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. 

In This Article

Novel Therapies for Chronic Hyperkalaemia


Patiromer (Veltassa; Relypsa, Inc., Redwood City, California, USA), a nonabsorbable organic polymer, was approved by the FDA on 21 October 2015.[50] It is a powder for suspension in water for oral administration and works by binding to potassium in the lumen of the gastrointestinal tract in exchange for calcium. Patiromer is a nonselective cation exchanger that can interact with other drugs in the gastrointestinal tract.[51] Patiromer is recommended to be initiated at 8.4 g once daily. The dose may be increased in increments of 8.4 mg at weekly intervals, with a maximum dose of 25.2 g once daily.[51] FDA labelling indicates that this agent should be separated by at least 3 h (before or after) from other medications to allow sufficient time for gastric contents to empty. Because of its nonselective cation exchanger property, patiromer can bind to magnesium in the colon and cause hypomagnesaemia in 5.3% of patients. Serum magnesium should be monitored and magnesium supplementation might be needed to avoid complications such as cardiac arrhythmias. Patiromer should be avoided in patients with severe constipation, bowel obstruction or impaction, including abnormal postoperative bowel motility disorders, because it may be ineffective and may worsen gastrointestinal conditions.[51]

Rattanavich et al.[52] reported on two kidney transplant patients on tacrolimus who were treated with patiromer for hyperkalaemia. The study revealed that the use of patiromer is effective in treating hyperkalaemia and does not affect tacrolimus trough levels when administered at least 3 h after the tacrolimus dose. A different single-centre, retrospective study evaluated the safety, effectiveness, and tolerability of patiromer in 19 kidney transplant recipients.[53] Fifteen of these patients were previously on SPS, and 10 patients started patiromer within the first posttransplant year. Fourteen patients were started at a dose of 8.4 g/day (five required dose escalation to 16.8 g/day, one required further escalation to 25.2 g/day), three patients at 16.8 g/day (one required a dose decrease to 8.4 g/day), one patient at 8.4 g/48 h and one patient at 8.4 g 3x/week. The study reported normal potassium level (<5.2 mmol/l) following therapy with patiromer in patients who were adherent to therapy. Seven individuals required a tacrolimus dose decrease within 1–4 weeks of patiromer initiation, which may be due to the effect of SPS on tacrolimus absorption. Neither studies reported serious adverse events. In another series by Singh et al.,[54] 37 solid organ transplant recipients, 73% being kidney transplants, with hyperkalaemia received patiromer at a median of 165 days after transplantation. Although serum potassium levels declined, a significant increase in mean tacrolimus concentrations, from a baseline of 6.9 to 8.3 ng/ml at 4 weeks, was observed, with 32% of patients requiring tacrolimus dose adjustments. Cyclosporine levels were not affected. A summary of these studies is outlined in Table 2.[52–55] A clinical trial investigating the pharmacokinetics of tacrolimus and mycophenolate mofetil in kidney transplant recipients receiving patiromer has been completed, with no published results to date (NCT03229265).

Sodium Zirconium Cyclosilicate

Sodium Zirconium Cyclosilicate (Lokelma; AstraZeneca, Wilmington, Delaware, USA), also known as ZS-9, is an inorganic, nonabsorbed selective cation binder.[56] It works by binding potassium in the small intestine and allows for faecal excretion in exchange for sodium and hydrogen. It is a powder formulation mixed with water for oral use and was approved by the FDA in May 2019. ZS-9 is unique for being specific for potassium even in the presence of other ions.[56,57] Patiromer has a relatively delayed onset of action compared with ZS-9 (7 vs. 1 h).[51,58]

The recommended dose of ZS-9 is 10 g administered three times a day for up to 48 h. For continued treatment, the recommended dose is 10 g once daily and the dose may be uptitrated based on the serum potassium level at intervals of 1 week or longer and in increments of 5 g. In patients administered 10 g three times daily (t.i.d.), the mean serum potassium reduction was −0.7 mEq/l at 48 h, whereas the decrease in serum potassium for the placebo group was −0.2 mEq/l at 48 h. Patients with higher starting potassium levels had a greater response to ZS-9.[58] Transplant recipients on ZS-9 should be monitored for signs of oedema because every 5 g of ZS-9 contains 400 mg of sodium. In clinical trials of ZS-9, oedema was generally mild to moderate in severity, and was reported in 4.4% of patients receiving 5 g, 5.9% of patients receiving 10 g and 16.1% of patients receiving 15 g ZS-9 compared with 2.4% of patients receiving placebo.[58] Due to its selectivity, ZS-9 does not cause other electrolyte abnormalities such as hypomagnesaemia.

There are currently no published clinical trials to assess the safety and efficacy of ZS-9 in transplant patients. In fact, renal transplant patients were excluded from all ZS-9 trials and should be the focus of future research.[59–61] A 2020 single-centre, retrospective study of 35 adult organ transplant patients assessed the effect of ZS-9 on both hyperkalaemia and immunosuppression concentrations. Of these, there were 16 kidney (45.7%), 14 liver (40%), two heart (5.7%), two combined kidney and liver (5.7%), and one combined kidney and heart transplants (2.9%). The median time from transplant to initiation of therapy was 75 days. A t.i.d. dosing regimen was given to 12 (34%) patients with severe hyperkalaemia for a mean K+ level of 6.2. The mean day 0 K+ level was 5.9 mEq/l, and the mean decrease in K+ levels from day 0 to day 7 was -1.3 mEq/l (P ≤ 0.001). Tacrolimus drug pharmacokinetics were not significantly impacted; the mean change in tacrolimus concentrations was −0.54 nm/ml (P = 0.82). The mean change in sodium and bicarbonate concentrations from days 0 to day 7 was +1.70 mEq/l (P = 0.002) and 1.60 mEq/L (P = 0.006), respectively. No major adverse events were reported, although mild oedema was seen in two patients.[55]

See Table 3 for a summary of medication therapy for hyperkalaemia. A proposed algorithm for the management of hyperkalaemia in organ transplant recipients is presented in Figure 2.

Figure 2.

Proposed algorithm for the management of hyperkalaemia in organ transplant recipients.