CJASN ePress. Published on February 17, 2020 as doi: 10.2215/CJN.09470819
Kidney Case
Conference:
How I Treat
Electrolyte Disorders in Kidney Transplantation
Clifford D. Miles and Scott Gregory Westphal
CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.09470819
Introduction
Kidney transplantation is the treatment of choice for
ESKD. However, transplantation is associated with
a variety of potential complications. Although much
of the focus surrounds immunosuppression, electrolyte imbalances frequently arise. Herein, we discuss
several common issues: hyperkalemia, hypomagnesemia, and hyperparathyroidism, with the emphasis
on management.
Hyperkalemia
Elevation in serum potassium is common after kidney
transplantation, reported in 25%–44% of patients (1).
Contributory factors include acute or chronic reduction
in GFR, metabolic acidosis, and medications, including
trimethoprim, b-blockers, angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers, and
calcineurin inhibitors. The latter (tacrolimus and cyclosporine) are noteworthy, as their contribution to
hyperkalemia can be significant, and stopping them
requires a new immunosuppressive regimen. Mechanisms by which calcineurin inhibitors affect potassium
include inhibition of mineralocorticoid production, mineralocorticoid resistance, and activation of the thiazidesensitive sodium-chloride cotransporter in the distal
convoluted tubule (1).
Although hyperkalemia can present with weakness
or cardiac conduction disturbance, it is most often
detected on routine laboratory monitoring. For relatively mild elevation of serum potassium (5.1–5.7
mEq/L), we begin by assessing the complete metabolic profile, immunosuppressant level, and clinical
picture, as well as minimizing dietary potassium. If
new allograft dysfunction is present, hyperkalemia
may be related, and management should be directed
toward diagnosing and treating the cause of kidney
injury. With stable graft function, metabolic acidosis
(usually nonanion gap in this setting) can be addressed by supplemental oral sodium bicarbonate,
with goal serum bicarbonate of .22 mEq/L. Although
the correction of metabolic acidosis may only marginally improve potassium levels, there may be longterm benefit in slowing of CKD progression. As
calcineurin inhibitor effects on serum potassium tend
to be level-related, the dose should be adjusted to achieve
the minimum acceptable concentration. Loop diuretics
may be useful in promoting kaliuresis, although we
www.cjasn.org Vol 15 March, 2020
reserve use of these agents for patients with evidence
of volume overload (edema, short-term weight gain).
Experimental evidence suggests that patients with a
phenotype of hyperkalemia, hypertension, and acidosis
(consistent with sodium-chloride cotransporter activation) may benefit from treatment with thiazides (2).
In refractory hyperkalemia, potassium binding
agents are often effective. The recently approved
agents patiromer and sodium zirconium cyclosilicate
may offer advantages over the older sodium polystyrene sulfonate. Although large-scale clinical studies have not been performed in transplant recipients,
we have used patiromer in patients with persistent
hyperkalemia and have seen positive results. This aligns
with a recent publication showing safety and efficacy
in 19 transplant patients managed with patiromer (3).
We instruct patients to take patiromer 4 hours after
their morning mycophenolate, and have not witnessed
issues with drug–drug interaction.
More extreme hyperkalemia may warrant evaluation
in the emergency department. This allows for electrocardiographic monitoring, careful volume assessment,
and the administration of transient membrane stabilization with intravenous calcium and potassium-shifting
therapy with insulin/dextrose. In our experience, acute
dialysis is seldom required, particularly if allograft
function is preserved.
Division of
Nephrology,
Department of Internal
Medicine, University
of Nebraska Medical
Center, Omaha,
Nebraska
Correspondence:
Dr. Clifford D. Miles,
Internal MedicineNephrology, University
of Nebraska Medical
Center, 983040
Nebraska Medical
Center, Omaha, NE
68198-3040. Email:
cdmiles@unmc.edu
Hypomagnesemia
Hypomagnesemia is very common early after transplantation, and persists in at least 20% of recipients
(4). Post-transplant hypomagnesemia may be caused
by both gastrointestinal and urinary magnesium
losses. Factors contributing to gastrointestinal losses
include diarrhea and medications, including proton
pump inhibitors and patiromer. Urinary losses may be
exacerbated by the use of loop or thiazide diuretics,
and by calcineurin inhibitors, which induce urinary
magnesium wasting via downregulation of EGF and
the distal magnesium transient receptor potential
melastatin 6 (5). Although hypomagnesemia can cause
confusion, weakness, and neuromuscular irritability,
it is usually asymptomatic, noted on routine laboratory
tests. However, hypomagnesemia may be associated
with glucose dysregulation, endothelial dysfunction,
and cardiovascular events, underscoring its potential
importance in long-term outcomes (6).
Copyright © 2020 by the American Society of Nephrology
1
2
CJASN
Unfortunately, hypomagnesemia tends to be difficult
to correct. Our algorithm starts with dietary modification
and oral supplementation with magnesium oxide. Some
patients require titration up to 800 mg twice daily, although
diarrhea is a frequent dose-limiting side effect. Magnesium
chloride is another oral preparation that may be better
tolerated, although neither in our experience will reliably
increase serum magnesium into the normal range. As with
hyperkalemia, it is prudent to ensure immunosuppressant
levels are appropriate. The need for loop or thiazide diuretics
and proton pump inhibitors should be reviewed, and
alternatives considered if appropriate, although thiazideinduced magnesium wasting may be blunted in patients
on calcineurin inhibitors (2). We have had success used
amiloride, the potassium (and magnesium)-sparing diuretic. It tends to be well tolerated, and we usually
administer it while continuing magnesium supplementation. Clearly, one needs to be cognizant of the effect on
potassium levels.
Post-Transplant Hyperparathyroidism
Disorders in bone-mineral metabolism, including hyperparathyroidism, are common in patients with ESKD. After
transplantation, restoration of kidney function generally
corrects the stimuli for hyperparathyroidism, including
hyperphosphatemia and hypovitaminosis D, resulting in
the return of autoregulation of parathyroid hormone (PTH)
secretion. However, parathyroid regression is frequently
incomplete, resulting in persistent post-transplant hyperparathyroidism. The functional allograft responds to elevated PTH and fibroblast growth factor-23 (FGF-23) with
hyperphosphaturia, resulting in hypophosphatemia. Likewise, post-transplant hypercalcemia develops in response
to persistently elevated PTH, reduced skeletal resistance to
PTH, and increasing active vitamin D levels.
Hypercalcemia and hypophosphatemia develop in approximately 50% of transplant recipients, often most pronounced
2–8 weeks after transplantation (7). Although FGF-23 levels fall
quickly, hyperparathyroidism frequently persists, with .85%
of recipients having elevated PTH levels 1 year after transplantation. Persistent post-transplant hyperparathyroidism
is associated with an increased risk of acute kidney allograft
injury, graft loss, fractures, and mortality (8).
When hypercalcemia develops, medications that increase
serum calcium should be discontinued, including vitamin
D analogs, calcium supplements, calcium-based phosphate
binders, and thiazide diuretics. Patients should maintain
adequate solute and water intake to avoid volume depletion,
which can exacerbate hypercalcemia through increased
kidney absorption. Post-transplant hypercalcemia is often mild and self-limited; however, when hypercalcemia
is severe or prolonged, additional interventions may be
warranted.
Before calcimimetics, parathyroidectomy was often the
only therapy to provide a durable response to hypercalcemia caused by post-transplant hyperparathyroidism.
However, with the availability of cinacalcet, this alternative
to surgical parathyroidectomy is now widely utilized. In a
recent randomized trial, parathyroidectomy was compared
with cinacalcet for the treatment of post-transplant hyperparathyroidism (9). All patients treated with parathyroidectomy
achieved normocalcemia versus 67% of those treated with
cinacalcet, and the PTH reduction was greater in the
surgical group. Parathyroidectomy was associated with
an improvement in femoral neck bone mineral density
with no improvement observed in the cinacalcet group.
An economic analysis estimated that the cost of parathyroidectomy was equivalent to 14 months of cinacalcet.
There are, however, reasons to avoid surgery, including
patient choice, specific surgical risk factors, and the desire
to avoid early short-term risk from the transplant program’s standpoint. For such reasons, calcimimetics are
being used with increasing frequency, especially in the
early post-transplant period, to avoid or delay parathyroidectomy. In a randomized, controlled trial in patients
with hypercalcemia attributed to post-transplant hyperparathyroidism, 79% of patients treated with cinacalcet
achieved normocalcemia compared with just 4% given
placebo (10). PTH in cinacalcet-treated patients dropped
significantly and phosphorus normalized, whereas there
was minimal change in the placebo group. However,
treatment with cinacalcet did not improve clinical outcomes
such as bone density, allograft function, or allograft/patient
survival. Further, after cinacalcet discontinuation, calcium
returned toward pretreatment levels, as did phosphorus
and PTH, suggesting that cinacalcet did not facilitate
involution of parathyroid hyperplasia.
At our center, we attempt to avoid parathyroidectomy
when possible, particularly within the first post-transplant
year, as some patients will develop at least partial resolution of hypercalcemia. We initiate cinacalcet in patients
with moderate hypercalcemia (.11.0 mg/dl), particularly
if graft dysfunction or symptoms are present. We start
cinacalcet at 30 mg daily, and titrate as tolerated to achieve
normocalcemia. Gastrointestinal side effects and cost can
be barriers to use and dose escalation. We subsequently
attempt to wean cinacalcet after the first transplant year.
If hypercalcemia redevelops as cinacalcet is weaned, we
discuss the risks and benefits of parathyroidectomy compared with remaining on cinacalcet indefinitely. We consider earlier parathyroidectomy in patients with refractory
hypercalcemia that cannot be managed with cinacalcet
because of cost, side effects, or ineffectiveness.
Although cinacalcet often raises serum phosphate, maintaining normal phosphate levels can be challenging in the
early post-transplant period, particularly in those with good
allograft function. Fortunately, significant symptoms rarely
develop until phosphorus is ,1.0 mg/dl. Mild hypophosphatemia can often be managed through increased dietary
intake (e.g., dairy products). When phosphorus levels drop
below 1.8 mg/dl, we initiate oral neutral phosphorus salt
supplementation. We generally do not titrate the dose above
500 mg two times per day even if phosphorus levels remain
low, as excessive supplementation can stimulate PTH and
FGF-23, enhancing phosphaturia.
Summary
Disturbances of potassium, magnesium, and calcium/
phosphorus are common after kidney transplantation,
and deserve careful management. Serial laboratory assessment of these electrolytes is central to titration of
supplements and other interventions. As a word of
CJASN 15: ccc–ccc, March, 2020
caution, the steps we have described here may lead to
significant increase in pill burden, as these disorders often
coexist. The potential effect on quality of life and adherence to immunosuppressive medications should be borne
in mind.
Disclosures
Dr. Miles and Dr. Westphal have nothing to disclose.
References
1. Pochineni V, Rondon-Berrios H: Electrolyte and acid-base disorders in the renal transplant recipient. Front Med (Lausanne) 5:
261, 2018
2. Hoorn EJ, Walsh SB, McCormick JA, Fürstenberg A, Yang CL,
Roeschel T, Paliege A, Howie AJ, Conley J, Bachmann S,
Unwin RJ, Ellison DH: The calcineurin inhibitor tacrolimus
activates the renal sodium chloride cotransporter to cause hypertension. Nat Med 17: 1304–1309, 2011
3. Lim MA, Sawinski D, Trofe-Clark J: Safety, effectiveness, and tolerability of patiromer in kidney transplant recipients. Transplantation
103: e281–e282, 2019
4. De Waele L, Van Gaal PJ, Abramowicz D: Electrolytes disturbances after kidney transplantation. Acta Clin Belg 74: 48–52,
2019
Electrolyte Disorders in Kidney Transplantation, Miles and Westphal
3
5. Van Laecke S, Van Biesen W: Hypomagnesaemia in kidney
transplantation. Transplant Rev (Orlando) 29: 154–160, 2015
6. Sinangil A, Celik V, Barlas S, Sakaci T, Koc Y, Basturk T, Akin EB,
Ecder T: New-onset diabetes after kidney transplantation and
pretransplant hypomagnesemia. Prog Transplant 26: 55–61, 2016
7. Wolf M, Weir MR, Kopyt N, Mannon RB, Von Visger J, Deng H, Yue
S, Vincenti F: A prospective cohort study of mineral metabolism
after kidney transplantation. Transplantation 100: 184–193, 2016
8. Pihlstrøm H, Dahle DO, Mjøen G, Pilz S, März W, Abedini S, Holme
I, Fellström B, Jardine AG, Holdaas H: Increased risk of all-cause
mortalityand renal graft loss in stable renal transplant recipients with
hyperparathyroidism. Transplantation 99: 351–359, 2015
9. Evenepoel P, Cooper K, Holdaas H, Messa P, Mourad G, Olgaard
K, Rutkowski B, Schaefer H, Deng H, Torregrosa JV, Wuthrich RP,
Yue S: A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism. Am J Transplant 14: 2545–2555, 2014
10. Cruzado JM, Moreno P, Torregrosa JV, Taco O, Mast R, GómezVaquero C, Polo C, Revuelta I, Francos J, Torras J, Garcı́a-Barrasa
A, Bestard O, Grinyó JM: A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in
kidney allograft recipients with hyperparathyroidism. J Am Soc
Nephrol 27: 2487–2494, 2016
Published online ahead of print. Publication date available at
www.cjasn.org.