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Key Words vances and several upcoming outcome trials will provide
Dyskalemia Acidosis Mineral bone disorder further information to guide treatment and improve patient
Dysnatremia Dysmagnesemia Chronic kidney disease outcomes. 2017 S. Karger AG, Basel
End-stage renal disease
Abstract Introduction
The kidneys play a pivotal role in the regulation of electrolyte
and acidbase balance. With progressive loss of kidney Chronic kidney disease (CKD) has become a global
function, derangements in electrolytes and acidbase inevi- epidemic with an estimated prevalence of 14% in the
tably occur and contribute to poor patient outcomes. As United States and 515% throughout the world [1, 2]. It
chronic kidney disease (CKD) has become a worldwide is associated with an increased risk of adverse cardiovas-
epidemic, medical providers are increasingly confronted cular outcomes, progression to end-stage renal disease
with such problems. Adequate diagnosis and treatment will (ESRD), and decreased survival. As the kidneys play a
minimize complications and can potentially be lifesaving. In central role in the regulation of body fluids, electrolytes
this review, we discuss the current understanding of the and acidbase balance, CKD and ESRD predictably result
disease process, clinical presentation, diagnosis and treat- in multiple derangements including hyperkalemia, meta-
ment strategies, integrating up-to-date knowledge in the bolic acidosis and hyperphosphatemia which, in turn,
field. Although electrolyte and acidbase derangements are lead to serious complications including muscle wasting,
significant causes of morbidity and mortality in CKD and bone-mineral disorder, vascular calcification and mortal-
end-stage renal disease patients, they can be effectively ity. Although, in patients with ESRD, some derangements
managed through a timely institution of combined preven- can be corrected by the renal replacement therapy, exist-
tive measures and pharmacological therapy. Exciting ad- ing dialysis modalities are far from ideal. In this review,
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E-Mail karger@karger.com
200 First Street SW, Rochester, MN 55905 (USA)
www.karger.com/bpu
E-Mail qian.qi@mayo.edu
we discuss the current understanding of disease process, and can cause multiple electrocardiographic changes in-
diagnosis, and treatment strategies in the areas of electro- cluding peaked T waves, prolonged PR interval, loss of P
lyte and acidbase regulation relevant to CKD and ESRD, waves and widening of QRS complex [9]. It should, how-
with specific emphasis on dyskalemia, acidosis and min- ever, be noted that ECG itself is insensitive in detecting
eral bone disorder (MBD). hyperkalemia. CKD patients can have severe hyperkale-
mia without any ECG manifestation [10]. In patients with
implanted cardioverter/defibrillator, severe hyperkale-
Potassium Derangements mia could alter the device-triggering threshold, leading to
under- or over-sensing, and triggering of inappropriate
Potassium (K) is the most abundant intracellular cat- shock [11].
ion with >98% of total body K located intracellularly and Another increasingly common and difficult scenario is
<2% extracellularly. The steep trans-cellular K gradient, the inability to use many potentially lifesaving therapies
generated in an energy-dependent (Na-K-ATPase) man- for CKD patients due to hyperkalemia. A compelling ex-
ner, is vital to the maintenance of cell membrane poten- ample is the use of renin-angiotensin-aldosterone (RAAS)
tial and multiple cellular functions. Kidneys, in response inhibitors. There is definitive evidence supporting the
to increased serum K, aldosterone, distal renal tubular benefit of RAAS inhibitors in heart failure, acute coro-
sodium (Na) delivery and tubular fluid flow, excrete 98% nary syndrome, CKD, and diabetic nephropathy; yet, hy-
of daily K intake and are the organs that play a major role perkalemia often limits their use. A database study (n =
in the maintenance of K homeostasis. CKD and ESRD 205,108) of patients on RAAS inhibitors has shown that
inevitably lead to K derangements and increased risk of RAAS inhibitors were discontinued in 1618% of the pa-
adverse cardiovascular events and mortality [3]. tients due to medication-associated hyperkalemia.
Among those who discontinued RAAS inhibitors, the
Hyperkalemia mortality rate was threefold higher than in those who
Hyperkalemia is one of the most common and life- continued with the treatment [12].
threatening electrolyte disorders in CKD and ESRD [4]. Until recently, therapeutic options for hyperkalemia
It becomes increasingly prevalent as CKD advances [5, 6]. have been limited to a low K diet, discontinuation of RAAS
Hyperkalemia has been classified somewhat arbitrarily inhibitors, and initiation of loop or thiazide diuretics and
into mild (5.1<6 mmol/l), moderate (6<7 mmol/l) and oral Na polystyrene sulfonate (a polymer that exchanges Na
severe (7 mmol/l) [7]. Diagnosis of hyperkalemia should for K, calcium, ammonium and magnesium (Mg) [13]). Al-
be confirmed to rule out pseudo-hyperkalemia, which though approved by the US Food and Drug Administra-
can be caused by poor phlebotomy technique, hemolysis tion (FDA) to treat hyperkalemia in 1958, Na polystyrene
in the test tube, thrombocytosis, and leukocytosis [8]. sulfonate has not been shown to increase fecal K loss in
Although primarily caused by reduced kidney function, human or animal study. A recent randomized controlled
hyperkalemia can also be caused or exacerbated by (1) study showed K reduction in a cohort of CKD patients (n=
trans-cellular shift due to insulin deficiency, mineral met- 33) with mild hyperkalemia [14]. Fatal colonic necrosis and
abolic acidosis and tissue breakdown (hemolysis, rhabdo- perforation have been reported with its use [15].
myolysis, tumor lysis, and tissue ischemia), (2) high K Patiromer is a newer K-lowering agent, a non-absorb-
intake (usually in patients with underlying CKD) and (3) able, sorbitol-containing, calcium-K exchange polymer,
medication-induced defects in renal K excretion, most which binds K primarily in the colon [16]. In healthy in-
commonly angiotensin converting enzyme (ACE) inhib- dividuals, patiromer exhibits a dose-dependent lowering
itors, angiotensin receptor blockers (ARBs), mineralo- of urine K, Na, phosphate and Mg, consistent with an in-
corticoid receptor antagonists, K sparing diuretics, and creased intestinal binding of these ions. It, on the con-
calcineurin inhibitors. Diabetic CKD patients are also at trary, increases urine calcium excretion, reflecting its cal-
risk for developing hyperkalemia due to hyporeninemic cium-releasing capacity [22]. It has an onset of action of
hypoaldosteronism (type 4 renal tubular acidosis). 7 h. The OPAL-HK study [17] demonstrated the achieve-
Clinical manifestations of hyperkalemia vary widely ment of normokalemia after 4 weeks of patiromer treat-
from nonspecific muscle weakness to paresthesia, paraly- ment in 76% of hyperkalemic CKD stages 3 and 4 patients
sis, cardiac arrhythmias and cardiac arrest. Cardiac man- (n = 237) on RAAS inhibitors. In AMETHYST-DN trial
ifestations of hyperkalemia are of critical importance. [18] involving CKD stages 3 and 4 patients (n = 306) on
Hyperkalemia reduces the transmembrane K gradient RAAS inhibitors with diabetes and hyperkalemia, signifi-
156.217.38.99 - 4/9/2017 3:55:26 PM
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