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Nephrology Patient Cases (Cont’d) 12. A study compared use of an ARB alone and in combination with an ACEI in patients with CKD. Acute kidney injury occurred in 80 of 724 patients (11%) receiving monotherapy and 130 of 724 patients (18%) receiving combination therapy. Given this information, which...

Nephrology Patient Cases (Cont’d) 12. A study compared use of an ARB alone and in combination with an ACEI in patients with CKD. Acute kidney injury occurred in 80 of 724 patients (11%) receiving monotherapy and 130 of 724 patients (18%) receiving combination therapy. Given this information, which most accurately depicts the number of patients needed to harm? A. 7. B. 14. C. 50. D. 105. D. Albuminuria or Proteinuria 1. Marker of kidney damage, progression factor, and cardiovascular risk factor. Can be classified as in Table 5 Table 5. KDIGO Categories of Albuminuria Category A1 A2 A3 Classification ACR (mg/g) < 30 30–300 > 300 Normal to mildly increased Moderately increased Severely increased albuminuria Nephrotic-range proteinuria Daily Excretion (mg/24 hr) < 30 30–300 > 300 > 3000 ACR = albumin/creatinine ratio. 2. Assessment for proteinuria: Usually assessed by measuring urinary ACR. Spot urine: Untimed sample is adequate for adults and children (screening test). A timed (24-hour) urine collection may be used to quantify severe proteinuria. E. Assessment of Kidney Function 1. Serum creatinine (SCr) a. Avoid use as the sole assessment of kidney function. b. Depends on age, sex, weight, and muscle mass c. All laboratories now use “standardized” SCr traceable to isotope dilution mass spectrometry, which decreases variability in results between laboratories. 2. Measurement of GFR: Inulin, iothalamate, and others are very rarely used in clinical practice. 3. Measurement of CrCl through urine collection a. Reserve for vegetarians, patients needing dietary assessment, or those with abnormal muscle mass (e.g., patients with low muscle mass, patients with amputations) or when documenting the need to start or continue dialysis. b. Urine collection yields a better estimate in patients with very low muscle mass. c. In most cases, equations overestimate kidney function because SCr concentrations are low in patients with very low muscle mass. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-274 Nephrology 4. Estimated CrCl using the Cockcroft-Gault equation (mL/minute): Overestimates GFR because of tubular secretion of creatinine CrCl = (140 − age) × body weight (× 0.85 if female) ______________________ SCr × 72 Although actual body weight was used in the original publication, either ideal body weight or adjusted body weight is often used instead. 5. eGFR with MDRD study data equation a.  eGFR (mL/minute/1.73 m2) in patients with known CKD (not accurate in patients with a GFR greater than 60 mL/minute/1.73 m 2 or less accurate in patient populations without kidney disease) b. Isotope dilution mass spectrometry–traceable four-variable MDRD formula correlates well with the original MDRD formula; simpler to use: eGFR (mL/minute/1.73 m2) = 175 × SCr−1.154 × age−0.203 (× 0.742 if female) (× 1.212 if African American) c.  This equation is available at www.niddk.nih.gov/health-information/health-communicationprograms/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-calculators.aspx or www.kidney.org. 6. CKD-EPI equation: Alternative equation based on sex, SCr, serum cystatin C, and age. This equation was updated in 2021 to no longer include race. More accurate than MDRD at GFR values greater than 60 mL/minute/1.73 m2. Available at https://www.kidney.org/professionals/kdoqi/gfr_calculator. 7. For children, use the modified Schwartz “bedside” formula; see https://www.niddk.nih.gov/healthinformation/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/childrenconventional-unit/Pages/default.aspx. F. Diabetic Kidney Disease 1. Pathogenesis a. Hypertension (systemic and intraglomerular) b. Glycosylation of glomerular proteins c. Genetic links 2. Diagnosis a. Long history of diabetes b. Proteinuria c. Retinopathy often coexists, suggestive of microvascular disease. 3. Monitoring a. Type 1 diabetes: Begin annual monitoring for albuminuria 5 years after diagnosis. b. Type 2 diabetes: Begin annual monitoring for albuminuria immediately (do not know how long patient has had diabetes mellitus). c. Monitor albuminuria twice annually if ACR is greater than 300 mg/g and/or estimated eGFR is 30–60 mL/min/1.73 m 2. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-275 Nephrology 4. Management and slowing progression a. Aggressive blood pressure management (Table 6) Table 6. Goal Blood Pressure Readings in Patients with Diabetes a Group ADA 2022 KDIGO 2021 Goal Blood Pressure (maximum) 140/90 mmHga SBP < 120 mmHg ACC/AHA 2017 130/80 mmHg Level of Evidence 2B SBP: B DBP: C Lower blood pressure targets (e.g., < 130/80 mmHg) should be considered in some patients based on anticipated risks and benefits. ACC/AHA = American College of Cardiology/American Heart Association; ADA = American Diabetes Association; DBP = diastolic blood pressure; SBP = systolic blood pressure. i. Either ACEIs or ARBs are preferred and should be used with any degree of proteinuria, even if the patient is not hypertensive. (a) Use moderate to high doses with proteinuria. (b) Hold ACEI or ARB if serum potassium is greater than 5.6 mEq/L or if SCr increases by more than 30% after initiation. Potassium binders such as patiromer or sodium zirconium cyclosilicate can be considered for chronic management of hyperkalemia. (c) Increased risk of hyperkalemia if combined with direct renin inhibitor ii. Most patients will need diuretic in combination (thiazide with stages 1–3 and loop diuretics in stages 4 and 5). Begin a two-drug regimen if blood pressure is greater than 20 mmHg above goal. iii. Calcium channel blockers (nondihydropyridine) are second line to ACEIs and ARBs. Data are emerging for combined therapy. iv. Dietary sodium consumption should be less than 2.4 g/day. Modify the Dietary Approaches to Stop Hypertension (DASH) diet to limit K intake as well. b. Intensive blood glucose control. Glycosylated hemoglobin (A1C) less than 7%. Less aggressive with more advanced CKD i. Consider the use of sodium-glucose cotransporter 2 inhibitors in adults with type 2 diabetes and estimated GFR greater than 25 mL/min/1.73 m 2 and ACR greater than 300 mg/g. c. Protein restriction: Data are insufficient in adults with diabetes, but 0.8 g/kg/day may slightly reduce progression in stage 4 or 5 CKD and decrease the risk of ESRD. Patients should avoid high-protein diets (greater than 1.3 g/kg/day). d. For patients with CKD who are at increased risk for cardiovascular events, progression of CKD, or unable to use a sodium–glucose cotransporter 2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (MRA) is recommended. i. Finerenone is a nonsteroidal MRA indicated to reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in adult patients with CKD associated with type 2 diabetes. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-276 Nephrology G. Nondiabetic Nephropathy 1. Management of hypertension a. 2021 KDIGO Guidelines recommend a goal systolic blood pressure less than 120 mmHg, regardless of severity of albuminuria. b. Initial treatment with ACEI or ARB, but not both (see Table 7) Table 7. KDIGO 2021 Guidelines on Management of Hypertension in CKD Subgroup Severely increased albuminuria (G1–G4, A3) Moderately increased albuminuria (G1–G4, A2) No albuminuria Recommendation Recommend ACEI or ARB Suggest ACEI or ARB ACEI or ARB may be reasonable Level of Evidence 1B 2C c. Combination therapy with thiazide-like diuretics and/or calcium channel blockers may be necessary to achieve blood pressure goals. Avoid combination therapy with direct renin inhibitors. d. ACEI or ARBs should be used at the highest tolerable doses. e. Blood pressure, serum potassium, and SCr should be monitored within 2–4 weeks of initiation or dosage increase. f. Before adjusting ACEI or ARB therapy because of hyperkalemia, attempts should be made to modify dietary potassium intake; discontinue potassium supplements, salt substitutes, or other drugs known to cause hyperkalemia or add potassium-wasting diuretics or oral potassium binders. g. The use of sodium–glucose cotransporter 2 inhibitors may also have a role in nondiabetic nephropathy. Dapagliflozin is indicated as an adjunctive agent for use in CKD in patients with persistently elevated urine albumin-to-creatinine ratio (200–5000 mg/g) who are receiving first line therapies. H. Other Guidelines to Slow Progression 1. Hyperlipidemia a. Assessment i. Newly identified CKD: Recommend evaluation of lipid profile (KDIGO, grade 1C) (Table 8). ii. Follow-up measurement of lipid concentrations not necessary for most patients (not graded) b. Treatment recommendations: Treatment and intensity of therapy is primarily based on ASCVD risk assessment. See Table 8 for 2013 KDIGO recommendations. Table 8. 2013 KDIGO Lipid Treatment Guidelines Target Group Adults ≥ 50 yr, GFR category G1–G2 Adults ≥ 50 yr, GFR category G3a–G5 Adults 18–49 yr with CKD before dialysis or transplant with CAD, diabetes, stroke, or estimated risk of coronary death or MI > 10% Adults on therapy when dialysis initiated Adults with dialysis-dependent CKD Adult kidney transplant recipients Treatment Recommendation Statin Statin or statin/ezetimibe Statin Grade 1B 1A 2A Continue statin or statin/ezetimibe Do not start therapy Statin 2C 2A 2A CAD = coronary artery disease; MI = myocardial infarction. Information from: Wanner C, Tonelli M; KDIGO Lipid Guideline Development Work Group Members. KDIGO clinical practice guideline for lipid management in CKD: summary of recommendation statements and clinical approach to the patient. Kidney Int 2014;85:1303-9. 2. Smoking cessation ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-277 Nephrology Patient Cases 13. A 70-year-old man is being assessed for HD access. He has a history of diabetes mellitus and hypertension but is otherwise healthy. Which HD access modality is best to use in this patient? A. Subclavian catheter. B. Tenckhoff catheter. C. Arteriovenous graft. D. Arteriovenous fistula. 14. A patient undergoing long-term HD has intradialytic hypotension. After nonpharmacologic approaches have been optimized, which medication is best to manage his low blood pressure? A. Levocarnitine. B. Sodium chloride tablets. C. Fludrocortisone. D. Midodrine. 15. A patient with CKD on peritoneal dialysis presents with fever and abdominal pain. She also notes that her peritoneal dialysate has become cloudy. Laboratory evaluation of dialysate reveals many white blood cells, primarily neutrophils. Gram stain and culture of the fluid are ordered. According to the 2016 International Society for Peritoneal Dialysis Peritonitis Recommendations, which is the best empiric therapy for this patient? A. Intravenous metronidazole plus gentamicin. B. Intravenous clindamycin plus vancomycin. C. Cefazolin plus ceftazidime instilled intraperitoneally. D. Vancomycin instilled intraperitoneally. IV. RENAL REPLACEMENT THERAPY A. Indications for RRT 1. A: Acidosis (not responsive to bicarbonate) 2. E: Electrolyte abnormality (hyperkalemia, hyperphosphatemia) 3. I: Intoxication (boric acid, ethylene glycol, lithium, methanol, phenobarbital, salicylate, theophylline) 4. O: Fluid overload (symptomatic [pulmonary edema]) 5. U: Uremia (pericarditis and weight loss) B. Two Primary Modes of Dialysis 1. Hemodialysis: Most common modality in United States 2. Peritoneal dialysis C. Hemodialysis (intermittent for ESRD) 1. Access a. Arteriovenous fistula: Preferred access i. Natural, formed by anastomosis of artery and vein ii. Lowest incidence of infection and thrombosis, lowest cost, longest survival iii. Fistula maturation often takes weeks or months to establish adequate blood flow. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-278 Nephrology b. Arteriovenous graft i. Usually synthetic (polytetrafluoroethylene) ii. Often used in patients with vascular disease c. Catheters i. Commonly used if permanent access unavailable ii. Problems include high infection and thrombosis rates. Low blood flow leads to inadequate dialysis. 2. Dialysis membranes a. Conventional: Not often used anymore. Small pores, smaller surface area b. High flux (large pores) and high efficiency (large surface area). Can remove drugs that were impermeable to standard membranes (vancomycin). Large amounts of fluid removed (ultrafiltrate) 3. Adequacy a.  Kt/V: Unitless parameter. K = clearance, t = time on dialysis, and V = volume of distribution of urea. KDOQI set a minimum of 1.2 (target Kt/V of 1.4). b. URR: Urea reduction ratio. URR = [(preBUN – postBUN)/preBUN] × 100%. Goal URR is greater than 65% (target URR of 70%). 4. Common complications of HD a. Intradialytic i. Hypotension: Related primarily to fluid removal. Common in older adults and in people with diabetes mellitus (a) Acute treatment: Trendelenburg position, decrease ultrafiltration rate; administer saline boluses (b) Prevention: Accurately set “dry weight”; limit fluid gains between sessions; midodrine 2.5–10 mg orally before dialysis (c) Less well-studied agents include fludrocortisone, selective serotonin reuptake inhibitors ii. Cramps: Vitamin E 400 international units at bedtime iii. Nausea and vomiting iv. Headache, chest pain, or back pain b. Vascular access complications: Most common with catheters i.  Infection: Staphylococcus aureus is the most common organism. Need to treat aggressively. May need to remove catheter ii. Thrombosis: Suspected with low blood flow. Oral antiplatelet agents for prevention not used because of lack of efficacy. Can treat with alteplase 2 mg or reteplase 0.4 unit per lumen; allow to dwell and try to aspirate after 30 minutes; may repeat dose if needed 5. Factors that affect the efficiency of HD a. Type of dialyzer used (changes in membrane surface area and pore size) b. Length of therapy c. Dialysis flow rate d. Blood flow rate D. Continuous RRT for Critically Ill Patients with AKI 1. Continuous venovenous hemofiltration (CVVH): Removes fluid and solutes by convection rather than by diffusion a. Drug removal depends on ultrafiltrate production rate and protein binding of drug. Predict drug removal by the sieving coefficient (SC): SC = _______________________________ concentration of drug in ultrafiltrate concentration of drug in blood b. Requires replacement fluid because of high ultrafiltration rate ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-279 Nephrology 2. 3.  ontinuous venovenous hemodialysis (CVVHD): Dialysate flows countercurrent to blood flow, and C solute is removed by diffusion. Continuous venovenous hemodiafiltration (CVVHDF): Ultrafiltration and dialysis; solute is removed by both convection and diffusion. Requires both replacement fluid and dialysate E. Peritoneal Dialysis 1. Peritoneal dialysis membrane is 1–2 m2 (approximates the body surface area) and consists of the vascular wall, the interstitium, the mesothelium, and the adjacent fluid films. 1.5–3 L of peritoneal dialysate fluid may be instilled in the peritoneum (fill) by a catheter, allowed to dwell for a specified time, and then drained. 2. Solutes and fluid diffuse across the peritoneal membrane. 3. Peritoneal dialysis is usually not used to treat AKI in adults. 4. Types of peritoneal dialysis a. Continuous ambulatory peritoneal dialysis: Classic. Requires mechanical process, which requires many manual exchanges throughout the day. Can disrupt daytime routine b. Automated peritoneal dialysis: Many variants exist, but continuous cycling peritoneal dialysis is the most common. Patient undergoes many exchanges during sleep by a cycling machine. May have one or two dwells during day. Minimizes potential contamination. Lowest incidence of peritonitis 5. Complications of peritoneal dialysis a. Peritonitis – Infection of the peritoneal cavity i. Patient technique and population variables influence the infection rate. Older adults or those with diabetes have a higher infection rate. Peritonitis is a main cause of failure of peritoneal dialysis. ii. Diagnosis: At least two of the following: (a) Clinical features consistent with peritonitis (i.e., abdominal pain and/or cloudy dialysis effluent) (b) Dialysis effluent WBC greater than 100/mm3 or greater than 0.1 × 103 cells/m3 (after a dwell time of at least 2 hours) with greater than 50% polymorphonuclear leukocytes (c) Positive dialysis effluent culture (International Society for Peritoneal Dialysis [ISPD] guideline, 1C) iii. Patients on peritoneal dialysis presenting with cloudy effluent can be presumed to have peritonitis and can be treated as such until diagnosis can be confirmed or excluded (ISPD guideline, 1C). iv. Etiologic organisms: Most common gram-positive organisms include Staphylococcus epidermis, S. aureus, and streptococci. Most common gram-negative organisms include Escherichia coli and Pseudomonas aeruginosa. v. Treatment based on ISPD guidelines (a) Empiric treatment should cover gram-positive and gram-negative bacteria. (b) Vancomycin or a first-generation cephalosporin is administered to cover gram-positive organisms, and a third-generation cephalosporin, an aminoglycoside, or aztreonam is added to cover gram-negative organisms. Intraperitoneal administration is preferred unless the patient has another systemic site of infection. (c) Adjust as needed on the basis of culture and sensitivity. b. Catheter exit-site infections i. Recommended that daily topical application of antibiotic (mupirocin or gentamicin) cream or ointment be applied to catheter exit site for prophylaxis. (ISPD guideline, 1B) ii. Prompt treatment of exit-site or catheter tunnel infection is recommended to reduce subsequent peritonitis risk (ISPD guideline, 1C). c. Hyperglycemia d. Fluid overload ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-280 Nephrology e. f. g. Electrolyte abnormalities: Hypercalcemia, hypocalcemia Malnutrition: Hypoalbuminemia Hernia Patient Case Questions 16 and 17 pertain to the following case. A 60-year-old patient on HD has had ESRD for 10 years. His HD access is a left arteriovenous fistula. He has a history of hypertension, coronary artery disease, mild HFrEF, type 2 diabetes, and a seizure disorder. Medications are as follows: epoetin alfa 14,000 units intravenously three times/week at dialysis, a renal multivitamin once daily, atorvastatin 20 mg/day, insulin, calcium acetate 2 tablets three times daily with meals, phenytoin 300 mg/day, and intravenous iron 100 mg/month. Laboratory values are as follows: Hgb 10.2 g/dL, PTH 800 pg/mL, Na 140 mEq/L, K 4.9 mEq/L, SCr 7.0 mg/dL, calcium 9.5 mg/dL, albumin 2.5 g/dL, and phosphorus 7.8 mg/dL. Serum ferritin is 550 ng/mL, and TSAT is 32%. The red blood cell count indices are normal. His WBC is normal, and he is afebrile. 16. Which is most likely contributing to this patient’s relative epoetin resistance? A. Hyperparathyroidism. B. Iron deficiency. C. Phenytoin therapy. D. Infection. 17. I n addition to diet modification and emphasizing adherence, which is best for managing this patient’s hyperparathyroidism? A. Increase calcium acetate. B. Change calcium acetate to sevelamer and add cinacalcet. C. Hold calcium acetate and add intravenous vitamin D analog. D. Add intravenous vitamin D analog. V. MANAGING THE COMPLICATIONS OF CHRONIC KIDNEY DISEASE A. Anemia 1. Several factors are responsible for anemia in CKD: Decreased erythropoietin production (most important), shorter life span of red blood cells, blood loss during dialysis, iron deficiency, anemia of chronic disease, and renal osteodystrophy 2. Prevalence: 26% of patients with a GFR greater than 60 mL/minute/1.73 m2 have anemia, compared with 78% of patients with a GFR less than 15 mL/minute/1.73 m2. 3. Signs and symptoms: Similar to those of anemia associated with other causes 4. Treatment: Treatment of anemia in CKD can decrease morbidity and mortality, reduce left ventricular hypertrophy, increase exercise tolerance, and increase quality of life. 5. Studies suggest that treatment with erythropoiesis-stimulating agents (ESAs) to high Hgb concentrations (greater than 13 g/dL) increases cardiovascular events. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), for example, failed to show a benefit in outcomes, but treatment with ESAs was associated with increased stroke (N Engl J Med 2009;361:2019-32). This supported earlier data from the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial (N Engl J Med 2006;355:2085-98) and the Cardiovascular Risk Reduction by Early Anemia Treatment with epoetin beta (CREATE) trial (N Engl J Med 2006;355:2071-84). ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-281 Nephrology a. Anemia workup: Initiate evaluation when CrCl is less than 60 mL/minute/1.73 m2 or when Hgb is less than 13 g/dL (men) or less than 12 g/dL (women). i. Hgb and Hct monitoring recommendations (Table 9) Table 9. Frequency of hemoglobin (Hgb) and Hematocrit (Hct) monitoring for patients at various stages of CKD Stage of CKD 3 4 and 5 (non-dialysis) 5 (dialysis) Frequency of Monitoring At least annually At least twice per year At least every 3 mo ii. Mean corpuscular volume iii. Reticulocyte count iv. Iron studies (a) TSAT (serum iron/total iron-binding capacity × 100): Assesses available iron (b) Ferritin: Measures stored iron v. Serum vitamin B12 and folate concentrations vi. Stool guaiac Figure 1. Management of anemia of CKD according to KDIGO and KDOQI guidelines. CKD = chronic kidney disease; ESA = erythropoiesis-stimulating agent; Fe = iron; Hb = hemoglobin; RBC = red blood cell; TIBC = total iron-binding capacity. b. ESAs i. Initiation (a) Patients with CKD (non-dialysis): Not to be initiated if Hgb is greater than 10 g/dL unless symptomatic. If Hgb is less than 10 g/dL, consider the rate of decline in Hgb and the need to reduce the likelihood of transfusion (particularly in patients who may receive a renal transplant). ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-282 Nephrology (b) Patients with CKD (dialysis): Initiate therapy for Hgb less than 10 g/dL (KDIGO guidelines recommend avoiding an Hgb decrease below 9 g/dL) (c) Use with caution, if at all, in patients with a history of stroke or cancer (evidence for increased risk of stroke is stronger in patients with nondialysis-dependent CKD compared with the risk in patients on dialysis.). (d) Iron stores should be replaced before initiating ESAs. (e)  Additional contraindications include uncontrolled hypertension and hypersensitivity reactions. ii. Maintenance of ESAs: Individualize dosing, and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions; adjust dosing as appropriate. iii. Epoetin alfa (Epogen, Procrit) (a) Same molecular structure as human erythropoietin (recombinant DNA technology) (b) Binds to and activates erythropoietin receptor (c) Administered subcutaneously or intravenously (d) Starting dose: 50–100 units/kg three times per week (e) Subcutaneous dosage requirement is typically 30% less than intravenous dosage requirement. iv. Darbepoetin alfa (Aranesp) (a) Molecular structure of human erythropoietin has been modified from 3 N-linked carbohydrate chains to 5 N-linked carbohydrate chains; increased duration of activity (b) The advantage is less-frequent dosing (e.g., once weekly, once every 2–3 weeks). (c) Starting dose: (1) Non-dialysis CKD: 0.45 mcg/kg once every 4 weeks (2) Dialysis CKD: 0.45 mcg/kg once per week or 0.75 mcg/kg every 2 weeks (d) Binds to and activates erythropoietin receptor (e) May be administered subcutaneously or intravenously v. Methoxy polyethylene glycol-epoetin beta (Mircera) (a) Molecular structure of human erythropoietin has been modified through the formation of a chemical bond with methoxyl polyethylene glycol butanoic acid; increased duration of action (b) Onset of Hgb increase occurs 7–15 days after initial dose. (c) Less-frequent dosing; initial dose 0.6 mcg/kg body weight once every 2 weeks (d) Once Hgb stabilizes, can double the dose and administer once monthly (e) Binds to and activates erythropoietin receptor (f) May be administered subcutaneously or intravenously c. Therapy goals i. Use the lowest possible dose of ESA to prevent blood transfusion. ii. In non-dialysis patients with CKD, hold or reduce the dose when Hgb is greater than 10 g/dL. iii. In dialysis patients, hold or reduce the dose when Hgb is greater than 11 g/dL (KDIGO suggests an upper limit of 11.5 g/dL). iv. Do not exceed an Hgb greater than 13 g/dL. d. ESA dose adjustment is based on Hgb response. i. Adjustment parameters are similar for epoetin alfa and darbepoetin alfa. ii. Maximal increase in Hgb is about 1 g/dL every 2–4 weeks. iii. Dosages should not be titrated more often than every 4 weeks. iv. In general, dose adjustments are made in 25% increments (i.e., dosages titrated or tapered by 25% according to current dose). ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-283 Nephrology e. ESA monitoring (Table 10) i. Hgb every 2–4 weeks during initiation phase. In maintenance phase of therapy, monitor Hgb at least monthly in dialysis patients and at least every 3 months in non-dialysis patients with CKD. ii. Monitor blood pressure because it may rise (treat as necessary). iii. Iron stores Table 10. KDOQI and KDIGO Iron Status Goals Laboratory Value TSAT Ferritin KDOQI > 20% > 100 ng/mL (non-dialysis CKD; PD) KDIGO > 30% > 500 ng/mL > 200 ng/mL (HD CKD) HD = hemodialysis; PD = peritoneal dialysis. Information from: KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target; Am J Kidney Dis 2007;50:471-530. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl 2012;2:279. f. Common causes of inadequate response to ESA therapy i. Iron deficiency is the most common cause of erythropoietin resistance; however, increased use of intravenous iron products has reduced this problem. ii. Infection and inflammation iii. Other causes include chronic blood loss, hyperparathyroidism, aluminum toxicity, folate or vitamin B12 deficiency, malignancies, malnutrition, hemolysis, and vitamin C deficiency. g. Iron therapy i. Oral iron is not recommended in patients with CKD on dialysis, but a 1- to 3-month trial may be done in predialysis patients with CKD requiring iron therapy. ii. Ferric citrate is FDA approved as a phosphate binder and may be useful for oral iron supplementation in patients with CKD not requiring dialysis. iii. Most patients with CKD who are receiving ESAs need parenteral iron therapy (increased requirements, decreased oral absorption). iv. For adult patients who undergo dialysis, an empiric cumulative or total dose of 1000 mg is usually given, and equations are rarely used. v. Monitor TSAT and ferritin as noted every 3 months. vi. Adverse effects (a) Anaphylactic-type reactions with iron dextran necessitate test dose. Hypersensitivity reaction may occur with all parenteral iron products. (b) Hypotension with administration of sodium ferric gluconate, iron sucrose, and ferumoxytol. Monitor during and up to 30 minutes after administration. (c) Hypertension. Transient increases in blood pressure occur with ferric carboxymaltose. (d) Bloodstream or other serious infections may be worsened by intravenous iron. In these circumstances, it may be appropriate to administer an ESA without repleting iron. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-284 Nephrology vii. Seven commercial parenteral iron preparations are approved in the United States (Table 11). Table 11. Parenteral Iron Therapy Iron Product Iron dextran (high-molecular-weight iron dextran: Dexferrum) (low-molecular-weight iron dextran: INFeD) Sodium ferric gluconate complex (Ferrlecit and generic) Iron sucrose (Venofer) Ferumoxytol (Feraheme) Ferric carboxymaltose (Injectafer) Replacement Therapy (TSAT < 30% and ferritin < 500 ng/mL) 100 mg IV three times/wk during HD × 10 doses (1 g) Maintenance Therapy (iron stores in goal) 25–100 mg/wk IV × 10 wk Initial Test Dose Yes; 25 mg one-time test dose 125 mg IV three times/wk during HD × 8 doses (1 g) 31.25–125 mg/wk IV × 10 wk None needed 100 mg IV three times/wk during HD × 10 doses (1 g) For non-HD CKD, 200 mg IV × 5 doses 25–100 mg/wk IV × 10 wk None needed 510 mg at up to 30 mg/s, followed by a second 510-mg IV dose 3–8 days later (all CKD) 15 mg/kg IV up to 750 mg; may repeat after at least 7 days (maximum 1500 mg of elemental iron per two-dose course) N/A None needed N/A None needed IV = intravenous(ly); N/A = not applicable; NS = normal saline solution. B. CKD–Mineral and Bone Disorder (CKD-MBD) 1. Pathophysiology: Calcium and phosphorus homeostasis is complex, involving the interplay of hormones affecting the bone, gastrointestinal (GI) tract, kidneys, and parathyroid gland. The process may begin as GFR decreases to less than 60 mL/minute/1.73 m 2. The consequences of CKD-MBD include renal osteodystrophy and vascular calcification. Factors contributing to CKD-MBD include the following: a. Hyperphosphatemia b. Decreased production of 1,25-dihydroxyvitamin D3 c. Reduced absorption of calcium in the gut d. Decreased ionized (free) calcium concentrations e. Direct stimulation of parathyroid hormone (PTH) secretion f. Elevated PTH concentrations cause decreased reabsorption of phosphorus and increased reabsorption of calcium in the proximal tubule. This adaptive mechanism is lost as GFR decreases below 30 mL/minute/1.73 m2. Important: Calcium is not well absorbed through the gut at this point, and calcium concentrations are maintained by increased bone resorption through elevated PTH. Unabated calcium loss from the bone results in renal osteodystrophy. 2. Prevalence a. Main cause of morbidity and mortality in patients undergoing dialysis b. Very common 3. Signs and symptoms a. Insidious onset: Patients may experience fatigue and musculoskeletal and GI pain; calcification may be visible on radiography; bone pain and fractures can occur if progression is left untreated. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-285