Nephrol Dial Transplant (2003) 18: Editorial Comments 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

2215 vs. glutamate at position 298. Proc Natl Acad Sci USA 2000; 97: 28322835 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 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 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 Boletta A, Qian F, Bhunia AK, Germino GG. PKD1-induced morphological changes in MDCK cells require PI3kinase. J Am Soc Nephrol 2002; 13: 105A Luscher TF, Noll G. Is it all in the genes...? Nitric oxide synthase and coronary vasospasm. Circulation 1999; 99: 28552857 Ruschitzka F, Corti R, Noll G, Luscher TF. A rationale for treatment of endothelial dysfunction in hypertension. J Hypertens 1999; 17: S25S35

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Nephrol Dial Transplant (2003) 18: 22152218 DOI: 10.1093/ndt/gfg323

Controversial issues in the treatment of hyperkalaemia

Kamel S. Kamel1 and Charles Wei2
Renal Division, St Michaels Hospital, University of Toronto, Toronto and 2Renal Division, Lakeridge Health Corporation, Oshawa, Canada
1

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.

potassium (PK) 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, hypertonic glucose may cause K to shift out of cells in patients with inadequate insulin reserves, leading to a rise in PK [8].

Insulin
Several clinical studies support the use of insulin for the treatment of acute hyperkalaemia in patients with endstage 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
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

b2-adrenergic agonists
The ability of 2-adrenergic stimulation to lower PK 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 PK within 30 min and the effect was sustained for at least 2 h. The mean maximum decrease in PK was 0.6 mM with the 10 mg dose and 1.0 mM with 20 mg. Two

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Nephrol Dial Transplant (2003) 18: Editorial Comments

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 cardiovascular 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 PK 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 PK with insulin (0.65 mM) or albuterol (0.66 mM). There was a substantially greater fall in PK with the combined regimen (1.2 mM). The dose of intravenous regular insulin used in this study was only 10 units, and PK fell less than in studies when higher doses of insulin were used [3]. Thus, it remains uncertain whether 2 agonists would have a PK-lowering effect additive to that of insulin if insulin were given at the higher doses.

NaHCO3
The administration of NaHCO3 decreases the concentration of H in the extracellular uid (ECF) compartment. In theory, if the Na/H exchanger (NHE) were in an active mode, and if the administration of NaHCO3 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 electrogenic 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 compartment and H in the ECF compartment) in steady state. A major activator of the NHE is intracellular acidosis. Several studies have found NaHCO3 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 NaHCO3 to haemodialysis patients who had mild hyperkalaemia. Although the mean plasma HCO3 concentration (PHCO3) rose from 21 to 34 mM, there was no change in PK after 60 min. A subsequent study [16] found a

moderate decline in PK, but only after 4 h of NaHCO3 infusion. Most of the decline was attributed to the volume of infused NaHCO3. The above studies that found a lack of effect of NaHCO3 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 NaHCO3 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 PK values ranging from 5.9 to 8.5 mM associated with ECG changes and a profound degree of acidosis (PHCO3 of 1.37.3 mM). With an infusion of between 150 and 400 mmol of NaHCO3, all four patients had a signicant reduction in PK 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 NaHCO3 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 NaHCO3 can induce hypernatraemia, ECF volume expansion, carbon dioxide retention and a fall in ionized serum calcium levels. Studies that examined the combined use of NaHCO3 with insulin had conicting results. Allon and Shanklin [5] found that the addition of NaHCO3 did not enhance the PK-lowering effect of insulin. In contrast, Kim [7] found a synergistic effect of NaHCO3 with insulin. It should be noted, however, that the patients studied by Allon and Shanklin [5] were not hyperkalaemic (mean PK 4.5 mM).

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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 Ca2 (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 decreases 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

Nephrol Dial Transplant (2003) 18: Editorial Comments

2217

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 gastrointestinal 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 NH4, Ca2 and Mg2. The concentration of NH4 in stool water may be high in patients with ESRD. Ca2 and Mg2 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 secretion 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 transepithelial 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/cm2 of rectal surface area [24,25]. Agarwal et al. [25] pointed out that a subject with an average rectal surface area of 100 cm2 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 PK 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 phenolphthalein 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 PK 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 PK. In summary, we do not use resins for treatment of acute hyperkalaemia. In the setting of chronic hyperkalaemia, it seems that the addition of resins to cathartics 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 emergency 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 NaHCO3 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.

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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 directors. N Engl J Med 1989: 320: 6061 3. Blumberg A, Weidmann P, Shaw S et al. Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. Am J Med 1988; 85: 507512 4. Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. Kidney Int 1990; 38: 869872 5. Allon M, Shanklin N. Effect of bicarbonate administration on plasma potassium in dialysis patients: interactions with insulin and albuterol. Am J Kidney Dis 1996; 28: 508514 6. Lens XM, Montoliu J, Cases A, Campisotol JM, Rever L. Treatment of hyperkalemia in renal failure: salbutamol v. insulin. Nephrol Dial Transplant 1989; 4: 228232 7. Kim HJ. Combined effect of bicarbonate and insulin with glucose in acute therapy of hyperkalemia in end-stage renal disease patients. Nephron 1996; 72: 476482 8. Conte G, Dal Canton A, Imperatore P et al. Acute increase in plasma osmolality as a cause of hyperkalemia in patients with renal failure. Kidney Int 1990; 38: 301307 9. Montoliu J, Lens XM, Revert L. Potassium-lowering effect of albuterol for hyperkalemia in renal failure. Arch Intern Med 1987; 147: 713717 10. Liou HH, Chiang SS, Wu SC et al. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure. Am J Kidney Dis 1994; 23: 266270

2218 11. Kemper MJ, Harps E, Muller-Wiefel DE. Hyperkalemia: therapeutic options in acute and chronic renal failure. Clin Nephrol 1995; 46: 6769 12. Allon M, Dunlay R, Copkney C. Nebulized albuterol for acute hyperkalemia in patients on hemodialysis. Ann Intern Med 1989; 110: 426429 13. Montoliu J, Almirall J, Ponz E et al. Treatment of hyperkalemia in renal failure with salbutamol inhalation. J Intern Med 1990; 228: 3537 14. Mandelberg A, Krupnik Z, Houri S. Salbutamol metered-dose inhaler with spacer for hyperkalemia: how fast? how safe? Chest 1999; 115: 617622 15. Halperin ML, Kamel KS. Potassium. Lancet 1998; 352: 135142 16. Blumberg A, Weidmann P, Ferrari P. Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. Kidney Int 1992; 41: 369374 17. Guttierez R, Schlessinger F, Oster JR et al. Effect of hypertonic versus isotonic sodium bicarbonate on plasma potassium concentration in patients with end-stage renal disease. Miner Electrolyte Metab 1991; 17: 297302 18. Schwarz KC, Cohen BD, Lubash GD et al. Severe acidosis and hyperpotassemia treated with sodium bicarbonate infusion. Circulation 1959; 19: 215220 19. Emmett M, Hootkins RE, Fine KD. Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion. Gastroenterology 1995; 108: 752760 Nephrol Dial Transplant (2003) 18: 22182221 DOI: 10.1093/ndt/gfg324

Nephrol Dial Transplant (2003) 18: Editorial Comments 20. Johnson LR. Fluid and electrolyte absorption. In: Johnson LR, ed. Gastrointestinal Physiology. Mosby Yearbook, Philadelphia, PA: 1997; 135145 21. Binder HJ, Sandle GI. Electrolyte absorption and secretion in mammalian colon. In: Johnson RL, ed. Physiology of the Gastrointestinal Tract. Raven Press, New York, NY: 1987; 13891418 22. Kanaghinis T, Lubran M, Coghil NF. The composition of ileostomy uid. Gut 1963; 4: 322338 23. Sandle GI, Gaiger E, Tapster S, Goodship THJ. Evidence for large intestinal control of potassium homeostasis in uremic patients undergoing long term dialysis. Clin Sci 1987; 73; 247252 24. Martin RS, Panese S, Virginillo M et al. Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 1988; 8: 105110 25. Agarwal R, Afzalpurkar R, Fordtran J. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology 1994; 107: 548571 26. Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol. N Engl J Med 1961; 264: 111115 27. Scherr L, Ogden DA, Mead AW. Management of hyperkalemia with a cation-exchange resin. N Engl J Med 1961; 264: 115119 28. Gruy-Kapral C, Emmett M, Santa Ana CA. Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease. J Am Soc Nephrol 1998; 9: 19241930

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Percutaneous coronary interventions in patients with mild to moderate chronic renal failure: to dilate or not to dilate?
Holger Reinecke1 and Roland M. Schaefer2
Department of Cardiology and Angiology and 2Department of Nephrology, Hospital of the University of Munster, Munster, Germany
1

Keywords: chronic renal failure; outcome; percutaneous 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 therapy 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

Correspondence and offprint requests to: Dr H. Reinecke, Medizinische Klinik und Poliklinik C, Universitatsklinikum Munster, D-48129 Munster, Germany. Email: reinech@uni muenster.de

Recent data from the ARIC (Atherosclerosis Risk in Communities) study [7] in 15 350 healthy subjects without known cardiovascular disease showed that a re-

Nephrol Dial Transplant 18(11) ERAEDTA 2003; all rights reserved