27.

Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram

JH, Krolewski AS. Risk of advanced diabetic nephropathy in
type 1 diabetes is associated with endothelial nitric oxide
synthase gene polymorphism. Kidney Int 2000; 57: 405413
28. Noiri E, Satoh H, Taguchi J et al. Association of eNOS
Glu298Asp polymorphism with end-stage renal disease.
Hypertension 2002; 40: 535540
29. Persu A, Stoenoiu MS, Messiaen T et al. Modier effect of
ENOS in autosomal dominant polycystic kidney disease.
Hum Mol Genet 2002; 11: 229241
30. Mendelsohn ME, Karas RH. The protective effects of estrogen
on the cardiovascular system. N Engl J Med 1999; 340:
18011811
31. Fischmann TO, Hruza A, Niu XD et al. Structural
characterization of nitric oxide synthase isoforms reveals
striking active-site conservation. Nat Struct Biol 1999; 6:
233242
32. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP,
Moss J. Intracellular processing of endothelial nitric oxide
synthase isoforms associated with differences in severity of
cardiopulmonary diseases: cleavage of proteins with aspartate
vs. glutamate at position 298. Proc Natl Acad Sci USA 2000;
97: 28322835
33. Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ,
Sessa WC. Acidic hydrolysis as a mechanism for the cleavage
of the Glu(298)!Asp variant of human endothelial nitric-oxide
synthase. J Biol Chem 2001; 276: 2667426679
34. Walker D, Consugar M, Slezak J et al. The ENOS
polymorphism is not associated with severity of renal disease
in polycystic kidney disease 1. Am J Kidney Dis 2003; 41: 9094
35. Devuyst O, Persu A, Stoenoiu MS, Lens X, Chauveau D,
Pirson Y. ENOS polymorphism and renal disease progression
in autosomal dominant polycystic kidney disease. Am J Kidney
Dis 2003; 41: 11241125
36. Boletta A, Qian F, Bhunia AK, Germino GG. PKD1-induced
morphological changes in MDCK cells require PI3kinase. J Am
Soc Nephrol 2002; 13: 105A
37. Luscher TF, Noll G. Is it all in the genes...? Nitric oxide synthase
and coronary vasospasm. Circulation 1999; 99: 28552857
38. Ruschitzka F, Corti R, Noll G, Luscher TF. A rationale for
treatment of endothelial dysfunction in hypertension.
J Hypertens 1999; 17: S25S35
Nephrol Dial Transplant (2003) 18: 22152218
DOI: 10.1093/ndt/gfg323
Controversial issues in the treatment of hyperkalaemia
Kamel S. Kamel
1
and Charles Wei
2
1
Renal Division, St Michaels Hospital, University of Toronto, Toronto and
2
Renal Division, Lakeridge Health
Corporation, Oshawa, Canada
Keywords:
2
-adrenergic agents; cation-exchange
resins; hyperkalaemia; insulin; sodium bicarbonate;
treatment
Introduction
Hyperkalaemia is a frequent medical emergency that
can cause life-threatening cardiac arrhythmias [1].
Its management remains controversial [2]. We shall
examine the clinical evidence for therapies used to
induce a shift of potassium (K

) into cells and the role

of cation-exchange resins.
Insulin
Several clinical studies support the use of insulin for the
treatment of acute hyperkalaemia in patients with end-
stage renal disease (ESRD) [37]. Blumberg et al. [3]
showed that the administration of close to 20 units
of regular insulin with glucose caused the plasma
potassium (P
K
) to fall rapidly; a drop of close to
1 mM was observed at 60 min. Supraphysiological
levels of insulin in plasma are required for maximal
K

shift. Hypoglycaemia is a frequent complication [3].

Supplementary parenteral glucose and blood glucose
monitoring are essential.
Although some advocate treating non-diabetic
hyperkalaemic patients with glucose without insulin,
we feel that this is unwise because the high levels of
insulin required might not be achieved. Also, hyper-
tonic glucose may cause K

to shift out of cells in

patients with inadequate insulin reserves, leading to a
rise in P
K
[8].
b
2
-adrenergic agonists
The ability of
2
-adrenergic stimulation to lower P
K
in
patients with ESRD has been demonstrated [4,6,914].
Allon et al. [12] treated patients on haemodialysis
who had hyperkalaemia with 10 or 20 mg of nebulized
albuterol or placebo on three separate occasions. The
administration of albuterol caused a decrease in P
K
within 30 min and the effect was sustained for at least
2 h. The mean maximum decrease in P
K
was 0.6 mM
with the 10 mg dose and 1.0 mM with 20 mg. Two
Nephrol Dial Transplant 18(11) ERAEDTA 2003; all rights reserved
Correspondence and offprint requests to: K. S. Kamel, MD, St
Michaels Hospital, 30 Bond Street, Toronto, Ontario, Canada
M5B 1W8. Email: kamel.kamel@utoronto.ca
Nephrol Dial Transplant (2003) 18: Editorial Comments 2215

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out of the 10 patients studied were resistant to the
hypokalaemic effects of albuterol. There was a minimal
increase in heart rate and a notable absence of cardio-
vascular side effects.
Nonetheless, we have reservations about the use of

2
agonists as a rst-line therapy in emergency
treatment of hyperkalaemia. First, 2040% of patients
studied have a decline in P
K
of <0.5 mM and it is not
possible to predict who will fail to respond. Secondly,
there are safety concerns because the doses used are
48 times those prescribed for the treatment of acute
asthma. Although no severe adverse events were
reported, most of these studies were performed in
stable patients. Some of these studies excluded patients
on -blockers and those with signicant coronary
heart disease or unstable heart rhythms. Therefore,
the safety of these agents was determined in a group of
patients that may not resemble the general ESRD
population.
Allon and Copkney [4] examined whether the effect
of nebulized
2
agonists is additive to that of insulin.
There was a similar decrease in P
K
with insulin
(0.65 mM) or albuterol (0.66 mM). There was a sub-
stantially greater fall in P
K
with the combined
regimen (1.2 mM). The dose of intravenous regular
insulin used in this study was only 10 units, and P
K
fell less than in studies when higher doses of insulin
were used [3]. Thus, it remains uncertain whether
2
agonists would have a P
K
-lowering effect additive to
that of insulin if insulin were given at the higher
doses.
NaHCO
3
The administration of NaHCO
3
decreases the con-
centration of H

in the extracellular uid (ECF)

compartment. In theory, if the Na

/H

exchanger
(NHE) were in an active mode, and if the administra-
tion of NaHCO
3
were to favour the movement of H

out of cells via the NHE, more Na

would enter the cell

in an electroneutral manner. The subsequent electro-
genic exit of Na

via the Na-K-ATPase would render

the cell interior voltage more negative and allow a shift
of K

into the cell [15]. It appears that the NHE is

normally inactive because the concentrations of its
substrates [Na

in the ECF compartment and H

in the
intracellular uid (ICF) compartment] are considerably
lower than that of its products (Na

in the ICF com-

partment and H

in the ECF compartment) in steady

state. A major activator of the NHE is intracellular
acidosis.
Several studies have found NaHCO
3
therapy to be
ineffective in the acute treatment of hyperkalaemia
[3,16,17]. Blumberg et al. [3] gave 100215 mmol of
intravenous isotonic or hypertonic NaHCO
3
to hae-
modialysis patients who had mild hyperkalaemia.
Although the mean plasma HCO
3

concentration
(P
HCO3
) rose from 21 to 34 mM, there was no change
in P
K
after 60 min. A subsequent study [16] found a
moderate decline in P
K
, but only after 4 h of NaHCO
3
infusion. Most of the decline was attributed to the
volume of infused NaHCO
3
.
The above studies that found a lack of effect of
NaHCO
3
were performed in stable haemodialysis
patients who did not have signicant acidosis and
therefore when the NHE was presumably in an inactive
mode. The question remains as to whether NaHCO
3
would be effective in patients with a more signicant
degree of acidosis. There are limited data in the
literature to answer this question. A report by
Schwarz et al. [18] described four uraemic patients
with P
K
values ranging from 5.9 to 8.5 mM associated
with ECG changes and a profound degree of acidosis
(P
HCO3
of 1.37.3 mM). With an infusion of between
150 and 400 mmol of NaHCO
3
, all four patients had a
signicant reduction in P
K
and improvement in ECG.
It is difcult to draw a denite conclusion from the
available data in the literature. Given this uncertainty,
we still use NaHCO
3
to treat acute hyperkalaemia
in patients with a signicant degree of acidosis, but not
as the only emergency therapy to shift K

into cells.
Caution is warranted, as excessive administration of
NaHCO
3
can induce hypernatraemia, ECF volume
expansion, carbon dioxide retention and a fall in
ionized serum calcium levels.
Studies that examined the combined use of NaHCO
3
with insulin had conicting results. Allon and Shanklin
[5] found that the addition of NaHCO
3
did not enhance
the P
K
-lowering effect of insulin. In contrast, Kim [7]
found a synergistic effect of NaHCO
3
with insulin.
It should be noted, however, that the patients studied
by Allon and Shanklin [5] were not hyperkalaemic
(mean P
K
4.5 mM).
Cation-exchange resins
A cation-exchange resin is a cross-linked polymer with
negatively charged structural units. The resin can
exchange bound Na

(Kayexalate) or Ca
2
(calcium
resonium) for cations including K

.
Kayexalate contains 4 mEq of Na

per gram. This

Na

is theoretically exchangeable for 4 mEq of K

.
Thus, 30 g of Kayexalate could possibly remove
120 mEq of K

. However, this degree of exchange

does not occur at the Na

and K

concentrations
found in the gastrointestinal tract. Based on in vitro
binding characteristics of Kayexalate, it seems that the
Na

and K

concentrations at which 50% of the initial

Na

would be exchanged for K

were 65 and 40 mM,

respectively [19]. With a higher concentration of Na

and/or a lower concentration of K

, less exchange
would be expected to take place. In the duodenum, Na

concentration is 140 mM and K

is close to 5 mM.
In the distal ileum, Na

concentration is 125 mM and

K

concentration is 9 mM. Na

concentration de-
creases in the colon to 40 mM and the concentration
of K

rises to 90 mM [20]. It seems that the only

favourable location for the exchange of Na

for K

is
in the lumen of the colon. Data from patients with
2216 Nephrol Dial Transplant (2003) 18: Editorial Comments

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ileostomia, however, indicate that the amount of K

that is not absorbed in the small intestine and hence

would have been delivered to the colon and be available
for that exchange is only 5 mmol per day [21,22].
In humans, active secretion of K

in the gastro-
intestinal tract occurs in the recto sigmoid portion of
the colon. One possible theoretical benet to the use of
cation-exchange resins is that, if they were to lower
the K

concentration in luminal feacal water, the net

secretion of K

by the colon would be enhanced. A

number of other cations are available in the colon to
exchange for resin-bound Na

, including NH
4

, Ca
2
and Mg
2
. The concentration of NH
4

in stool water
may be high in patients with ESRD. Ca
2
and Mg
2
have an even greater afnity for the resin than K

because of their divalent positive charge.

Colonic secretion of K

in normal subjects is
4 mmol per day [21]. It has been suggested that
patients with ESRD have an enhanced colonic secre-
tion of K

that is perhaps mediated by aldosterone

[23,24]. Balance data are conicting, and the evidence
that there is a substantial increase in K

excretion by
the gastrointestinal tract in patients with ESRD is not
convincing [25]. Even if there was an adaptive increase
in colonic K

secretion, stool volume would be

limiting. If one assumes a lumen negative transepithe-
lial voltage of as high as 90 mV (measured values are
signicantly lower, close to 40 mV [23]) and a plasma
K

of 5 mM, the concentration of K

in stool water
would be 100 mM. With a usual stool weight of 125 g,
of which 75% is water, only 10 mmol of K

would
be excreted. In experiments where dialysis bags were
placed into the rectum of subjects with chronic renal
failure, the rate of net K

secretion was 1.5 mmol/h/cm

2
of rectal surface area [24,25]. Agarwal et al. [25] pointed
out that a subject with an average rectal surface area
of 100 cm
2
would only be able to have a net secretion of
4 mmol of K

per day. If, however, this high rate of K

secretion was to be present unabated throughout the

entire colon, faecal K

excretion would be as high as

70 mmol per day, if stool volume was not limiting. It is
also notable that these studies have likely signicantly
overestimated the rate of K

secretion by the rectum,

since they were conducted with a low K

concentration
in the bags.
Two reports are commonly cited to support the
use of resins for treatment of hyperkalaemia [26,27].
Although both studies concluded that resins were
useful for treating hyperkalaemia, it should be noted
that several doses were given, sometimes for a number
of days, and that the effect on P
K
was noted after 15
days. Furthermore, it is not clear whether the effect was
due to the resin or merely to the induction of diarrhoea
with hypertonic glucose or other cathartics.
Two recent studies have re-examined the effect of
cathartics and/or resins on faecal K

excretion [19,28].
Emmett et al. [19] showed that, in normal subjects, the
addition of the resin to sorbitol or sodium sulphate did
not signicantly increase stool K

excretion compared
to either laxative alone. Phenolphthalein resulted in the
highest stool K

excretion rate compared to the other

laxatives; the addition of Kayexalate to phenolphtha-
lein increased K

excretion only modestly.

Gruy-Kapral et al. [28] studied the effect of a single
dose of cathartic and/or resin on faecal K

excretion
and P
K
in ESRD patients. Their results show that resins
do not contribute to faecal K

excretion above the

effect of cathartics alone. Although the patients were
not initially hyperkalaemic, none of the regimens used
reduced P
K
.
In summary, we do not use resins for treatment of
acute hyperkalaemia. In the setting of chronic hyper-
kalaemia, it seems that the addition of resins to cathar-
tics adds little to the induction of diarrhoea alone.
Conclusions
Evidence supports the use of insulin with glucose as the
rst-line therapy to induce a shift of K

in the emer-
gency management of hyperkalaemia.
2
agonists lower
plasma K

concentration to a similar degree as insulin

but are ineffective in a signicant number of patients,
and questions remain about their safety. We continue
to use NaHCO
3
in patients with a signicant degree of
acidosis, but not as the only therapy. Cation-exchange
resins are not effective in the treatment of acute
hyperkalaemia. The addition of resins does not
signicantly enhance the excretion of K

beyond the
effect of diarrhoea induced by osmotic or secretory
cathartics.
Conict of interest statement. None declared.
References
1. Weiner DI, Wingo CS. Hyperkalemia: a potential silent killer.
J Am Soc Nephrol 1998; 9: 15351543
2. Iqbal Z, Friedman EA. Preferred therapy of hyperkalemia in
renal insufciency: survey of nephrology training-program
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3. Blumberg A, Weidmann P, Shaw S et al. Effect of various
therapeutic approaches on plasma potassium and major regulat-
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4. Allon M, Copkney C. Albuterol and insulin for treatment of
hyperkalemia in hemodialysis patients. Kidney Int 1990; 38:
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hyperkalemia in renal failure with salbutamol inhalation.
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14. Mandelberg A, Krupnik Z, Houri S. Salbutamol metered-dose
inhaler with spacer for hyperkalemia: how fast? how safe?
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15. Halperin ML, Kamel KS. Potassium. Lancet 1998; 352:
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16. Blumberg A, Weidmann P, Ferrari P. Effect of prolonged
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20. Johnson LR. Fluid and electrolyte absorption. In:
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23. Sandle GI, Gaiger E, Tapster S, Goodship THJ. Evidence for
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24. Martin RS, Panese S, Virginillo M et al. Increased secretion of
potassium in the rectum of humans with chronic renal failure.
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with a cation-exchange resin. N Engl J Med 1961; 264: 115119
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Nephrol Dial Transplant (2003) 18: 22182221
DOI: 10.1093/ndt/gfg324
Percutaneous coronary interventions in patients with mild to moderate
chronic renal failure: to dilate or not to dilate?
Holger Reinecke
1
and Roland M. Schaefer
2
1
Department of Cardiology and Angiology and
2
Department of Nephrology, Hospital of the University of Mu nster,
Mu nster, Germany
Keywords: chronic renal failure; outcome; percuta-
neous coronary intervention
Introduction
Worldwide, the incidence of chronic kidney disease has
risen relentlessly over recent years due to an increasing
prevalence of diabetes mellitus and arteriosclerotic
vascular disease [14]. A further increase in the
number of patients with chronic renal failure has to
be expected in the coming years [4,5]. Thus, adequate
management of these patients will become a more and
more pressing issue in clinical medicine.
It is well known from patients with end-stage renal
failure that a large number will develop cardiovascular
disease over time and that coronary heart disease
(CHD), myocardial infarction and congestive heart
failure represent major causes of morbidity and
mortality in these patients [6]. Moreover, chronic
renal failure not yet requiring renal replacement ther-
apy has not been recognizedat least by many
cardiologistsas an important cardiovascular risk
factor. However, a few but very consistent recent
studies provided good evidence that even mild to
moderate chronic renal failure is associated with
markedly impaired long-term survival.
Chronic renal failure and cardiovascular risk
Recent data from the ARIC (Atherosclerosis Risk in
Communities) study [7] in 15 350 healthy subjects with-
out known cardiovascular disease showed that a re-
Nephrol Dial Transplant 18(11) ERAEDTA 2003; all rights reserved
Correspondence and offprint requests to: Dr H. Reinecke,
Medizinische Klinik und Poliklinik C, Universita tsklinikum
Mu nster, D-48129 Mu nster, Germany. Email: reinech@uni-
muenster.de
2218 Nephrol Dial Transplant (2003) 18: Editorial Comments

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