Nephrology PDF

Nephrology b. Laboratory abnormalities (Table 12) i. Phosphorus ii. Corrected calcium (measured calcium + 0.8[4 – serum albumin]) iii. Parthyroid hormone (PTH) iv. Alkaline phosphatase v. 25-hydroxyvitamin D Table 12. KDIGO Guidelines for Frequency of Laboratory Monitoring...

Nephrology b. Laboratory abnormalities (Table 12) i. Phosphorus ii. Corrected calcium (measured calcium + 0.8[4 – serum albumin]) iii. Parthyroid hormone (PTH) iv. Alkaline phosphatase v. 25-hydroxyvitamin D Table 12. KDIGO Guidelines for Frequency of Laboratory Monitoring in Stage 3–5 CKDa Calcium Phosphorus PTH Alkaline phosphatase 25-hydroxyvitamin D G3a–G3b CKD G4 CKD G5–G5D CKD Every 6–12 mo Every 6–12 mo Baselineb Baseline Baseline Every 3–6 mo Every 3–6 mo Every 6–12 mo Every 12 moc,d Baseline Every 1–3 mo Every 1–3 mo Every 3–6 mo Every 12 moc,d Baseline More frequent monitoring may be needed in patients receiving treatment. Subsequent frequency based on baseline concentration and CKD progression. c May be monitored more often in the presence of elevated PTH. d Repeat testing may be determined by baseline value and treatments. G5D = G5 on dialysis; PTH = parathyroid hormone. a b c. Diagnostic testing i. Bone mineral density testing: Suggested for patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis if results will affect treatment decisions (KDIGO 2017, grade 2B) ii. Bone biopsy: Reasonable if knowledge of type of renal osteodystrophy will affect treatment decisions (KDIGO 2017, not graded) 4. Treatment should be based on serial assessments of phosphate, calcium, and PTH concentrations, considered together (KDIGO 2017, not graded). a. Therapy goals for patients with CKD G3a–G5D i. Suggest lowering phosphate concentrations toward normal range (KDIGO 2017, grade 2C) ii. In adults, suggest avoiding hypercalcemia (KDIGO 2017, grade 2C) iii. In patients with CKD G3a–G5 not on dialysis, evaluate for modifiable causes in patients with PTH progressively rising or persistently above the upper normal limit (KDIGO 2017, grade 2C). iv. In patients with CKD G5D, suggest maintaining PTH concentrations 2–9 times the upper normal limits. Marked changes in either direction should prompt initiation of or change in therapy (KDIGO 2017, grade 2C). b. Nondrug therapy i. Dietary phosphorus restriction 800–1000 mg/day in CKD category G3 or higher, alone or in combination with other treatments (KDIGO 2017, grade 2D). Reasonable to consider phosphate source in making dietary recommendations (KDIGO 2017, not graded) ii. Dialysis removes various amounts of phosphorus, depending on treatment modalities; however, by itself, dialysis is insufficient to maintain phosphorus balances in most patients. iii. Parathyroidectomy: Reserved for patients with unresponsive hyperparathyroidism ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-286 Nephrology c. Phosphate binders: Take with each meal to bind phosphorous in the gut; products from different groups may be used together for additive effect (Table 13). Table 13. Phosphate Bindersa Product Calcium carbonate Calcium acetate (PhosLo, Phoslyra) Sevelamer hydrochloride (Renagel) Sevelamer carbonate (Renvela) Lanthanum carbonate (Fosrenol) Aluminum hydroxide Ferric citrate (Auryxia) Dosage Form 500, 1000, 1250 mg (40% elemental calcium) 667-mg capsule, tablet 667 mg/5 mL solution (25% elemental calcium) 400-, 800-mg tablet Typical Mealtime Dose 1250 mg 800-mg tablet 0.8-g, 2.4-g packet 500-, 750-, 1000-mg chewable tablet 800–2400 mg 320 mg/5 mL suspension 1 g (210 mg of ferric ion) tablet 300–600 mg 2 g (420 mg of ferric ion) 2001 mg 800–2400 mg 250–500 mg Typical dose is administered three times daily with meals. a i. Decisions about phosphate-lowering treatment should be based on progressively or persistently elevated serum phosphate (KDIGO 2017, not graded). ii. Calcium-containing binders are often the initial phosphate binder for stage 3 and 4 CKD. Either calcium-containing or nonionic binders can be the initial binder of choice in stage 5 CKD. No data analyses suggest that any phosphate binder is superior to another in clinical outcomes (mortality or hospitalization). In adult patients, suggest restricting the dose of calcium-based phosphate binders (KDIGO 2017, grade 2B) iii. Aluminum-containing phosphate binders (aluminum hydroxide, aluminum carbonate, and sucralfate) effectively lower phosphorus concentrations. In general, avoid long-term use (grade 1C). Not used as often because of aluminum toxicity (adynamic bone disease, encephalopathy, and erythropoietin resistance). Caution in patients with AKI due to the potential for aluminum toxicity. Use should be limited to a single short-term (4 week) course. iv. Calcium-containing phosphate binders (calcium carbonate and calcium acetate) (a) Widely used phosphate binder. Carbonate salt is inexpensive. (b) Carbonate is also used to treat hypocalcemia, which sometimes occurs in patients with CKD, and can decrease metabolic acidosis. (c) Calcium acetate is a better binder than carbonate and contains less elemental calcium. Less calcium absorption (d) Use may be limited by development of hypercalcemia; consider reducing dose or discontinuing even in the absence of hypercalcemia because of increased harm. (e) Total elemental calcium is 2000 mg/day (1500-mg binder; 500-mg diet). v. Sevelamer: A nonabsorbable phosphate binder (a) Effectively binds dietary phosphorus (b) As with calcium, considered primary therapy in stage 5 CKD. In particular, consider whether the patient has hypercalcemia or whether calcium intake exceeds the recommended dose with calcium-containing binders. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-287 Nephrology (c)  Decreases low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol. (d) Metabolic acidosis may worsen with sevelamer hydrochloride, sevelamer carbonate preferred. vi. Lanthanum carbonate (a) As effective as aluminum in phosphate-binding capability. Not widely used, but indications similar to sevelamer (b) Flavorless, chewable tablet (c) Consider using if patient has hypercalcemia vii. Ferric citrate: Iron-based phosphate binder (a) 1 g of ferric citrate contains 210 mg of ferric ion. (b) Initial dose: 2 tablets (420 mg ferric ion) three times daily with meals (c) GI adverse effects and potential drug interactions similar to other oral iron preparations viii. Sucroferric oxyhydroxide: Iron-based phosphate binder (a) Initial dose: 500 mg three times daily with meals (b) Tablet must be chewed. (c) GI adverse effects and potential drug interactions similar to other oral iron preparations d. Vitamin D and vitamin D analogs: Suppress PTH synthesis and reduce PTH concentrations; therapy is limited by resultant hypercalcemia i. In adults with CKD G3a–G5, routine use of calcitriol and vitamin D analogs is not suggested (KDIGO 2017, grade 2C). Reasonable to reserve for patients with CKD G4–G5 with severe and progressive hyperparathyroidism (not graded) ii.  Ergocalciferol (vitamin D2): Inactive form of vitamin D. May be used in stage 3 or 4 CKD for patients with low serum 25-hydroxyvitamin D concentrations; repeat vitamin D concentrations after 6 months of therapy. Usually doses weekly or monthly (Table 14) iii.  Cholecalciferol (vitamin D3): Inactive vitamin D. May be used as alternative to ergocalciferol. Usually dosed daily iv.  Calcifediol (25-hydroxyvitamin D3): Undergoes 1-α-hydroxylation to calcitriol. May be used in patients with stage 3 or 4 CKD as alternative to ergocalciferol Table 14. Ergocalciferol Repletion Serum 25-Hydroxyvitamin D (ng/mL) <5 Assessment Dosing Regimen Severe deficiency Weekly oral doses × 12 wk, then monthly or Single intramuscular dose 5–15 Mild deficiency 16–30 Insufficiency Weekly oral doses × 4 wk, then monthly Monthly oral doses v. Calcitriol (Calcijex, Rocaltrol): The pharmacologically active form of 1,25-dihydroxyvitamin D3 is FDA label approved for managing hypocalcemia and preventing and treating secondary hyperparathyroidism. (1) Oral and parenteral formulations (2) Does not require hepatic or renal activation (3) Low-dose daily oral therapy reduces hypocalcemia but does not significantly reduce PTH concentrations. (4) High incidence of hypercalcemia, limiting PTH suppression (5) Dose adjustment at 4-week intervals ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-288 Nephrology vi. Paricalcitol (Zemplar): Vitamin D analog; FDA label approved for the treatment and prevention of secondary hyperparathyroidism (1) Parenteral and oral formulations (2) Does not require hepatic or renal activation (3) Lower incidence of hypercalcemia than with calcitriol (decreased mobilization of calcium from the bone and decreased absorption of calcium from the gut) vii. Doxercalciferol (Hectorol): Vitamin D analog; FDA label approved for the treatment and prevention of secondary hyperparathyroidism (1) Parenteral and oral formulations (2) Prodrug; requires hepatic activation; may have more physiologic concentrations (3) Lower incidence of hypercalcemia than with calcitriol (decreased mobilization of calcium from the bone and decreased absorption of calcium from the gut) e. Calcimimetics: Indicated for secondary hyperparathyroidism, especially in patients with high calcium and phosphate concentrations when vitamin D analogs cannot be used or cannot be increased i. Cinacalcet hydrochloride (Sensipar): A calcimimetic that attaches to the calcium receptor on the parathyroid gland and increases the sensitivity of receptors to serum calcium concentrations, thus reducing PTH (1) Initial dose is 30 mg by mouth once daily, irrespective of PTH concentration. (2) Monitor serum calcium within 1 week after starting therapy or increasing the dose (risk of hypocalcemia is about 5%); do not initiate therapy if corrected serum calcium is less than 8.4 mg/dL. (3) Monitor PTH (at least 12 hours post-dose) 1–4 weeks after initiating or adjusting therapy. (4) Can be used in patients irrespective of phosphate binder or vitamin D analog use (5) Caution in patients with seizure disorder (hypocalcemia may exacerbate) (6) Adverse effects are nausea (30%) and diarrhea (20%). (7) Cinacalcet inhibits cytochrome P450 (CYP) 2D6 metabolism, thereby inhibiting the metabolism of CYP2D6 substrates such that dose reductions in drugs with narrow therapeutic indices may be required (e.g., flecainide, tricyclic antidepressants, thioridazine). (8) Cinacalcet is metabolized primarily by CYP3A, so drugs that are potent inhibitors of CYP3A (ketoconazole) may increase cinacalcet concentrations by up to 2-fold. ii. Etelcalcetide (Parsabiv): A synthetic peptide calcimimetic that activates the calcium-sensing receptor on the parathyroid gland, thus reducing PTH (1) Initial dose is 5 mg intravenously three times per week after HD. (2) Dose can be titrated in 2.5- to 5-mg increments at intervals of at least every 4 weeks. (3) If doses are missed for more than 2 weeks, reinitiate therapy at 5 mg three times per week. (4) Monitor corrected serum calcium before initiation and 1 week after initiation or dose adjustment. Once the dose is stabilized, monitor serum calcium every 4 weeks. (5) Monitor serum PTH before initiation and 4 weeks after initiation or dose adjustment. (6) Adverse effects include hypocalcemia, nausea, diarrhea, QT prolongation; may worsen heart failure (7) Use with caution in patients with seizure disorder (hypocalcemia may exacerbate). (8) Discontinue cinacalcet for at least 7 days before initiating etelcacetide, and discontinue etelcalcetide for 4 weeks before initiating cinacalcet.. f. Osteoporosis treatment i. CKD category G1–G2 with osteoporosis and/or high risk of fracture, manage as for the general population (KDIGO 2017, grade 1A) ii. CKD category G3a–G3b with normal PTH and osteoporosis and/or high risk of fracture, suggest treatment as for the general population (KDIGO 2017, grade 2B) ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-289 Nephrology iii. CKD category G3a–G5D with biochemical abnormalities of CKD-MBD and low bone mineral density and/or fragility fractures, treatment choices consider the magnitude and reversibility of biochemical abnormalities and progression of CKD, with consideration of a bone biopsy (KDIGO 2017, grade 2D) Patient Case 18. A 40-year-old patient on dialysis with a history of grand mal seizures takes phenytoin 300 mg/day. His albumin concentration is 3.0 g/dL. His total phenytoin concentration is 5.0 mcg/mL. Which best interprets the phenytoin concentrations? A. Subtherapeutic; a dose increase is needed. B. Therapeutic; no dosage adjustment is needed. C. Toxic; a dose reduction is needed. D. Not interpretable. VI. DOSAGE ADJUSTMENTS IN KIDNEY DISEASE A. The dosages of many drugs will require adjustment to prevent toxicity in patients with CKD. Adjustment strategies vary depending on whether the patient is receiving RRT and, if so, which type. The National Kidney Disease Education Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases suggests that either eGFR or eCrCl be used for drug dosing. If eGFR is used in very large or small patients, it should be multiplied by the actual body surface area to obtain eGFR in milliliters per minute. B. Pharmacokinetic Principles Guiding Therapy Adjustments 1. Absorption: Oral absorption can be decreased. a. Nausea and vomiting b. Increased gastric pH (uremia) c. Edema d. Physical binding of drugs to phosphate binders 2. Distribution a. Changes in concentrations in highly water-soluble drugs occur as extracellular fluid status changes. b. Acidic and neutral protein-bound drugs are displaced by toxin buildup. Other mechanisms include conformational changes of the plasma protein–binding site. Phenytoin is a classic example. The “normal” free fraction of phenytoin is 10%. Free fraction can be as high as 30% in patients with ESRD and hypoalbuminemia. Metabolic acidosis also increases dissociation of phenytoin from protein-binding sites. i. Hypoalbuminemia correction: concentration adjusted = concentration measured/[(0.2 × measured albumin) + 0.1] ii. Renal failure adjustment: concentration adjusted = concentration measured/[(0.1 × measured albumin) + 0.1] iii. Patients have lower total concentrations despite having adequate free concentrations (increased free fraction). iv. Empiric dosage adjustments are usually not needed for phenytoin in patients with kidney disease. However, interpretation of serum phenytoin concentrations should consider alterations in plasma protein binding. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-290 Nephrology 3. 4. Metabolism: Variable changes can occur with uremia; metabolites can accumulate. Excretion: Decreased C. Pharmacodynamic changes can also occur (e.g., patients with CKD can be more sensitive to benzodiazepines). D. General Recommendations 1. Patient history and clinical data 2. Estimate CrCl (Jelliffe or Brater equation in AKI; Cockcroft-Gault or MDRD study equations in stable kidney function). 3. Identify medications that require modification (Table 15). Table 15. Dose Adjustments and Precautions in Decreased Kidney Function Drug Class Antibiotics Anticoagulants Cardiac medications Lipid-lowering therapy Narcotics Antipsychotic and antiepileptic agents Hypoglycemic agents Antiretrovirals a Agents Requiring Dose Adjustment Almost all antibiotics require dosage adjustment (exceptions: ceftriaxone, clindamycin, linezolid, metronidazole, macrolides, nafcillina) Enoxaparin, fondaparinux, apixaban, rivaroxaban, edoxaban, dabigatran Atenolol, ACEIs, digoxin, nadolol, sotalol; avoid potassium-sparing diuretics if CrCl < 30 mL/min/1.73 m2 Clofibrate, fenofibrate, statins (particularly rosuvastatin) Codeine, use caution with meperidine and morphine; other agents may also accumulate Chloral hydrate, gabapentin, lacosamide, levetiracetam, lithium, paroxetine, primidone, topiramate, trazodone, vigabatrin Acarbose, alogliptin, canagliflozin, chlorpropamide, dapagliflozin, exenatide, glyburide, glipizide, insulins, liraglutide, metformin, saxagliptin, sitagliptin Individualize therapy: Monitor CD4+ counts, viral load, and adverse effects (agents requiring dose adjustment: lamivudine, adefovir, emtricitabine, didanosine, stavudine, tenofovir, and zidovudine) Nafcillin requires dosage adjustment with concomitant renal and liver failure 4. Calculate drug doses individualized for the patient. a. Published data b. Rowland-Tozer estimate i. Q = 1 − [Fe(1 − KF)] ii. Q = kinetic parameter or drug dose adjustment factor iii. Fe = fraction of drug excreted unchanged in the urine iv. KF = ratio of patient’s CrCl to normal (120 mL/minute/1.73 m 2) 5. Monitor patient (e.g., kidney function, clinical parameters) and drug concentration (if applicable). 6. Revise regimen as appropriate. E. Drug Dosing in HD 1. Dosing changes in patients with HD may be necessary because of accumulation caused by kidney failure or because the procedure may remove the drug from the circulation or because of pharmacodynamic effects (e.g., blood pressure medication reduction because of intradialytic hypotension). 2. Drug-related factors affecting drug removal during dialysis a. Molecular weight: With high-flux membranes, larger molecules (e.g., vancomycin) can be removed compared with conventional filters. b. Water soluble: Insoluble drugs are not likely to be removed. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-291 Nephrology 3. c. Protein binding: Because albumin cannot pass through membranes, protein-bound drugs cannot pass through either. d. Volume of distribution: Drugs with a small volume of distribution (less than 1 L/kg) available in central circulation for removal. Large volumes of distribution cannot be removed (digoxin and tricyclic antidepressants), even if the protein binding is very low. Procedure-related factors affecting drug removal a. Type of dialyzer: High flux, widely used now b. Blood flow rate: Elevated rates increase delivery and maintain gradient across membrane. c. Duration of dialysis session d. Dialysate flow rate. High rates of flow increase removal by maintaining the gradient across membranes. Special Acknowledgment: ACCP gratefully acknowledges the contribution of previous chapter author, Dr. John M. Burke. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-292