelet count Absolute reticulocyte count Serum ferritin level Serum transferrin saturation (TSAT) Serum Vitamin B12 and Folate levels Important Steps in Managing Anemia of CKD 1. Check Iron (Fe) Status 2. Replenish Fe (if deficient) 3. Re-Check RBC indices 4. Consider adding erythrocyte stimulating agents (ESAs) 5. Blood (RBC) transfusion (Last resort, if needed) Step 1-Obtain the Relevant Labs Check the following: Hemoglobin (g/dL): Oxygen carrying capacity of the blood [>12g/dL] Tsat (%): Amount of iron transported in blood bound to transferrin [>30%] Ferritin(ng/mL): Iron stores [within macrophages] [>500ng/mL] Often misleading as it is elevated during inflammation Step 2 – Replenish Iron (if needed) Oral Iron Supplementation (Examples) Product Strength (Elemental Fe) Dose Frequency Ferrous sulfate 325 mg (65mg) 100-200 mg elemental Fe daily Divided into 2-3 doses Ferrous gluconate 325 mg (36 mg) 100-200 mg elemental Fe daily Divided into 2-3 doses Side Effects: Constipation Abdominal pain/ distress Intravenous (IV) Iron Supplementation (Some Examples) IV Formulation Dose form Important facts Iron Sucrose (Venofer) IV Most commonly used Ferumoxytol (Feraheme) IV Infuse 510 mg at the rate of 1 mg/sec as a single dose. Then a second 510 mg dose, 3-8 days from the initial Iron Dextran (Dexferrum) IV A test dose of 25 mg is required, to rule out risk of anaphylactic reactions Ferric carboxymaltose (Injectafer) IV Used in non-dialysis patients with iron deficiency anemia Ferric Pyrophosphate Citrate (Triferic)* Powder for dialysate Add powder into bicarbonate dialysate to form a 110 mcg/L and administer during dialysis (hemodialysis patients only) Ferric Citrate* (Auryxia) Tablets Used in non-dialysis patients with iron deficiency anemia *Newer drugs: more data required Side effects of IV Iron Hypersensitivity reactions (especially Iron dextran) Iron overload Step 3: Replenish Erythropoietin Commonly used Erythropoiesis -Stimulating Agents (ESAs) Generic/ Brand name (s) Initial dose/ Frequency/ Route Expected Response Dose Adjustments Epoetin alfa (Epogen®, Procrit®) 50-100 units/kg 3 times per week/ Subcutaneous or IV Hb is expected to rise by ~ 1mg/dL in 4 weeks at the appropriate dose Dose adjustments made in +/- 25% previous dose Epoetin alfa-epbx (Retacrit®) 50-100 units/kg 3 times per week/ Subcutaneous or IV Hb is expected to rise by ~ 1mg/dL in 4 weeks at the appropriate dose Dose adjustments made in +/- 25% previous dose Darbepoetin alfa (Aranesp®) 0.45 mcg/kg once weekly or 0.75 mcg/kg once every 2 weeks SubQ or IV Hb is expected to rise by ~ 1mg/dL in 4 weeks at the appropriate dose Dose adjustments made in +/- 25% previous dose Side Effects of ESAs FDA “Boxed” warning o Increased risk of tumor progression o Risk of death from cardiovascular events o Risk of thrombosis Others o Hypertension o Pulmonary edema Monitoring Patient with Anemia of CKD If on ESA When first initiated on ESAs; o Monitor Hb every 2 weeks o When stable within acceptable range, monitor Hb every month If on Fe Supplementation also monitor Fe indices; o Every month (along with Hb) o Then, at least every 3 months when stable Newer Agents for Anemia of CKD The FDA recently (early this year) approved a new drug for adults with anemia of CKD o Daprodustat (Jesduvroq®) This medication is in tablet formulation only (for now) Daprodustat Mechanism of Action: It inhibits Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) triggering the hypoxic stress response which includes the increase production of erythropoietin Adverse Reactions o Exacerbation of hypertension, hypersensitivity reactions, gastrointestinal erosion Still too early to determine its place in therapy CKD -Mineral Bone Disease (CKD-MBD) Mineral bone disease in CKD is a general term used to describe disorders of bone metabolism Over 75% of people with CKD 3-5 have some manifestation of CKD-MBD Comprises of the following disorders o Vitamin D deficiency o Hypocalcemia o Hyperphosphatemia o Secondary hyperparathyroidism (sHPT) Can lead to renal osteodystrophy Monitoring of hypocalemia, hyperphosphatemia, and secondary hyperparathyroidism should be considered together The KDIGO 2017 guidelines does not set specific targets for Phosphorus, Calcium, or iPTH levels but the goal is to target normal range Primary goal is to reduce the risk of cardiovascular disease (especially vascular and valvular calcification) and death Vitamin D Deficiency Normal Vitamin D levels is defined as 25-hydroxyvitamin D (Calcidiol) > 30 ng/mL 25-hydroxyvitamin D is a measure of the body's vitamin D stores Causes: o Poor dietary intake o Low exposure to sunlight o Urinary excretion (25-hydroxyvitamin D bound to vitamin D-binding protein (DBP) in nephrotic syndrome Vitamin D Supplementation Ergocalciferol (Vitamin D2) Cholecalciferol (Vitamin D3) Serum Vitamin D (ng/mL) Definition Supplementation Cholecalciferol 50,000 units weekly Ergocalciferol 50,000 units weekly < 10 Severe deficiency 10 - 20 Mild deficiency Cholecalciferol 2000 units daily Ergocalciferol 2000 units daily 21 - 30 Insufficiency Cholecalciferol 1000 units daily Ergocalciferol 1000 units daily Assessing Calcium Levels Adjust Ca levels for in patients with low albumin ( 10.2 mg/dL Non-Calcium based Phosphate Binders Generic name Brand(s) Starting Dose/Frequency Place in therapy Sevelamer carbonate Renvela 800 mg PO TID with meals 1st Line Sevelamer HCl Renagel 800 mg PO TID with meals 1st Line Lanthanum carbonate Fosrenol 750 – 1500 mg PO TID with meals 1st line Aluminum hydroxide Amphojel 300-600 mg PO TID with meals Less favorable Sucroferric Velphoro Oxyhydroxide 500 mg TID with meals Newer drug Ferric Citrate 420 mg TID with meals (Also approved for iron deficiency anemia in non-dialysis patients) Newer drug Auryxia Sevelamer There are 2 formulations o Sevelamer Carbonate (Renvela®) – preferred due to lower risk of acidosis o Sevelamer Hydrochloride (Renagel®) Dosing: 800-1600 mg PO TID with meals o 800 mg of sevelamer ~ 667 mg calcium acetate Aluminum Hydroxide Aluminum hydroxide (ALternaGEL®) and others Very effective but not NOT 1st-line… Short-term use only and/or as an adjunct to other phosphate binders Potential for accumulation and aluminum toxicity o Neuromuscular side effects o GI side effects Management of Secondary Hyperparathyroidism (sHPT) The goal intact PTH levels vary depending on the stage of CKD Patients above their target goal need should be treated with: o Active vitamin D – if the Calcium and Phosphorus are low or within normal range ▪ Calcitriol o Switch to active vitamin D analogs if the Calcium and/ or Phosphate is elevated ▪ Doxercalciferol ▪ Paricalcitol Vitamin D Options for sHPT Generic/Brand(s) Dosage forms Calcitriol [Rocaltrol® (PO) Calcijex® (IV)] Oral IV Active Vitamin D (First-Line) Secondary HPT in all stages of CKD Paricalcitol (Zemplar) Oral IV Analog of Calcitriol Secondary HPT in all stages of CKD Doxercalciferol (Hectorol) Oral IV Analog of Calcitriol Secondary HPT in all stages of CKD Calcifediol (Rayaldee) Oral Analog of Calcidiol Secondary HPT in CKD 3 and 4 only Classification Indication Calcimimetics There are currently 2 FDA approved calcimimetics o Cinacalcet (Sensipar®) o Etelcalcetide (Parsabiv®) Mechanism of Action: Increase the sensitivity of the calcium-sensing receptor (CaSR) on the parathyroid gland, resulting in direct suppression of PTH release o This results in a lowering of serum calcium levels (so caution is recommended) May be used in conjunction with calcitriol or as monotherapy Generic/ Brand Initial dose Cinacalcet (Sensipar®) 30 mg PO daily Etelcalcetide 5 mg (Prasibiv®) IV 3 times a week after dialysis Common Adverse Effects Hypocalcemia Nausea/ Vomiting Diarrhea Hypocalcemia Vomiting Muscle spasms Monitoring for Calcimimetics Calcium, Phosphorus: at baseline and within 1 week of initiation of therapy or dose adjustment; monthly thereafter iPTH: at baseline and then 4 weeks after initiation of therapy and/or dose adjustment, then Q1-3 months Frequency of monitoring and follow up for CKD-MBD CKD Stage Calcium & Phosphorus PTH 25-Hydroxyvitamin D (calcidiol) G3 (a/ b) Q6-12 Months Once, then based on clinical judgement Every 6 months G4 Q3-6 Months Q6-12 Months Every 6 months G5/ 5D Q1-3 Months Q3-6 Months Every 6 months KDIGO 2017 Guidelines CKD-MBD: Targets and Goals CKD Stage Corrected Calcium Phosphorus Intact PTH (iPTH) 3a/b 4 5 Normal Range Normal Range 5D Towards normal range 2- 9 times upper limit of normal KDIGO 2017 Guidelines Note: Corrected Calcium = [0.8 x (4.0 g/dl – Pt Albumin)] + Measured Calcium Other Complications of CKD Hyperkalemia You have covered hyperkalemia in the previous section but here we will address chronic hyperkalemia specifically When eGFR gets below 60ml/min/1.73m2 the kidneys ability to excrete electrolytes like potassium decreases We monitor a BMP monthly in CKD 4-5 and manage electrolyte imbalances Management of Hyperkalemia Dose Mechanism of Action Adverse Effects Sodium polystyrene sulfonate (Kayexalate, Kionex) 15g PO 1-4 times daily OR 30-50 g Rectally Q6H Exchanges Na for K in the large intestine and binds to potassium increasing its elimination in feces and reduction of K concentration in serum Diarrhea, Constipation, Hypernatremia, Hypokalemia Patiromer (Veltassa) 8.4 g PO once daily (Max. 25.2 g/day) Binds potassium in the lumen of the gastrointestinal tract increasing fecal elimination of potassium resulting in a reduction of serum potassium levels Diarrhea, Constipation, Hypokalemia Sodium zirconium cyclosilicate (Lokelmia) Initial dose: 10 g PO TID for 48 hrs, then adjust weekly based on K levels Maintenance: 5 g every other day -15 g once daily (Max. : 15 g/day) Binds and preferentially exchanges potassium for hydrogen and sodium in gastrointestinal lumen, increasing the fecal elimination of K and lowering serum potassium levels Edema, Hypokalemia Metabolic Acidosis Metabolic Acidosis (covered previously) The kidneys play a major role in the body’s buffering system o In CKD this system becomes compromised as the disease progresses On a BMP presents as a HCO3 (or CO2) of < 22 mEq/L o An ABG or VBG can be ordered to confirm acidemia Monitor with BMP every month in CKD 4 and 5 Management of Metabolic Acidosis Already covered in acid-base disorders Due to the chronic nature of the disease we typically use oral medications with buffering capability o Sodium bicarbonate o Sodium citrate/ citric acid (Bicitra) It is important to avoid formulations containing potassium as this can increase the risk of hyperkalemia Other complication, Hypertension (Covered already in previous lecture) Growth impairment (In children) Cardiovascular Disease (You will cover this in PT2)