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A Closer Look at the Nephrology PRN

Published on: Apr 4, 2022

Overview of the PRN

The Nephrology PRN is made up of nephrology pharmacists practicing in internal medicine, ambulatory care, academia, research, the pharmaceutical industry, and more, with members located all around the world. The PRN was established in 1993 with 73 inaugural members. Today, the group has almost 200 members and consists of nephrology experts, newcomers, and everyone in between. The Nephrology PRN strives not only to advance the scope of nephrology pharmacotherapy through excellence in education, clinical practice, research, and involvement in professional nephrology organizations but also to promote optimal outcomes for patients with kidney disease. The PRN has sponsored travel awards for students and new practitioners.


Opportunities and Resources for Resident and Fellow Members of the PRN

In 2021, the PRN supported two student members’ attendance at the ACCP Virtual Annual Meeting. These individuals presented their research findings at the Nephrology PRN virtual business meeting at the ACCP Annual Meeting last October. Students, residents, and fellows are encouraged to join the PRN’s subcommittees (e.g., Member Advocacy, Nominations, Programming, and Research) and have an active presence in the PRN. Through the Member Advocacy subcommittee, students and residents are frequent contributors to the PRN’s newsletter, NephNews. This newsletter incorporates member spotlights, journal article reviews, and clinical pearls related to nephrology. In addition, the PRN offers trainees opportunities to showcase their clinical knowledge through webinar presentations, network through online and in-person meetings, and present their research posters and receive verbal feedback from practicing pharmacists during poster walk-throughs. Nephrology PRN trainee members have greatly contributed to PRN activities, and their continued participation and success within the PRN will be welcomed and highly anticipated.


Current Clinical Issues Important to Nephrology PRN Members

Given the many critical functions of the kidney, a knowledge of nephrology is important for pharmacists across a variety of practice settings. At the most recent ACCP Annual Meeting, the PRN focus session was dedicated to examining current controversies and recommendations for race and estimations of kidney function. Following are selected examples of additional clinical issues of interest to Nephrology PRN members.


Clinical Issue: Novel Pharmacologic Agents in Hyperkalemia

Patients with renal insufficiency are at increased risk of hyperkalemia. Hyperkalemia in patients with renal disease often arises from decreased renal excretion but can also result from factors such as excess potassium intake, mineralocorticoid deficiency, oliguric renal failure, and medications such as renin-angiotensin-aldosterone system (RAAS) inhibitors, which are used to slow chronic kidney disease (CKD) progression and improve cardiovascular outcomes.1 Hyperkalemia is associated with increased morbidity and mortality and can cause muscle weakness and abnormal cardiac conduction.2,3 Because of these serious effects, hyperkalemia should be prevented in patients with renal insufficiency. Sodium zirconium cyclosilicate (ZS-9, Lokelma) and patiromer (Veltassa) are two FDA-approved potassium binders for the treatment of nonemergency hyperkalemia.4,5


ZS-9 is a cation exchanger with a highly selective affinity for potassium over other cations such as calcium and magnesium.4 ZS-9 works throughout the GI tract lumen to bind potassium in exchange for sodium and hydrogen, which results in increased fecal excretion of potassium.4 Onset of action is 1 hour, with normokalemia occurring in around 24 hours.6,7 ZS-9 is formulated as a powder that must be reconstituted into a suspension.

  • Warnings/Precautions: Medication warnings include hypokalemia and GI mobility disorders; thus, ZS-9 is not recommended in patients with severe constipation and bowel obstruction or impaction. There is also a potential for edema, especially in those with heart failure, given that every 5 g contains around 400 mg of sodium.4
  • Efficacy: ZS-9 has been established to substantially decrease serum potassium in patients with stage 3 CKD, with the greatest effect using 10 g.8 The HARMONIZE extension trial found that ZS-9 had greater potassium-reducing effects and maintained normokalemia for 28 days compared with placebo in patients with hyperkalemia and heart failure and in those receiving RAAS inhibitors.7
  • Pharmacy Pearls: Drug-drug interactions should be monitored because ZS-9 can increase gastric pH, potentially interfering with drugs that have a pH-dependent solubility. Oral medications must be separated by 2 hours before or after administration of ZS-9.


Patiromer is a cation exchanger that exchanges calcium for potassium and binds magnesium. Unlike ZS-9, patiromer works primarily in the distal colon to bind potassium and increase fecal potassium excretion.5 Onset of action is 7 hours, with normokalemia occurring in around 1 week.9 Patiromer is also formulated as a powder for reconstitution.

  • Warnings/Precautions: Medication warnings include hypomagnesemia and GI effects. Like ZS-9, patiromer should be avoided in patients with severe constipation and bowel obstruction or impaction.
  • Efficacy: The OPAL-HK trial showed that patiromer treatment was associated with decreased serum potassium concentrations and reduced the recurrence of hyperkalemia compared with placebo in patients with CKD who were receiving RAAS inhibitors and had hyperkalemia.10 The PEARL-HF trial showed that patiromer prevented hyperkalemia and was well tolerated in patients with heart failure receiving standard therapy and spironolactone.11 The AMETHYST-DN trial found that among patients with hyperkalemia and diabetic kidney disease, patiromer significantly decreased serum potassium after 4 weeks of treatment, with continued effect through 52 weeks.12
  • Pharmacy Pearls: Patiromer can bind other drugs and must be separated by 3 hours from other oral medications.


In conclusion, ZS-9 has a faster time to onset and time to normokalemia with a high binding affinity for potassium. ZS-9 works throughout the GI tract to bind potassium, whereas patiromer works in the colon. These medications are only available as a powder for reconstitution. ZS-9 contains sodium and may therefore cause edema, and patiromer increases the risk of hypomagnesemia. ZS-9 and patiromer have both been clinically shown to return patients to normokalemia and allow for maintenance of RAAS inhibitor therapy. However, patiromer may play a more significant role in maintenance, given that it has been proven efficacious for up to 52 weeks.


Table 1. Comparison of Potassium Binders


Sodium Zirconium Cyclosilicate



  • Initial: 10 g three times daily for up to 48 hr
  • Adjust dose by 5 g daily at 1-wk intervals
  • Maintenance: 10–15 g once daily
  • Initial: 8.4 g once daily
  • Adjust dose at ≥ 1-wk intervals in increments of 8.4 g
  • Maximum dose: 25.2 g/day

Mechanism of action

Preferentially binds potassium in exchange for hydrogen and sodium

Exchanges calcium for potassium

Onset of action

1 hr

7 hr

Time to normokalemia

24 hr

1 wk

Drug-drug interactions

Oral medications with pH-dependent solubility should be administered 2 hr before or 2 hr after

Can bind to drugs, so must be separated from other oral medications either 3 hr before or 3 hr after

Site of action

GI tract

Distal colon

Adverse effects

GI effects, hypokalemia, edema

GI effects, hypomagnesemia


Faster onset


Faster time to normokalemia


Works throughout the GI tract


Specificity for potassium

Once daily, so better adherence potential


Plays a more significant role in maintenance of normokalemia (proven continued effect through 52 wk)


Contains sodium (each 5 g contains ~400 mg of sodium), so must monitor for edema


Initially taken three times daily

Only works in the colon


Also binds magnesium, which can lead to hypomagnesemia





  1. Hollander-Rodriguez JC, Calvert JF Jr. Hyperkalemia. Am Fam Physician 2006;73:283-90.
  2. Luo J, Brunelli SM, Jensen DE, et al. Association between serum potassium and outcomes in patients with reduced kidney function. Clin J Am Soc Nephrol 2016;11:90-100.
  3. An JN, Lee JP, Jeon HJ, et al. Severe hyperkalemia requiring hospitalization: predictors of mortality. Crit Care 2012;16:R225.
  4. Lokelma® [package insert]. AstraZeneca, 2018.
  5. Veltassa (patiromer) [prescribing information]. Relypsa, May 2018.
  6. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015;372:222-31.
  7. Anker SD, Kosiborod M, Zannad F, et al. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail 2015;17:1050-6.
  8. Ash SR, Singh B, Lavin PT, et al. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int 2015;88:404-11.
  9. Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia. Kidney Int 2015;88:1427-33.
  10. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372:211-21.
  11. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011;32(7):820-8.
  12. Bakris GL, Pitt B, Weir MR, et al. Effect of patiroer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN randomized clinical trial. JAMA 2015;314(2):151-161.



Clinical Issue: Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Tolvaptan (Jynarque), which was FDA approved on April 23, 2018, is a selective vasopressin V2-receptor antagonist indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).1 Autosomal dominant polycystic kidney disease is a common disorder that affects about 1 in 1000 live births; however, ADPKD is not often diagnosed because the disease is clinically silent. Seventy-eight percent of patients who inherit this disease have an abnormality on chromosome 16, the PKD1 locus. This defect is the main causative gene for the large cysts that grow on the kidneys, as well as earlier-onset end-stage kidney disease (mean age 54.3 years), versus patients who inherit a different, but less severe phenotype of the disease.2 By selectively inhibiting the vasopressin V2-receptor in the kidneys, vasopressin can no longer bind to cysts on the kidney, yielding decreased cell proliferation and fluid secretion of the cysts. This process prevents further growth of the cysts that can contribute to decreased clinical outcomes of the disease.3

Tolvaptan was shown to slow the rate of renal function decline in patients at high risk of rapidly progressing ADPKD in the TEMPO and REPRISE trials, with both studies showing statistical significance and an efficacy profile that was generally consistent across various subgroups.1 Patients should be considered for tolvaptan if they meet the criteria listed: if their Mayo classification of disease is 1C, 1D, or 1E with eGFR in stage 3 CKD or higher; if their average kidney length is greater than 16.5 cm and they are younger than 50; if they are 55 and younger with an eGFR less than 65 mL/minute/1.73 m2; and if their PROPKD score – an algorithm to predict renal survival in patients with ADPKD – is greater than 6.4,5

Tolvaptan is dosed twice daily, with initial doses of a 45-mg tablet followed by a 15-mg tablet 8 hours later every day, titrated to a target dosage of a 90-mg tablet followed by a 30-mg tablet 8 hours later every day. Tolvaptan should be titrated as tolerated, with titrations halted if the patient is experiencing any intolerable adverse effects of the drug, including excessive polyuria/polydipsia, hypernatremia, or hepatic transaminitis, or if the serum creatinine increases by 30% from baseline. Tolvaptan is also contraindicated in patients with a history of significant hepatic impairment or injury, concomitant use of strong CYP3A4 inhibitors, abnormal serum sodium concentrations, or hypersensitivity to tolvaptan or any of its components. Doses should be adjusted and/or therapy modified in patients taking moderate CYP3A4 inhibitors. K:   Diuretics should also typically be avoided in patients taking tolvaptan to prevent dehydration and hypovolemia. Tolvaptan is also a REMS medication because of the risk of hepatic injury. Patients and providers must be enrolled in the REMS program to ensure compliance with ongoing monitoring requirements.1

Patients should consistently be monitored at the start of therapy for abnormal serum sodium and potassium concentrations, serum uric acid, and volume status, as well as provided neurologic status checks at the beginning of therapy and on a regular basis throughout. Transaminases and bilirubin should be measured before initiating treatment, 2 and 4 weeks after initiation, and then monthly for the first 18 months and every 3 months thereafter. The medication should be discontinued immediately if the patient has any signs/symptoms of liver disease or injury.1

Overall, tolvaptan holds clinical significance in patients diagnosed with ADPKD. However, a thorough patient workup should be performed and several precautions taken before initiating tolvaptan with respect to adverse effects, drug interactions, and REMS program monitoring.



  1.  Jynarque® (tolvaptan) [package insert]. Otsuka, 2020.
  2. Davies F, Coles GA, Harper PS, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med 1991;79:477-85.
  3. Indication and Important Safety Information for Jynarque® (tolvaptan). Available at
  4. Cornec-Le Gall E, Blais JD, Irazabal MV, et al. Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial. Nephrol Dial Transplant 2018;33:645-52.
  5. Soroka S, Alam A, Bevilacqua M, et al. Assessing risk of disease progression and pharmacological management of autosomal dominant polycystic kidney disease: a Canadian Expert Consensus. Can J Kidney Health Dis 2018;5:2054358118801589.


Submitted by:

Overview of the PRN, Opportunities and Resources

Marissa L. Ostroff, Pharm.D., BCPS, BCGP

Co-chair, Membership Subcommittee

Clinical Associate Professor of Ambulatory Care

Western New England University College of Pharmacy and Health Sciences

Springfield, Massachusetts


Katherine H. Cho, Pharm.D., BCACP

Chair, Programming Committee

Clinical Assistant Professor, Ambulatory Care

Temple University School of Pharmacy

Philadelphia, Pennsylvania


Novel Agents in Hyperkalemia

Annmarie Vallomthail, Pharm.D.

PGY1 Pharmacy Resident

Texas Health Harris Methodist Hospital

Fort Worth, Texas


Tolvaptan in ADPKD

Matthew Rozic, Pharm.D. Candidate 2022

Duquesne University

Pittsburgh, Pennsylvania