Kidney International, Vol. 56 (1999), pp. 198–205

Hyperkalemia in patients infected with the humanimmunodeficiency virus: Involvement of a systemic mechanism

CARLOS CARAMELO, ELENA BELLO, ELISA RUIZ, ADELA ROVIRA, ROSA M. GAZAPO,JOSE M. ALCAZAR, NIEVES MARTELL, LUIS M. RUILOPE, SANTOS CASADO,and MANUEL FERNANDEZ GUERRERO

Fundacion Jimenez Dıaz, Hospital Clınico and Hospital 12 de Octubre, Universidad Autonoma, Madrid, Spain

Hyperkalemia in patients infected with the human immunode- Several electrolyte disturbances have been describedficiency virus: Involvement of a systemic mechanism. in individuals infected with the human immunodeficiency

Background. The appearance of hyperkalemia has been de- virus (HIV) [1, 2]. Among them, a number of casesscribed in human immunodeficiency virus (HIV)-positive pa-of hyperkalemia have been reported in HIV-positivetients treated with drugs with amiloride-like properties. Recentsubjects treated with pentamidine [3, 4] or trimethoprim-in vitro data suggest that individuals infected with HIV have

alterations in transcellular K1 transport. sulfamethoxazole [5, 6], or having hyporeninemic hypo-Methods. With the objective of examining the presence of aldosteronism [1, 7, 8]. In these three circumstances, an

alterations in transmembrane K1 equilibrium in HIV-positive impaired renal excretion of potassium has been impliedpatients, we designed a prospective, interventional study in-as the cause of the increase in plasma potassium; thisvolving 10 HIV-positive individuals and 10 healthy controls,hyperkalemia was characterized by a delayed, progres-all with normal renal function. An infusion of l-arginine (6%,

intravenously, in four 30-min periods at 50, 100, 200, and 300 sive onset. Further data, however, have raised the possi-ml/hr) was administered, and plasma and urine electrolytes, bility that HIV infection might be accompanied by alter-creatinine, pH and osmolality, total and fractional sodium and ations in the ionic transport mechanisms involvingpotassium excretion, transtubular potassium gradient, plasma

transmembrane potassium equilibrium. In this regard,insulin, renin, aldosterone, and cortisol were measured.an alteration in K1 channels has been proposed as aResults. A primary disturbance consisting of a significant

rise in plasma [K1] induced by l-arginine was detected in only major pathogenetic mechanism in AIDS-related demen-the HIV patients but not in the controls (P , 0.001 between tia [9]. Furthermore, even though pentamidine and tri-groups). A K1 redistribution origin of the hyperkalemia was

methroprim-sulfamethoxazole appeared to act by thesupported by its rapid development (within 60 min) and theblockade of an amiloride-sensitive site in the distal seg-lack of significant differences between HIV-positive individuals

and controls in the amount of K1 excreted in the urine. The fact ments of the nephron, no convincing explanation hasthat the HIV-positive individuals had an inhibited aldosterone been provided to date about the increased frequencyresponse to the increase in plasma K1 suggested a putative of hyperkalemia related to these drugs in HIV-infectedmechanism for the deranged K1 response.

individuals. This phenomenon raises the possibility thatConclusions. These results reveal that HIV-infected individ-HIV patients may have a defect in systemic K1 equilib-uals have a significant abnormality in systemic K1 equilibrium.

This abnormality, which leads to the development of hyperka- rium. To give more support to the probability of anlemia after the l-arginine challenge, may be related, in part, alteration in systemic K1 equilibrium, in a case reportedto a failure in the aldosterone response to hyperkalemia. These by Lachaal and Venuto [3], the increase in plasma K1

results provide a new basis for understanding the pathogenesisstarted during the first day of pentamidine administra-of hyperkalemia in HIV individuals, and demonstrate that thetion, several days before the appearance of renal insuffi-risk of HIV-associated hyperkalemia exists even in the absence

of amiloride-mimicking drugs or overt hyporeninemic hypoal- ciency, and too early to be considered as secondary todosteronism. an amiloride-like tubular effect. Based on these data, we

hypothesized that HIV infection might induce alter-ations leading to deranged transmembrane turnover ofKey words: HIV, AIDS, aldosterone, potassium turnover, hyporenin-

emic hypoaldosteronism, amiloride. K1, which will augment plasma K1 independently of anyputative renal effect. The aim of this study was, therefore,Received for publication October 8, 1998to examine the presence of a systemic alteration in K1and in revised form February 5, 1999

Accepted for publication February 19, 1999 equilibrium in patients infected with HIV. With this pur-pose, we used an infusion of the cationic aminoacid 1999 by the International Society of Nephrology

198

Caramelo et al: Hyperkalemia in HIV 199

l-arginine as a research tool to increase plasma K1 by K1 tween 9:30 and 10:00 a.m. After the insertion of a butter-fly needle in a peripheral arm vein, the subjects were inredistribution between the intracellular and extracellular

compartments. at least 30 minutes of rest following an overnight fast.All were submitted to a moderate water load (10 ml/kgbody wt) to ensure the availability of an adequate volume

METHODS of diuresis during the procedure. The infusion was de-Selection and characteristics of the subjects signed according to previous studies [15, 16], using a dose

of l-arginine adequate to induce renal hemodynamicThe study was carried out on 10 HIV patients (9 maleschanges but without evidence of hyperkalemia in no-and 1 female) aged 35.7 6 2.2 years (range 27 to 45HIV people. The subjects received a mean intravenousyears) and 10 controls (3 female and 7 male) who weredose of 19.0 6 3.4 g (0.29 6 0.02 and 0.28 6 0019 g/kghealthy volunteers, aged 41.0 6 4.2 years (range 20 tobody wt in HIV and control individuals, respectively)56 years). The putative causes of HIV infection wereof a 6% solution of arginine hydrochloride (Veyron ethomosexual (N 5 5) or heterosexual (N 5 2) sexualFroment, Marseilles, France) in two hours. The velocitycontact and parenteral drug addiction (N 5 3). Eightof the infusion was 50, 100, 200, and 300 ml/hr in eachpatients were included in group IV of the Centers forone of four 30-minute periods. Blood and urine samplesDisease Control (CDC) classification system, and twowere withdrawn at baseline and at 60 and 120 minutes;patients were in CDC group II. In the HIV-positivea further blood sample was extracted 60 minutes afterindividuals, CD4 were more than 500 in one patient,the end of the l-arginine infusion. Arterial blood pres-between 200 and 500 in three, between 100 and 200 in

three, and less than 100 in three cases. Body weight was sure was regularly monitored during the procedure.66.4 6 4.6 kg (range 45 to 80 kg) in HIV patients and

Analytical methods69.3 6 4.8 kg (range 50 to 84 kg) in controls. Four patientswere on trimethoprim-sulfamethoxazole at the time of K1, Na1, Cl2, osmolality, and creatinine concentra-the study. Four patients were taking combination ther- tions in plasma and urine were measured with usualapy with nucleoside analogues and protease inhibitors. routine methods. Creatinine clearance (CCr), total andAt the time of the study, no patient was receiving drugs fractional sodium excretion (FENa), total and fractionalwith potential effects on K1 metabolism other than tri- potassium excretion (FEK), and transtubular K1 gradientmethoprim-sulfamethoxazole; this exclusion involved (TTGK), were calculated. Plasma cortisol was measuredpentamidine, angiotensin-converting enzyme inhibitors, by a chemoluminescence method (Inmulite, DIPESA,b blockers, prostaglandin inhibitors, distal diuretics, or Madrid, Spain). Radioimmunoassays were used for mea-heparin [10]. suring plasma insulin (Linco Research Inc., St. Charles,

The purpose, nature, and potential risks of the study MO, USA), plasma renin activity (Sorin, Vercelli, Italy),were explained to all of the subjects, and written in- and plasma aldosterone (Sorin).formed consent was obtained before their participation.

StatisticsThe protocol was approved by our Institutional ReviewBoard and by the Review Comitee of the Fondo de The Gaussian distribution of the data was tested byInvestigaciones Sanitarias from the Ministerio de San- the Kolmogoroff–Smirnov test. Comparisons betweenidad. two sets of data were done by Student’s t-test for un-

paired observations. Comparisons between data beforeL-Arginine infusion procedure and after the l-arginine infusion were done by Student’s

The rationale for the use of l-arginine was based on t-test for paired observations. Regression analysis wasseveral previous studies that described the ability of this used to compare two continuous numerical variables,cationic amino acid to induce an increase in plasma K1 and the chi-square method was applied for significance[11–14]. The l-arginine infusion was chosen as the prefer- in 2 3 2 table distributions. All of the data are expressedential research maneuver instead of K1 infusions be- as mean 6 sd. A P value of less than 0.05 was consideredcause of the previously proven absence of risk and sec- significant.ondary effects [15], the simplicity of administration, andthe similarity with frequently used treatments, as paren-

RESULTSteral nutrition or dietary supplements [15, 16]. The alter-native procedure, namely, infusion of K1, was not used At baseline, three differences between the HIV-posi-

tive patients and the normal controls were evident: thebecause of its potential risks and the need of cannulationof major veins. All of the studies were performed in the HIV-positive individuals had decreased plasma [Na1]

and plasma [HCO32] and increased plasma [Cl2] (TableClinical Research Facility of the Nephrology Service or

the Infectious Diseases ward. The tests were started be- 1). As a result of these combined data, baseline values

Caramelo et al: Hyperkalemia in HIV200

Table 1. Plasma biochemical data in HIV patients and healthy controls at baseline and at the end of the l-arginine infusion

Plasma Na1 Plasma K1 Plasma Cl2

Plasma Cr Anion BicarbonatemEq/liter pH mg/dl gap mmol/liter Osmolality

BaselinePatients 13561.2 4.260.5 10560.7 7.3660.01 0.9 60.1 8.6 63 21.260.6 283.0612.4Controls 13961.6a 4.460.2 100.661.5a 7.3560.01 0.7 60.04 14.866.4a 23.860.6a 285.3618.2

EndPatients 13461.3 5.160.8b 10860.8 7.3560.02 1.1 60.4 5.7 64.1 20.860.7 284.3614.2Controls 14060.7a 4.260.3a 10461.8a 7.3460.03 0.7 60.1 13.764.3a 22.460.4 286.1615a P , 0.05 with respect to the other groupb P , 0.05 with respect to the baselinec The anion gap was calculated as Na1-Cl2-HCO3

2

Table 2. Effects of l-arginine infusion on creatinine clearance and in the response to l-arginine infusion observed betweenfractional excretion of sodium in HIV patients and controls

the HIV-positive and -negative individuals were not re-Patients Controls lated to the differences in the urinary excretion of K1,

CCr FENa CCr FENa because both controls and HIV-positive individuals didTime ml/min % ml/min % not have significant differences in the increase in K1

0 min 109 611.9 0.7 60.1 122610.8 0.7 60.1 filtration load, but also had a similar and rather constant60 min 174 618.3a 160.2a 180624.2a 160.2a

fractional excretion of K1 (Table 3). In addition, no120 min 146 626.2 1.4 60.3a 127.5610 1.2 60.2a

differences in baseline K1 excretion were evident be-Abbreviations are: CCr, creatinine clearance; FENa, fractional excretion ofsodium. tween both groups. A trend to present a smaller TTGK

a P , 0.05 with respect to time zerowas evident in the HIV-positive group during the l-argi-nine infusion, and the differences in TTGK reached sta-tistical significance at the 60-minute time period (Table3). When the data within the HIV-positive group wereof plasma anion gap were smaller in the HIV group.analyzed as a function of the administration or withhold-Plasma albumin concentrations were also decreased ining of trimethroprim-sulfamethoxazole, no differencesthe HIV-positive individuals (plasma albumin HIV posi-in K1 handling related to this treatment were detectedtive, 2.9 6 0.6; controls, 4.1 6 0.3, P , 0.01). These(plasma K1 at baseline, 1 hr, and 2 hr for patients takingdifferences persisted throughout the l-arginine infusiontrimethroprim-sulfamethoxazole was 4.3 6 0.2, 4.7 6at a similar level (Table 1). The changes in plasma osmol-0.08, 5.1 6 0.3 mmol/liter, respectively; for patients notality during l-arginine infusion did not reach statisticaltaking trimethroprim-sulfamethoxazoleit was 4.4 6 0.2,significance (Table 1). All of the patients and controls,4.8 6 0.4, 5.3 6 0.4 mmol/liter, respectively, P 5 NSexcept one, had normal K1 concentrations; there wasbetween groups; total urinary K1 at baseline at 1 hr, andonly one exception in the HIV group, in which one indi-2 hr in patients taking trimethroprim-sulfamethoxazolevidual (patient 7) had decreased baseline K1 levels as awas 2.6 6 1.5, 4.5 6 2.8, and 4.6 6 1.3 mmol/hr, respec-consequence of severe diarrhea lasting until two daystively; for patients taking no trimethroprim-sulfamethox-before the study. In this patient, plasma K1 did notazole it was 2.9 6 0.5, 6.28 6 0.7, 4.5 6 1.5 mmol/hr,increase with the l-arginine infusion (discussed later inrespectively, P 5 NS between groups). The doses ofthis article). In addition, a significant increase in CCr andtrimethroprim-sulfamethoxazole were, however, on asodium excretion (fractional and total) was observedminimal, preventive range and probably were not highwith the l-arginine infusion. These data are shown inenough to provoke any relevant action on renal potas-Table 2.sium excretion. As a reference, the total K1 excretionAs a principal finding, our study revealed that thein the controls at baseline, one hour, and two hours wasinfusion of l-arginine induced a significant rise in plasma3.9 6 0.5, 4.4 6 0.3, 3.4 6 0.3 mmol/hr (P 5 NS with[K1] in only the HIV-positive patients (Fig. 1A). Norespect to the HIV individuals).changes in plasma [K1] were observed with the same

The effects of l-arginine on plasma insulin, plasmainfusion in the control individuals (P , 0.001 betweenrenin activity, and plasma aldosterone are representedgroups; Fig. 1B). The changes in [K1] occurred rapidlyin Table 4. No differences between both groups in theseand were significant from the first hour of the l-arginine

infusion (Fig. 1A). Potassium concentration returned to three variables were present at baseline (Table 4). Asexpected, during the l-arginine infusion, a tendency tonormality within 60 minutes after the end of the infusion

(data not shown). As shown in Table 3, the differences increase the insulin levels was evident, albeit without

Caramelo et al: Hyperkalemia in HIV 201

Fig. 1. (A) Values of plasma K1 (mmol/liter)in HIV patients before and during L-arginineinfusion. Mean values at zero, one, and twohours (end) of l-arginine infusion. The aster-isk indicates significant values of P. Patient 7,who had hypokalemic values, has been omit-ted from this figure (discussed in text). (B)Values of plasma K1 (mmol/liter) in control,healthy individuals before and during l-argi-nine infusion. Mean values at zero, one, andtwo hours (end) of l-arginine infusion.

reaching statistical significance. A small decrease oc- increased markedly in the controls after l-arginine,curred in renin levels, which was near statistical signifi- whereas it persisted identically in the HIV patients (Ta-cance at the P 5 0.059 level in the controls, but reached ble 5). Both ratios indicate the absence of an appropriatea P value of 0.004 in the HIV-positive individuals. In aldosterone response to hyperkalemia in the HIV indi-the control subjects, the plasma aldosterone concentra- viduals. Values of baseline plasma renin activity andtion did not parallel, however, the decrease in plasma aldosterone within the range of hyporeninemic hypoal-renin activity. Actually, a tendency to increase in plasma dosteronism were present in only HIV-positive patientaldosterone was observed in these individuals (P 5 0.06). 7 (plasma renin activity, 0.4 ng/ml/hr; plasma aldoste-On the contrary, the opposite tendency, that is, a de- rone, 1.8 ng/dl), who, however, was the only one withcrease in plasma aldosterone, was observed in the HIV- decreased plasma K1. Plasma cortisol values were nor-positive group (P 5 0.08). Of note, this occurred in spite mal in all of the individuals (controls, 16.4 6 2.2 mg/dl;of the putative stimulus represented by the increase in HIV positive, 15 6 1.9 mg/dl; P 5 NS between groups).serum K1. Two further calculations were useful to evi- The infusion of l-arginine did not induce any significantdence the discrepancies in the renin-aldosterone axis change in arterial pressure (data not shown) and also didresponse to l-arginine infusion between the HIV-posi- not provoke any other reaction that could be detected bytive individuals and controls. First, the ratio between clinical means.plasma aldosterone and plasma K1, which was similarbetween groups at baseline, became significantly higher

DISCUSSIONin the control group after the infusion of l-arginine,These results disclose that HIV-infected individualswhereas it did not change and even tended to decrease

have a systemic abnormality in K1 equilibrium, whichin the HIV group (Table 5). In the same line of evidence,the ratio between plasma renin and plasma aldosterone favors the development of hyperkalemia by a mechanism

Caramelo et al: Hyperkalemia in HIV202

Fig. 1. Continued.

Table 3. Parameters of renal potassium management in HIV patients and controls

Patients Controls

K1 filtered loadc FEK1e K1 filtered loadc FEK1e

Time mmol/min TTKGd % mmol/min TTKGd %

0 min 0.460.06 5.7 62.4 11.362.5 0.560.05 6.7 61.2 14.461.460 min 0.860.1 3.9 62b 13.163.9 0.760.09 5.8 61.6 11.460.5120 min 0.760.2 3.5 61.5a 11.562.1 0.560.04 4.1 61.1a 11.461.07a

a P , 0.05 with respect to the baselineb P , 0.05 between groupsc K1 filtered load was calculated as plasma K1 concentration (mmol/liter) 3 CCr (ml/min)d TTKG: transtubular potassium gradient, calculated as [K1]u 3 [Osm]p/[K1]p 3 [Osm]ue FEK1, fractional excretion of K1

unrelated to renal K1 excretion. Accordingly, a systemic these mechanisms, however, can explain our currentfindings. In the first place, no significant differences ex-disturbance affecting K1 redistribution was revealed un-

der challenge with l-arginine. isted between the HIV individuals and the controls inthe urinary management of K1, although the values ofThese data may significantly change the previous ideas

regarding the HIV-associated potassium disturbances. In TTKG suggest that a disturbed K1 secretion was presentin the HIV individuals (discussed later in this article).prior years, hyperkalemic episodes have been reported in

HIV patients that were attributed to factors involving Second, the similarities in plasma osmolality ruled outthat the differences in K1 are due to an osmotic effect.renal excretion of K1, that is, hyporeninemic hypoaldo-

steronism [3–7, 17], administration of pentamidine or Third, in spite of the reduced mean plasma albumin, thesimilarities in baseline plasma and urinary K1 do nottrimethoprim-sulfamethoxazole [3, 5, 6, 18]. None of

Caramelo et al: Hyperkalemia in HIV 203

Table 4. Renin, aldosterone and insulin values in HIV patients and controls

Patients Controls

Reninb Aldosterone Insulin Reninb Aldosterone InsulinTime ng/ml/hr ng/dl u/liter ng/ml/hr ng/dl U/liter

0 min 1.561.3 10.767.0 13.1 65.9 1.360.9 10.365.2 12.4 63.8120 min 0.961.4a 9.468.4 18.6614.7 0.660.5 18.8611.2 17.6 615.6

a P , 0.05 with respect to the basalb Renin denotes plasma renin activity

Table 5. Relationship between plasma aldosterone and plasma tion for the increased frequency of hyperkalemia in HIVrenin activity, and plasma aldosterone and plasma potassium

patients taking drugs with amiloride-like properties. ThePatients Controls relevant role of aldosterone in the acute response to a

Time PA/PRA PA/K1 PA/PRA PA/K1 potassium load was substantiated in earlier studies innon-HIV populations [20, 21]. Other studies are, how-0 min 8.166 2.5 61.7 7.965.5 2.4 61.2

120 min 10.567 1.7 61.4 30.369.4a 4.662.6a ever, critical with this role of the absence of aldosteroneAbbreviations are: PA/PRA, relationship between plasma aldosterone and [22]. In addition to the possible role of aldosterone-

plasma renin activity; PA/K1, relationship between plasma aldosterone andrelated mechanisms, other possible interpretations forplasma potassium.

a P , 0.05 between patients and controls the deranged K1 turnover in the HIV patients can beraised. In this regard, in spite of the similar body weightof controls and HIV individuals, the possibility that thelatter had a decreased skeletal muscle mass could befavor the existence of a decreased K1 intake in the HIVtaken into account. Such a reduced muscular mass maygroup, which might induce a different K1 equilibriumdecrease the space for potassium reuptake under theand adaptation. Fourth, the timing of the plasma K1

influence of insulin. This type of re-uptake is critical inincrease, that is, within the first hour of l-arginine infu-the return to normality after hyperkalemia. Similarly,sion, diminishes the possible importance of a renal effect,the existence in HIV patients of a lower extracellularwhich would require a longer time to become relevant.volume in which to distribute the K1 driven from cellsIn fact, the time profile of the increased K1 could onlyby l-arginine can be a factor influencing the altered K1

be traced to K1 redistribution from the intracellular toturnover. As an additional consideration, even thoughthe extracellular space. Fifth, even though no baselinewe believe that a renal defect in HIV patients cannotdata of the presence of hyporeninemic hypoaldosteron-explain these findings by itself, it is possibile that a pre-ism were evident, with the exception of one patient,viously existent, deranged renal K1 excretion could beour results support the possibility that the aldosterone-partially involved in delaying the return of plasma K1

releasing response to K1 was abnormal in the HIV-posi-to normality. The main difficulty in accurately assessingtive individuals. Actually, these patients may have athis issue is that a study would be required in a controlsubclinical form of aldosterone hyporesponsiveness,group with an equivalent degree of hyperkalemia inresulting in an abnormal aldosterone response to thewhich renal K1 excretion could be monitored. The exper-increase in plasma K1. The possible existence of a de-imental approach to this topic, however, may involveranged aldosterone response in HIV has been suggestedsubstantial health risks to the volunteers.previously [17], but our current study provides the first

Our study reports the possibility of using l-argininedirect evidence of the existence of this type of alteration,infusions as a research tool for the clinical examinationto our knowledge, in a group of patients without baselineof K1 turnover. Even though this application has notabnormalities of plasma or urinary K1. The derangedbeen specifically described in the past, its rationale isaldosterone response during the l-arginine infusion infirmly supported on the previous data from the literaturethe HIV patients occurred without previous evidence of[11–14].hyporeninism and, therefore, does not fit in the classic

The absence of increase in plasma K1 by l-arginineclinical picture of hyporeninemic hypoaldosteronismin the control individuals differs from the hyperkalemia[19]. Experiments aimed to induce renin and aldosteronereported by other authors [13, 14]. This outcome was,stimulation separately, that is, captopril test and low-however, rather predictable, because we used a markedlydose angiotensin II infusions, may clarify the specificsmaller total dose over a longer time of administration.mechanisms involved. The data on TTKG are furtherThe groups reporting hyperkalemia in normal individu-suggestive of a decreased aldosterone effect in these

patients. Such a defect would provide a putative explana- als used l-arginine doses of approximately 0.5 g/kg body

Caramelo et al: Hyperkalemia in HIV204

Reprint requests to Carlos Caramelo, M.D., Laboratorio de Nefro-wt, administered in 30 minutes [13, 14]. In contrast withlogıa, Fundacion Jimenez Dıaz, Universidad Autonoma de Madrid,previous reports in non-HIV individuals [11], none of Avenue Reyes Catolicos, 2, 28040 Madrid, Spain.

our patients had renal insufficiency and no differences E-mail: ccaramelo@fjd.esexisted in the total l-arginine dose by body weight, fac-tors that minimize the possibility that a different l-argi- REFERENCESnine pharmacokinetics was involved in the observed hy-

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