Novel Approaches to Management of Hyperkalaemia in Kidney Transplantation

John Rizk; David Quan; Steven Gabardi; Youssef Rizk; Kamyar Kalantar-Zadeh

Curr Opin Nephrol Hypertens. 2021;30(1):27-37.

Abstract and Introduction

Abstract

Purpose of Review: Medications used frequently after kidney transplantation, including calcineurin inhibitors, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers and antimicrobials, are considered the leading culprit for posttransplant hyperkalaemia in recipients with a well functioning allograft. Other risk factors include comorbidities such as diabetes, hypertension and heart failure; and consumption of a potassium-enriched diet. We review the mechanisms for hyperkalaemia following kidney transplantation that are addressed using nonpharmacological and pharmacological interventions. We also discuss emerging therapeutic approaches for the management of recurrent hyperkalaemia in solid organ transplantation, including newer potassium binding therapies.

Recent Findings: Patiromer and sodium zirconium cyclosilicate are emerging potassium binders approved for the treatment of hyperkalaemia. Patiromer is a polymer that exchanges potassium for calcium ions. In contrast, sodium zirconium cyclosilicate is a nonpolymer compound that exchanges potassium for sodium and hydrogen ions. Both agents are efficacious in the treatment of chronic or recurrent hyperkalaemia and may result in fewer gastrointestinal side effects than older potassium binders such as sodium polystyrene sulfonate and calcium polystyrene sulfonate. Large-scale clinical studies have not been performed in kidney transplant patients. Patiromer may increase serum concentrations of tacrolimus, but not cyclosporine. Sodium zirconium cyclosilicate does not appear to compromise tacrolimus pharmacokinetics, although it may have a higher sodium burden.

Summary: Patiromer and sodium zirconium cyclosilicate may be well tolerated options to treat asymptomatic hyperkalaemia and have the potential to ease potassium dietary restrictions in kidney transplant patients by maintaining a plant-dominant, heart-healthy diet. Their efficacy, better tolerability and comparable cost with respect to previously available potassium binders make them an attractive therapeutic option in chronic hyperkalaemia following kidney transplantation.

Introduction

Metabolic derangements can occur following kidney transplantation. The most common posttransplant electrolyte and acid--base disturbances, ranked according to the likelihood of occurrence during the first several months, are hyperkalaemia, hypophosphatemia, hypomagnesemia, metabolic acidosis, hypercalcemia and hyperphosphatemia.^[1,2] Hyperkalaemia is defined as a serum potassium concentration of more than 5.3 mEq/l in adults.^[3] It is a common, potentially life-threatening complication following transplantation that can lead to clinical manifestations such as haemodynamic instability, central nervous system adverse events and fatal cardiac arrhythmias. Most patients are asymptomatic or manifest nonspecific signs and symptoms, including, skeletal muscle weakness, fatigue, cardiac complications, including bradycardia or other arrhythmias, and impaired gastrointestinal motility.^[2]

Kidney transplant recipients are at an increased risk of developing hyperkalaemia due to both pharmacologic and pathophysiological-related mechanisms. The incidence of hyperkalaemia ranges from 25 to 44% in renal transplant recipients receiving a calcineurin inhibitor (CNI).^[4,5] Simultaneous kidney-pancreas transplant recipients with bladder drainage are more susceptible to hyperkalaemia, with one study reporting an incidence of 73%.^[5] Hyperkalaemia is reported to be prevalent during the first 3 months postkidney transplantation.^[5]

In this review, we discuss the cause and management strategies of hyperkalaemia observed after kidney transplantation. We also discuss novel United States Food and Drug Administration (FDA) approved therapies for the management of chronic or recurrent hyperkalaemia, which appear to be well tolerated in this patient population.

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Next Section

Abstract and Introduction
Causes of Hyperkalaemia in Kidney Transplant Patients
Nonpharmacological Management
Pharmacological Management
Novel Therapies for Chronic Hyperkalaemia
Conclusion
References
Sidebar

Table 1. Medications associated with hyperkalaemia in kidney transplantation
Medications	Utility in kidney transplantation
ACEi and ARB	Hypertension
Beta-blockers (nonselective and beta 2-selective)	Hypertension
Potassium-sparing diuretics (amiloride, triamterene, spironolactone)	Hypertension
Trimethoprim, pentamidine	PCP prophylaxis
Heparin	Prevent clot formation during transplant procedure
Succinylcholine	Used in transplant recipients in need for rapid sequence intubation and rapid airway control
Calcineurin inhibitors (cyclosporine, tacrolimus)	Immunosuppressive agents
NSAIDs	Headache or pain

ACEi, angiotensin-converting-enzyme inhibitors; ARB, angiotensin II receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs; PCP, Pneumocystis pneumonia.

Table 2. Clinical studies of patiromer and ZS-9 in transplant patients with hyperkalaemia
Drug	Investigators	Design	Transplant population	Endpoints	Results
Patiromer	Singh et al. [54]	Retrospective, single-centre study	37 SOT patients: kidney (73%), liver (21%), kidney-pancreas (3%), lung (3%)	Primary: Change in K⁺ levels from baseline to 4, and 12 weeks; difference in tacrolimus levels at baseline, 4, and 12 weeks. Secondary: GI side effects, electrolyte abnormalities, insurance coverage of patiromer.	Statistically significant improvement in K⁺ levels (baseline K⁺ = 5.44) at week 4 (K⁺ = 4.99) and week 12 (K⁺ = 5). Statistically significant increase in tacrolimus levels (7.19–9.22 ng/ml) at week 4. No reported GI side effects, constipation in 8%. 81% obtained insurance coverage.
Patiromer	Lim et al. [53]	Retrospective, single-centre study	19 kidney transplant recipients	Safety, effectiveness, and tolerability of patiromer	All adherent patients had K⁺ levels <5.2 mmol/l at last follow-up. Seven patients required tacrolimus dose reduction within 1–4 weeks of patiromer initiation; six were previously on SPS and one with prior supratherapeutic levels. No intolerable side effects; two had constipation, one had diarrhoea, one required an emergency room visit for hyperkalaemia during patiromer dose adjustment
Patiromer	Rattanavich et al. [52]	Not described	Two kidney transplant recipients	Effect of patiromer on treating hyperkalaemia and on tacrolimus trough levels	Patiromer use is effective in treating hyperkalaemia and does not affect tacrolimus tough levels. Patient 1: hyperkalaemia resolved within days with K⁺ levels between 4.0 and 5.5 mEq/l. Patient 2: hyperkalaemia resolved but returned upon patiromer discontinuation with K⁺ levels between 5.5 and 6.5 mEq/l. No need for tacrolimus dose adjustment.
ZS-9	Winstead et al. [55]	Retrospective, single-centre study	35 SOT patients: 16 kidney (45.7%), 14 liver (40%), two heart (5.7%), two kidney-liver (5.7%), one kidney-heart (2.9%)	Primary: Change in K⁺ from day 0 to day 7. Secondary: Change in tacrolimus, Na⁺, and bicarbonate levels from day 0 to day 7 and any reported adverse events.	K⁺ levels decreased by −1.3 mEq/l from day 0 to day 7. Mean change in concentrations from days 0 to 7: tacrolimus = −0.54 ng/ml, Na⁺ = +1.7 mEq/l, bicarbonate = +1.6 mEq/l. Two reports of mild oedema.

K+, potassium; Na+, sodium; SOT, solid organ transplant; SPS, sodium polystyrene sulfonate; ZS-9, sodium zirconium cyclosilicate.

Table 3. Nondialytic treatments for hyperkalaemia management. Cost information was obtained from Lexicomp database
Treatments	Dose	Route of administration	Onset of action	Mode of action	Common adverse events	Contraindications	Drug interactions	Cost
Membrane stabilization
Calcium gluconate (10%)	10 ml over 10 min	i.v.	1–3 min	Antagonizes cardiac membrane excitability	Local soft tissue inflammation and necrosis, calcinosis cutis, calcification related to extravasation	Hypercalcaemia	Not significant (single dose) but may interact with aspirin, furosemide, insulin	$5.4 per 10 ml dose
Redistribution
Regular Insulin	10 units push with 25–40 g dextrose 50% solution	i.v.	20 mins	Enhances activity of Na⁺/K⁺-ATPase pumps on cell membranes	Hypoglycaemia, hyperglycaemia (side effect of dextrose), hypokalaemia, local or systemic allergy, weight gain, peripheral oedema	Hypoglyacemia, hypersensitivity to regular insulin or any component of the formulation	Not significant (single dose) but may interact with aspirin, furosemide, atorvastatin	$178.4 per 10 units dose
Albuterol	10–20 mg in 4 ml of 0.9% NaCl over 10 min	Inhalation	30 min	Directly stimulates the Na⁺/K⁺-ATPase pump in skeletal muscles	Headache, tremor, tachycardia, pain, dizziness, pharyngitis, rhinitis.	Hypersensitivity to albuterol or any other aerosol components	Beta-blockers	$1.08–$2.08 per 10 mg dose
Elimination
Sodium bicarbonate	50 mEq over 5 min, may repeat	i.v.	2–10 min	Shift K⁺ into cells via an H⁺/K⁺ exchange mechanism. Bicarbonate may be directly transported into muscle cells along with K⁺.	Metabolic alkalosis, tetany, hypernatremia, hypocalcaemia, hypokalaemia	Alkalosis, hypernatremia, volume overload, severe pulmonary oedema, hypocalcaemia	May precipitate when given with morphine, magnesium, calcium chloride. May deactivate sympathomimetic.	$10.5–$24 per 50 ml (50 mEq) dose
Loop diuretics	Furosemide: 40–80mg Bumetanide: 2–4 mg	i.v.	15 min	Act on the Na⁺-K⁺-2Cl⁻ symporter in the thick ascending limb of loop of Henle	Intravascular depletion, renal dysfunction, prerenal azotemia, hypotension, ototoxicity	Anuria, hypersensitivity to furosemide or any component of the formulation	In patients receiving cyclosporine, furosemide use is associated with hyperuricemia and the occurrence of gout.	Furosemide: $16.4–$112 per 40 mg dose Bumetanide: $1.26–$1.66 per 2 mg dose
Fludrocortisone	0.1 to 0.4 mg per day	Oral	Not described, but 1–2 weeks to see effects	Increases density of Na⁺ channels on apical side of renal tubule cells. Increases density of Na⁺-K⁺-ATPase on the basolateral side	Sodium and water retention, hypertension, hyperglycaemia, osteoporosis, cardiac hypertrophy, oedema, hypokalaemia, bruising, diaphoresis, urticaria, allergic rash	Hypersensitivity to fludrocortisone or any component of the formulation, systemic fungal infections	May decrease serum concentration of tacrolimus by inducing the enzymes CYP3A4 and CYP3A5. Caution when used with strong CYP3A4 inhibitors and/or inducers	$0.75–$0.79 per tablet
Sodium polystyrene sulfonate	15–30 g in 15–30 ml	Oral, rectal	Hours to days	Exchanges sodium for potassium, calcium, ammonium and magnesium	Anorexia, nausea, vomiting, constipation, hypokalaemia, hypocalcaemia, hypomagnesemia, significant sodium retention	Hypersensitivity to sodium polystyrene sulfonate, polystyrene sulfonate resins or any component of the formulation, obstructive bowel disease, hypokalaemia	Lithium, thyroxine, nonabsorbable cationdonating antacids and laxatives (e.g. magnesium hydroxide, aluminium hydroxide)	$2.7 per 15 g dose (oral suspension), $11.1 per 30 g dose (rectal)
Patiromer	8.4–25.2 g daily	Oral	7 h	Binds to potassium in the lumen of the GI tract in exchange for calcium	Hypomagnesemia, hypokalaemia, constipation, diarrhoea, abdominal distress, flatulence, nausea	Hypersensitivity to patiromer or any component of the formulation	Significant interactions with ciprofloxacin, thyroxine, metformin.	$44 per 8.4 g packet
Sodium Zirconium Cyclosilicate	10 g three times a day for up to 48 h	Oral	1 h	Binds potassium in small intestine in exchange for sodium and hydrogen	Oedema, peripheral oedema, hypokalaemia	No contraindications listed in the manufacturer's labelling, but use with caution in patients with GI motility disorders and oedema	Furosemide, atorvastatin	$26.98 per 10 g packet