Renal Replacement Therapy: Indications & Dialysis

Renal Replacement Therapy (RRT) Indications

• Acidosis, not responsive to bicarbonate, is an indication for RRT.
• Electrolyte abnormalities like hyperkalemia or hyperphosphatemia necessitate RRT.
• Intoxication with substances such as boric acid, ethylene glycol, lithium, methanol, phenobarbital, salicylate, or theophylline requires RRT.
• Fluid overload, especially symptomatic pulmonary edema, is an indication for RRT.
• Uremia presenting as pericarditis or weight loss warrants RRT.

Primary Modes of Dialysis

• Hemodialysis is the most common modality in the United States.
• Peritoneal dialysis is another primary mode of dialysis.

Hemodialysis Access (Intermittent for ESRD)

• Arteriovenous (AV) fistula is the preferred access method.
• AV fistulas are natural, created by anastomosing an artery and vein.
• AV fistulas have the lowest infection and thrombosis incidence, cost, and the longest survival.
• Fistula maturation can take weeks or months to establish adequate blood flow.
• Arteriovenous graft, typically synthetic (polytetrafluoroethylene), is an alternative access.
• AV grafts are often used in patients with vascular disease.
• Catheters are used when permanent access isn't feasible.
• Catheters come with higher infection and thrombosis rates, and lower blood flow can lead to inadequate dialysis.

Dialysis Membranes

• Conventional dialysis membranes, with small pores and surface area, are infrequently used.
• High flux dialysis membranes have large pores and high efficiency due to their large surface area.
• High flux membranes can remove drugs previously impermeable to standard membranes and facilitate fluid removal (ultrafiltrate).

Adequacy of Hemodialysis

• Kt/V is a unitless parameter indicating dialysis adequacy: K = clearance, t = time, V = urea distribution volume.
• A minimum Kt/V of 1.2, target 1.4, is recommended by KDOQI.
• URR (Urea Reduction Ratio) is calculated as [(preBUN – postBUN)/preBUN] × 100%.
• The goal URR is greater than 65%, with a target of 70%.

Common Hemodialysis Complications

• Intradialytic complications often relate to fluid removal.
• Hypotension is common in older adults and those with diabetes mellitus.
• For acute management of hypotension: Trendelenburg position, reduce ultrafiltration rate, administer saline boluses.
• Hypotension can be prevented by accurately setting “dry weight," limiting fluid gains, and in some cases, midodrine 2.5–10 mg orally before dialysis.
• Other agents include fludrocortisone and selective serotonin reuptake inhibitors, though these are not as well-studied.
• Cramps can be alleviated with vitamin E 400 international units at bedtime.
• Additional complications include nausea, vomiting, headache, chest pain, and back pain.

Vascular Access Complications with Catheters

• Catheter-related infections are most commonly caused by Staphylococcus aureus.
• Aggressive treatment is necessary and catheter removal might be required.
• Thrombosis is suspected with low blood flow.
• Oral antiplatelet agents for prevention are ineffective.
• Thrombosis can be treated with alteplase 2 mg or reteplase 0.4 unit per lumen, allowing to dwell for 30 minutes, with repeat dosing if needed.

Factors Affecting Hemodialysis Efficiency

• The type of dialyzer used affects efficiency depending on membrane surface area and pore size.
• Hemodialysis therapy length.
• Dialysis flow rate.
• Blood flow rate.

Continuous RRT for Critically Ill AKI Patients

• Continuous venovenous hemofiltration (CVVH) removes fluid and solutes by convection, not diffusion.
• Drug removal depends on ultrafiltrate production rate and protein binding.
• Drug removal can be predicted via sieving coefficient (SC = drug concentration in ultrafiltrate/drug concentration in blood).
• CVVH requires replacement fluid due to its high ultrafiltration rate.
• Continuous venovenous hemodialysis (CVVHD) uses a dialysate flowing countercurrent to blood, removing solute by diffusion.
• Continuous venovenous hemodiafiltration (CVVHDF) combines ultrafiltration and dialysis.
• Solutes are removed by both convection and diffusion, requiring both replacement fluid and dialysate.

Peritoneal Dialysis (PD)

• The peritoneal dialysis membrane, approximately 1–2 m2, comprises the vascular wall, interstitium, mesothelium, and adjacent fluid films.
• In PD, 1.5–3 L of dialysate fluid is instilled into the peritoneum via a catheter, dwells for a time, and is drained.
• Solutes and fluid diffuse across the peritoneal membrane.
• Peritoneal dialysis is usually not used to treat AKI in adults.

Peritoneal Dialysis Types

• Continuous Ambulatory Peritoneal Dialysis (CAPD) is classic.
• Requires manual exchanges during the day, potentially disrupting routines.
• Automated Peritoneal Dialysis (APD) includes many variants like continuous cycling PD.
• Utilizes a cycling machine for exchanges, mostly at night, with optional daytime dwells.
• APD minimizes contamination and has the lowest peritonitis incidence.

Peritoneal Dialysis Complications

• Peritonitis, an infection of the peritoneal cavity, is a major complication.
• Patient technique and population factors affect infection rates, with higher rates in older adults and those with diabetes.
• Peritonitis is a primary reason for PD failure.
• Diagnosis involves at least two of: clinical peritonitis signs, dialysis effluent WBC > 100/mm3 (or > 0.1 × 103 cells/m3 after ≥2 hours dwell) with > 50% polymorphonuclear leukocytes, or positive effluent culture.
• Patients with cloudy effluent are presumed to have peritonitis until proven otherwise.
• Common causative organisms: gram-positive (Staphylococcus epidermis, S. aureus, streptococci) and gram-negative (Escherichia coli, Pseudomonas aeruginosa).
• Treatment follows ISPD guidelines, covering both gram-positive and gram-negative bacteria empirically.
• Vancomycin or a first-generation cephalosporin covers gram-positive organisms, a third-generation cephalosporin, aminoglycoside, or aztreonam covers gram-negative.
• Intraperitoneal administration preferable, unless systemic infection site exists.
• Antibiotic selection should be adjusted based on culture and sensitivity results.
• Catheter exit-site infections should be managed.
• Daily topical mupirocin or gentamicin cream is recommended for prophylaxis.
• Treat exit-site infections promptly to reduce peritonitis risk.
• Other complications include: hyperglycemia, fluid overload, electrolyte abnormalities (hypercalcemia, hypocalcemia), malnutrition (hypoalbuminemia), and hernia.

Anemia in CKD

• Anemia in CKD results from decreased erythropoietin production, shorter RBC lifespan, blood loss during dialysis, iron deficiency, chronic disease, and renal osteodystrophy.
• Anemia prevalence: 26% in patients with GFR > 60 mL/minute/1.73 m2 versus 78% in patients with GFR < 15 mL/minute/1.73 m2.
• Signs and symptoms are similar to anemia from other causes.
• Treating anemia in CKD can improve morbidity, mortality, LVH, exercise tolerance, and quality of life.
• Treating with ESAs to high Hgb concentrations (> 13 g/dL) may increase cardiovascular events.

Anemia Workup in CKD

• Anemia evaluation should be initiated when CrCl < 60 mL/minute/1.73 m2 or Hgb is less than 13 g/dL (men) or less than 12 g/dL (women).
• Include MCV and Reticulocyte count.
• Perform iron studies: TSAT (serum iron/total iron-binding capacity × 100) assesses available iron, Ferritin measures stored iron.
• Check serum vitamin B12 and folate concentrations.
• Test for stool guaiac.
• Monitor Hgb and Hct based on CKD stage; annually for stage 3, twice yearly for stages 4-5 (non-dialysis), and every 3 months for stage 5 (dialysis).

ESA Initiation

• ESAs should not be started in CKD patients (non-dialysis) if Hgb > 10 g/dL unless symptomatic.
• For Hgb < 10 g/dL, consider decline rate and need to reduce transfusion likelihood.
• In CKD patients on dialysis, start ESA therapy for Hgb < 10 g/dL (KDIGO suggests avoiding Hgb decrease below 9 g/dL).
• Use ESAs cautiously, if at all, in patients with stroke or cancer history (stroke risk is higher in non-dialysis-dependent CKD).
• Prior to ESA initiation, iron stores should be at optimal levels.
• Contraindications for use also include uncontrolled hypertension and hypersensitivity reactions.

ESA Maintenance

• Individualize dosing; use the lowest effective ESA dose to minimize transfusions, adjusting appropriately.
• Epoetin alfa (Epogen, Procrit):
• Shares the same molecular structure as human erythropoietin and binds to/activates the erythropoietin receptor.
• Administered subcutaneously or intravenously.
• Starting dose: 50–100 units/kg three times per week.
• Subcutaneous dosages typically about 30% lower requirements than intravenous dosages.
• Darbepoetin alfa (Aranesp):
• Modified molecular structure compared to epoetin, with increased duration of activity, which changes frequency of dosing.
• Can be dosed once weekly, or once every 2-3 weeks.
• Starting dose for non-dialysis CKD: 0.45 mcg/kg once every 4 weeks
• Starting dose for dialysis CKD: 0.45 mcg/kg once per week or 0.75 mcg/kg every 2 weeks.
• Binds to erythropoietin receptor, is administered subcutaneously or IV.
• Methoxy polyethylene glycol-epoetin beta (Mircera):
• Modified molecule with increased duration, Hgb increases 7-15 days after initial dose.
• Initial dose of 0.6 mcg/kg body weight once every 2 weeks.
• Once Hgb stabilizes, can double the dose and administer once monthly.
• Binds and activates erythropoietin receptor and administered SC or IV.

Therapy Goals, and ESA Adjustments

• Use the lowest dose of ESA to prevent blood transfusion
• In non-dialysis patients with CKD, hold or reduce ESA dose when Hgb is greater than 10 g/dL.
• In dialysis pts, hold or reduce ESA dose when Hgb is > 11 g/dL (KDIGO suggests an upper limit of 11.5 g/dL).
• Do not exceed an Hgb greater than 13 g/dL.
• ESA dose adjustment is based on Hgb response; parameters are similar for epoetin alfa and darbepoetin alfa; adjust every 4 weeks.
• Adjustments by 25% increments of current dose when making changes.

ESA Monitoring

• Monitor Hgb every 2–4 weeks during the initiation phase.
• During the maintenance phase, monitor Hgb at least monthly in dialysis patients and every 3 months in non-dialysis patients with CKD.
• Monitor BP due to potential BP increase with treatment.
• Monitor iron stores.
• KDOQI target goals are TSAT > 20% and Ferritin > 100 ng/mL (non dialysis CKD, PD) and > 200 ng/mL (HD CKD); KDIGO target goals are TSAT >30% and Ferritin > 500 ng/mL.

Causes of Poor ESA Response

• Iron deficiency is the most common.
• Infection and inflammation.
• Also consider: chronic blood loss, hyperparathyroidism, aluminum toxicity, folate or vitamin B12 deficiency, malignancies, malnutrition, hemolysis, and vitamin C deficiency.

Iron Therapy

• Oral iron is not recommended in patients with CKD on dialysis, but a 1- to 3-month trial may be done for pre-dialysis patients with CKD requiring iron therapy.
• Ferric citrate is an FDA-approved phosphate binder potentially useful for PO iron supplementation in CKD patients not requiring dialysis.
• Most CKD patients receiving ESAs require parenteral iron therapy due to requirements and decreased oral absorption.
• For adult patients on dialysis, give an empiric cumulative or total dose of 1000 mg IV.
• Monitor TSAT and ferritin every 3 months.

Iron Therapy Adverse Effects

• Anaphylactic-type reactions can occur with iron dextran, necessitating a test dose.
• Hypersensitivity may occur with all parenteral iron products.
• Hypotension can occur with sodium ferric gluconate, iron sucrose, and ferumoxytol. Monitor during and for 30 minutes after administration.
• Hypertension can occur transiently with ferric carboxymaltose.
• Bloodstream, or other serious infections, may be worsened by IV iron.

CKD-Mineral and Bone Disorder (CKD-MBD) Pathophysiology

• Calcium and phosphorus homeostasis involves the interplay of hormones affecting the bone, GI tract, kidneys, and parathyroid gland.
• Processes begin as GFR decreases to less than 60 mL/minute/1.73 m2.
• CKD-MBD results in renal osteodystrophy and vascular calcification.
• Factors include: hyperphosphatemia, decreased production of 1,25-dihydroxyvitamin D3, reduced absorption of calcium in gut, decreased ionized calcium concentrations, direct stimulation of parathyroid hormone (PTH) secretion.
• Elevated PTH concentrations induce decreased phosphorus reabsorption and increased calcium reabsorption in the proximal tubule.
• As GFR decreases below 30 mL/minute/1.73 m2, this adaptive mechanism is lost. Calcium is not well absorbed through the gut, and calcium concentrations are maintained by increased bone resorption through elevated PTH, resulting in bone loss.

CKD-MBD Prevalence and Symptoms

• CKD-MBD is a main cause of morbidity and mortality in dialysis patients and is very common.
• It has an insidious onset; patients may experience fatigue and musculoskeletal and GI pain.
• Calcification may be visible on radiology, bone pain, and fractures can occur if progression is left untreated.

CKD-MBD Laboratory Abnormalities

• Phosphorus, corrected calcium (measured calcium + 0.8[4 – serum albumin]), parathyroid hormone (PTH), alkaline phosphatase, and 25-hydroxyvitamin D can be measured.
• Frequency of monitoring depends on stage.

CKD-MBD Diagnostic Testing

• Bone mineral density testing is suggested for CKD G3a–G5D patients with CKD-MBD evidence and/or osteoporosis risk factors.
• Bone biopsy is reasonable if renal osteodystrophy knowledge affects treatment decisions.

CKD-MBD Treatment

• Treatment should be based on serial assessments of phosphate, calcium, and PTH concentrations, considered together.
• Therapy goals include lowering phosphate concentrations toward normal range, avoiding hypercalcemia, and evaluating modifiable causes in stages G3a-G5 patients not on dialysis with progressively rising PTH.
• In CKD G5D patients, suggest maintaining PTH concentrations 2–9 times the upper normal limits.
• Marked changes in either direction should prompt initiation of or change in therapy.

CKD-MBD Nondrug Therapy

• Dietary phosphorus restriction of 800–1000 mg/day in CKD category G3 or higher.
• Dialysis removes phosphorus, however insufficient to maintain balances in most patients.
• Parathyroidectomy is reserved for patients with unresponsive hyperparathyroidism.

CKD-MBD Phosphate Binders

• Take with each meal to bind phosphorous in the gut; products from different groups may be used together for additive effect.
• Decisions about phosphate-lowering treatment should be based on progressively or persistently elevated serum phosphate.
• Calcium-containing binders are initial phosphate binder; either calcium-containing or nonionic binders can be the initial binder of choice in stage 5 CKD.
• Use calcium-based restrictedly.
• Aluminum-containing phosphate binders lower phosphorus concentrations (avoid long-term use grade 1C).
• Calcium-containing phosphate binders (calcium carbonate and calcium acetate): widely used and carbonate salt is inexpensive. Use may be limited by development of hypercalcemia.
• Total elemental calcium is 2000 mg/day (1500-mg binder; 500-mg diet).
• Sevelamer binds dietary phosphorus and may decrease LDL cholesterol and increase HDL cholesterol. Metabolic acidosis may worsen with sevelamer hydrochloride, sevelamer carbonate preferred.
• Lanthanum carbonate has indications similar to sevelamer.

Additional Phosphate Binders

• Ferric citrate contains 210 mg of ferric ion. The initial dose: 2 tablets given TID with meals.
• Sucroferric oxyhydroxide initial dose: 500 mg three times daily with meals; tablet must be chewed and comes with Gl effects.

Vitamin D and analogs

• They suppress PTH but use is limited by resultant hypercalcemia.
• Routine use of calcitriol and vitamin D analogs is not generally suggested; might be reserved for patients with progressive hyperparathyroidism.
• Ergocalciferol may be used in stage 3 or 4 CKD for patients with low serum 25-hydroxyvitamin D concentrations.
• Recheck Vitamin D after 6 months.
• Usually doses are weekly or monthly.
• Cholecalciferol (vitamin D3) may be used as alternative and is dosed daily.
• Calcifediol (25-hydroxyvitamin D3) undergoes 1-a-hydroxylation to calcitriol and could be an alternative to ergocalciferol
• Calcitriol requires hepatic or renal activation. Low dose is used to reduce hypocalcemia. High incidence of hypercalcemia
• Paricalcitol does not require hepatic or renal activation with a lower hypercalcemic.
• Doxercalciferol requires hepatic activation and has lower hypercalcemia reported

Calcimimetics

• Indicated for secondary hyperparathyroidism, particularly when hypercalcemia is a concern with vitamin D analogs.
• Cinacalcet hydrochloride attaches to the calcium receptor on the parathyroid gland, increasing the sensitivity of receptors to serum calcium concentrations, thus also reducing PTH.
• Initial dose is 30 mg by mouth once daily, monitor calcium levels within 1 week after starting treatment, do not start if serum calcium is less than 8.4 mg/dL.
• Monitor PTH 1–4 weeks when initiating. Can be used irrespective of vitamin analog and calcium binder use. Caution in those with seizure disorder.
• Notable drug interactions.
• Etelcalcetide a is synthetic peptide that activates the calcium-sensing receptor, thus reducing PTH, given 3 times per week after HD and must discontinue other medication before initiating.

Osteoporosis Treatment

• CKD categories G1-G2 with high fracture, manage as general, and with categories stage G3a-G3b management is the same if PTH normal.
• CKD category G3a–G5D with abnormalities, consider the magnitude, reversibility, and CKD progression, considering biopsy.