Therapeutics of Complications Chronic Renal Failure and Renal Replacement (51-52)

What are the main indications for starting dialysis according to the lecture?

Plan for dialysis when eGFR is <30 mL/min/1.73 m²; discuss benefits/risks when GFR is <15; actual initiation is primarily based on clinical status and persistent symptoms, usually around eGFR 5–10. Symptoms include anorexia, N/V, weight loss, fatigue, declining serum albumin, uncontrolled HTN/CHF, neurologic deficits, and pruritus.

What is hemodialysis (HD)?

HD passes blood and a physiologic salt solution on opposite sides of a semipermeable membrane so uremic toxins, drugs, water, urea, creatinine, etc. can move between them by diffusion and convection.

What is diffusion in dialysis?

Diffusion is movement of a substance from an area of HIGH concentration to an area of LOW concentration across the semipermeable membrane.

What is convection/ultrafiltration in dialysis?

Convection/ultrafiltration moves water across the dialysis membrane because of a pressure gradient; solutes can be dragged along with the water. It is especially important for removing excess fluid.

What factors increase dialysis clearance/removal?

Higher blood flow rate, higher dialysate flow rate, longer dialysis duration, and membranes with greater permeability/high-flux membranes increase removal.

How does a high-flux dialyzer differ from a conventional dialyzer?

High-flux membranes have larger pores/surface area and can remove larger molecules and more fluid than conventional membranes. They can remove drugs such as vancomycin more effectively.

What are the common vascular accesses for hemodialysis?

AV fistula, AV graft, and venous catheter. An AV fistula has the lowest infection/thrombosis risk and longest survival but requires time to mature; a graft matures faster; a catheter can be used immediately but has the highest infection and thrombosis risk.

What is the usual conventional hemodialysis schedule?

Conventional HD is generally 3 times/week for about 3–5 hours per treatment. Daily shorter treatments and long slow nocturnal treatments are also options discussed in the lecture.

What is peritoneal dialysis (PD)?

PD uses the patient's peritoneal membrane as the semipermeable membrane. Dialysate is placed into the peritoneal cavity, allowed to dwell, and then drained.

What are the two major types of peritoneal dialysis?

CAPD (continuous ambulatory peritoneal dialysis) and APD (automated peritoneal dialysis).

How do dextrose and icodextrin work in peritoneal dialysis?

Dextrose solutions create hyperosmolarity and draw water by crystalloid osmosis, but dextrose can be absorbed and is cytotoxic. Icodextrin is a starch-derived glucose polymer that creates colloidal osmosis and provides ultrafiltration during long dwells with fewer metabolic effects.

What are common complications of peritoneal dialysis?

Mechanical problems such as catheter kinking/movement and inflow pain; medical problems such as increased adipose tissue, decreased appetite, and fibrin formation; and infections such as peritonitis and catheter-related infections.

What characteristics make a drug easy to remove by dialysis?

A drug is efficiently removed when it has LOW molecular weight, is WATER-SOLUBLE, has LOW protein binding, and has a LOW volume of distribution.

How does molecular weight affect dialysis drug removal?

As molecular weight increases, dialysis removal generally decreases. High-flux membranes can remove larger molecules than conventional membranes.

How does water solubility affect dialysis drug removal?

Water-soluble drugs are removed more efficiently by dialysis.

How does protein binding affect dialysis drug removal?

Highly protein-bound drugs are removed less efficiently because only the unbound drug can readily cross the dialysis membrane.

How does volume of distribution affect dialysis drug removal?

A higher volume of distribution decreases dialysis removal because more drug is distributed into tissues rather than remaining in the blood. A large Vd is arbitrarily defined as >0.7 L/kg and is the most important determinant of drug removal.

When do dialysis parameters increase drug removal?

High-flux membranes, increased blood flow, increased dialysate flow, and longer dialysis duration all increase drug removal.

How should drug dosing generally be handled around dialysis?

Loading and maintenance doses may need adjustment. Maintenance doses are generally given AFTER dialysis because dialysis can remove the drug.

When might a drug with high dialysis clearance NOT need to be redosed after dialysis?

If the drug has a high volume of distribution, much of the drug is already in tissues and may not have been significantly removed despite high dialysis clearance.

What defines anemia of CKD in the lecture?

Hemoglobin <13.5 g/dL in adult males or <12 g/dL in adult females.

What is the most important cause of anemia in CKD?

Decreased erythropoietin production by the diseased kidneys.

What are other causes of anemia in CKD?

Blood loss from dialysis/labs, iron deficiency, folate/B12 deficiency, shortened RBC lifespan from uremia, anemia of chronic disease, and renal osteodystrophy.

What type of anemia is usually seen in CKD?

Usually normocytic and normochromic unless iron, B12, or folate deficiency is also present.

When is anemia of CKD most common?

It can occur at any stage but is most common when GFR is <60 mL/min/1.73 m²; in diabetes it tends to occur earlier and be more severe.

How is anemia of CKD monitored?

Screen annually in all CKD patients and more frequently when GFR is <60 or the patient has diabetes. Evaluate Hgb/Hct, MCV, reticulocyte count, stool guaiac, Tsat, and ferritin.

What is the target hemoglobin for ESA therapy in CKD?

10–11.5 g/dL. The goal is the lowest ESA dose needed to prevent transfusion, generally keeping Hgb <11 g/dL.

Why should hemoglobin generally NOT be pushed above 11.5 g/dL with ESAs?

Higher hemoglobin targets are associated with cardiovascular events, stroke, heart failure, and death and carry a black-box warning.

What are the target iron indices in CKD?

Tsat should be >20%. Ferritin should be >100 ng/mL in stage 4 CKD/PD and >200 ng/mL in hemodialysis patients.

What are the three ESAs covered in the lecture?

Epoetin alfa, darbepoetin alfa, and methoxy-PEG-epoetin beta.

How do epoetin alfa, darbepoetin alfa, and methoxy-PEG-epoetin beta differ?

Darbepoetin has a longer half-life than epoetin and therefore requires less frequent dosing. Methoxy-PEG-epoetin beta has an even longer half-life and can be dosed less frequently.

What is the half-life of epoetin alfa?

Approximately 10 hours IV and 20 hours subcutaneous.

What is the half-life of darbepoetin alfa?

Approximately 25.3 hours IV and 48.8 hours subcutaneous.

What is the half-life of methoxy-PEG-epoetin beta?

Approximately 119 hours IV and 124 hours subcutaneous.

What is the usual epoetin alfa dose in hemodialysis?

50–100 units/kg IV or SC 3 times weekly; IV is preferred in HD.

What is the usual epoetin alfa dose in nondialysis/early CKD?

Approximately 75–150 units/kg weekly; subcutaneous administration is preferred.

What is the usual darbepoetin alfa dose in hemodialysis?

0.45 mcg/kg weekly IV or SC.

What is the usual darbepoetin alfa dose in nondialysis CKD?

0.75 mcg/kg every 2 weeks.

What is the usual methoxy-PEG-epoetin beta dose?

0.6 mcg/kg every 2 weeks, then 1.2 mcg/kg monthly once stable.

How should ESA therapy be adjusted when hemoglobin rises too quickly or approaches the target?

Decrease the ESA dose by about 25% when Hgb approaches 11 g/dL or rises >1 g/dL in any 2-week period.

How should ESA therapy be adjusted when hemoglobin does not respond?

If Hgb does not rise by about 1 g/dL after 4 weeks, increase the ESA dose by about 25%. Dose adjustments should generally not occur more often than every 2–4 weeks.

What are the major adverse effects of ESAs?

Hypertension is the most common; other important effects include vascular access thrombosis, seizures, and pure red blood cell aplasia (PRCA).

What is pure red blood cell aplasia (PRCA) from ESA therapy?

PRCA is antibody-mediated resistance to ESA therapy that causes severe reduction in RBC production and may require intermittent blood transfusions.

Which ESA administration is particularly associated with PRCA?

Subcutaneous epoetin alfa, historically associated with the formulation/excipients and rubber stopper.

When should PRCA be suspected?

Suspect it with a rapid fall in Hgb of about 0.5–1 g/dL/week or the need for 1–2 RBC transfusions despite normal WBC/platelets and an absolute reticulocyte count <10,000.

What is ESA hyporesponsiveness?

It is an inadequate increase in hemoglobin despite ESA therapy.

What is the most common cause of ESA hyporesponsiveness?

IRON DEFICIENCY—even when ferritin may appear normal.

What other conditions can cause ESA hyporesponsiveness?

Infection/inflammation, chronic blood loss, osteitis fibrosa/bone disease, aluminum toxicity, hemoglobinopathies, folate/B12 deficiency, multiple myeloma, malnutrition, hemolysis, and vitamin C deficiency.

Which iron labs should be checked when ESA response is inadequate?

Ferritin and Tsat should be checked. The lecture targets Tsat >20% and ferritin >100 ng/mL in stage 4/PD and >200 ng/mL in HD.

When is oral iron generally used in CKD?

Oral iron can be used in early CKD and peritoneal dialysis. The lecture notes at least about 200 mg elemental iron/day.

What are common adverse effects of oral iron?

Constipation, nausea, and abdominal cramps. Take on an empty stomach when possible, but taking with food can improve tolerance.

Why is parenteral iron commonly used in patients receiving ESAs?

Parenteral iron improves ESA responsiveness and reduces the ESA dose required to achieve/maintain the desired hemoglobin.

What is the typical parenteral iron correction dose?

Approximately 1000 mg total, with the specific formulation determining how that dose is administered.

Which parenteral iron product requires a test dose?

IRON DEXTRAN is the only preparation in the lecture requiring a test dose because of its risk of anaphylaxis.

What are major adverse effects of parenteral iron?

Hypotension, anaphylaxis, nausea/vomiting, diarrhea, headache, low back pain, dyspnea, arthralgia, and arthritis. Patients should be observed during and immediately after infusion.

What is CKD-mineral and bone disorder (CKD-MBD)?

It is calcium/phosphate imbalance with hyperparathyroidism that can cause renal osteodystrophy, vascular calcification, and increased cardiovascular mortality.

What is the most important driving force behind secondary hyperparathyroidism in CKD?

HYPERPHOSPHATEMIA.

What is osteitis fibrosa cystica?

It is a high-bone-turnover disease caused by high circulating PTH, with increased bone formation/turnover and peritrabecular/bone marrow fibrosis.

What is adynamic bone disease?

It is a low-bone-turnover disease with low bone formation/mineralization activity. Causes include aluminum toxicity, high dialysate calcium, high doses of calcium-containing phosphate binders, and excessive vitamin D/PTH suppression.

What is osteomalacia in CKD?

It is a low-bone-turnover disorder characterized by abnormal mineralization.

What are common signs/symptoms and laboratory findings of renal osteodystrophy?

Bone pain and fractures occur late after significant skeletal damage. Labs include elevated iPTH, elevated phosphorus, elevated corrected calcium as described in the lecture, low vitamin D, and elevated calcium-phosphate product.

When should CKD-MBD monitoring begin?

Monitoring should begin in stage 3 CKD with the goal of preventing secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy.

What is the corrected calcium formula?

Corrected Ca (mg/dL) = measured Ca + 0.8 × (4 − albumin).

How do you calculate corrected calcium if measured Ca = 8.0 mg/dL and albumin = 2 g/dL?

Corrected Ca = 8.0 + 0.8 × (4 − 2) = 8.0 + 1.6 = 9.6 mg/dL.

Why is corrected calcium important in CKD?

It helps interpret calcium levels when albumin is abnormal and helps guide selection of CKD-MBD therapy.

What is the general dietary phosphorus recommendation in CKD stages 3–5 when phosphorus/PTH are elevated?

Restrict dietary phosphorus to approximately 800–1000 mg/day.

Why are phosphate binders needed in dialysis patients?

Dialysis removes relatively little phosphorus, so phosphate binders are used to bind dietary phosphorus in the GI tract and reduce phosphorus absorption.

When are calcium-containing phosphate binders useful, and when should they be avoided?

They may be useful earlier when hypocalcemia is common, but should be avoided in advanced disease or when tissue/vascular calcification is a concern. Avoid calcium binders when calcium is >10.2 mg/dL.

How does calcium acetate compare with calcium carbonate as a phosphate binder?

Calcium acetate binds approximately twice as much phosphorus as calcium carbonate.

What medications can reduce calcium carbonate phosphate binding?

PPIs and H2 blockers can reduce calcium carbonate binding because they increase gastric pH.

What is sevelamer and when is it preferred?

Sevelamer is a non-calcium phosphate binder. Sevelamer is preferred when calcium is normal/elevated and is especially useful in dialysis patients with severe vascular or soft-tissue calcification. Sevelamer carbonate also causes fewer GI effects and can reduce metabolic acidosis compared with sevelamer HCl.

What are important points about lanthanum and aluminum phosphate binders?

Lanthanum should be taken at the end of the meal. Aluminum-containing binders should only be used short-term, generally no longer than about 4 weeks.

What are the newer iron-based phosphate binders?

Sucroferric oxyhydroxide and ferric citrate. Ferric citrate also provides better iron absorption.

What does vitamin D therapy do in secondary hyperparathyroidism?

Vitamin D lowers PTH by increasing calcium, directly inhibiting the parathyroid gland, and lowering the calcium set point.

What are the major risks of excessive vitamin D therapy in CKD?

Hypercalcemia, hyperphosphatemia, and excessive PTH suppression leading to adynamic bone disease.

When should vitamin D therapy be held according to the lecture?

Hold when calcium-phosphate product is >55, calcium is >10.2 mg/dL, or PTH is <150.

What is the role of ergocalciferol in CKD?

Ergocalciferol is vitamin D2 that requires activation. It can be used in stage 3–4 CKD when 25-OH vitamin D is low and PTH is elevated.

What is the role of calcitriol in CKD?

Calcitriol is active vitamin D3 and can be given orally or IV. It does not require activation but has a greater risk of hypercalcemia.

What is the role of paricalcitol in CKD?

Paricalcitol is an active vitamin D analog that does not require activation and has less risk of hypercalcemia/hyperphosphatemia than calcitriol; it is often preferred in dialysis patients.

What is the role of doxercalciferol in CKD?

Doxercalciferol is a vitamin D analog given PO or IV that is activated by the LIVER rather than the kidney.

What is the mechanism of calcimimetics?

Calcimimetics bind the calcium-sensing receptor and increase its sensitivity to extracellular calcium, thereby decreasing PTH without increasing serum calcium or phosphorus.

What are the two calcimimetics covered in the lecture?

Cinacalcet and etelcalcetide.

What is the dosing and administration of cinacalcet?

30 mg PO once daily, titrated monthly as needed to a maximum of 180 mg/day. Give with food.

What are the monitoring requirements and adverse effects of cinacalcet?

Baseline calcium should be >8.4 mg/dL. Check calcium/phosphorus after about 1 week and PTH monthly. Major adverse effects include hypocalcemia, nausea/vomiting, diarrhea, and myalgia.

What is the dosing and administration of etelcalcetide?

5 mg IV 3 times weekly after hemodialysis, titrated as needed to a maximum of 15 mg.

What are important features of etelcalcetide?

It binds the extracellular domain of the calcium-sensing receptor, is renally eliminated and removed by HD, and has no major drug-drug interaction concerns. Baseline calcium should be >8.4 mg/dL.

How is hyperkalemia managed/prevented in advanced CKD?

Restrict dietary potassium to about 50–80 mEq/day, avoid potassium-sparing diuretics and beta blockers when possible, and avoid ACE inhibitors/ARBs when possible if hyperkalemia is a problem. Severe hyperkalemia requires temporizing therapy and dialysis.

Why can constipation worsen hyperkalemia in CKD?

The colon provides an important route for potassium excretion; constipation decreases colonic potassium elimination.

How does patiromer lower potassium?

Patiromer binds potassium in the colon in exchange for calcium, increasing GI potassium elimination.

How does sodium zirconium cyclosilicate lower potassium?

It exchanges sodium/hydrogen for potassium throughout the GI tract, increasing potassium elimination.

What is the treatment goal for chronic metabolic acidosis in CKD?

Maintain serum bicarbonate >22 mEq/L.

What treatments are used for chronic metabolic acidosis in CKD?

Sodium bicarbonate, sodium citrate, or citric acid can be used. Severe cases may require dialysis. Sodium-containing therapies require caution because of sodium overload.

What are important sodium-management principles in CKD?

Sodium restriction beyond a no-added-salt diet is not routinely recommended unless the patient has hypertension or edema.

What is the major cardiovascular concern in CKD?

Cardiovascular disease is the #1 cause of death in CKD.

What are the blood pressure goals given in the lecture?

General goal <140/90 mmHg; for CKD with ≥2+ proteinuria, goal <130/80 mmHg.

Who should receive statin or statin/ezetimibe therapy according to the lecture?

Patients >50 years old with eGFR <60 mL/min/1.73 m² who are not on chronic dialysis or a kidney transplant should receive statin or statin/ezetimibe therapy.

Should a new statin be started after a patient becomes dialysis-dependent?

No. Do not initiate a new statin after dialysis dependence begins, but continue a statin if the patient was already taking one before dialysis.

What is uremic pruritus and what factors may contribute to it?

It affects about 60–90% of patients with ESRD. Proposed contributors include dry skin, hyperparathyroidism, increased vitamin A, and increased histamine. It is associated with male sex, high BUN, high β2-microglobulin, hypercalcemia, and hyperphosphatemia.

How is uremic pruritus treated?

Treatments include antihistamines, topical anesthetics/agents, gabapentin, ondansetron, and IV lidocaine during dialysis.

What causes uremic bleeding?

Uremia causes platelet biochemical abnormalities and abnormal platelet-vessel wall interactions, impairing platelet function despite a normal platelet count.