renin-aldosterone system can respond to furosemide in patients with hyperkalemic hyporeninism

Renin-aldosterone system can respond to furosemide in patients with hyperkalemic hyporeninism

RICHARD CHAN, JEAN E. SEALEY, MICHAEL F. MICHELIS, ALEXANDER SWAN, ANTONY E. PFAFFLE, MARIA V. DEVITA, and PAUL M. ZABETAKIS

NEW YORK, NEW YORK

Thirty-four patients (65.3 _+ 3.3 years of age, mean +_ SEM) with hyperkalemia (serum potassium >5.0 mEq/L) had measurement of their renin-aldosterone system. Nine- teen patients (56%) had plasma renin activity (PRA) >1.5 ng/mL/h, which was not low, while 15 (44%) had PRA <1.5. Twelve of the 15 hyporeninemic hyperkalemic patients were studied to determine whether their renin-aldosterone system responded to 2 weeks of furosemide, 20 mg daily. Four were nonresponders: PRA averaged 0.3 _+ 0. I ng/mL/h, and it did not increase with furosemide or respond to captopril before or after furosemide. Eight patients were responders: PRA averaged 0.6 _+ 0.2 ng/mL/h and increased with furosemide to 5.5 _+ 3.4 ng/mL/h. Captopri l failed to increase PRA before furosemide, but PRA increased to 15.3 _+ 8.4 ng/mL/h after furosemide. Plasma aldosterone was low in both nonresponders and responders (3.5 _+ 1.2 ng/dL vs 5.8 + 2.5 ng/dL) and did not increase signif icantly with furosemide (4.3 + 1.7 ng/dL vs 8.7 _+ 2.5 ng/dL). Serum potassium did not fall and therefore did not limit the rise in aldosterone. Renin responders had greater body weight, were predominantly female (6/8 vs 2/4) and were more likely to have diabetes mellitus (7/8 vs 0/4). Plasma atrial natriuretic pept ide (ANP) fell with furosemide in 8 of 8 responders and in I of the 2 nonresponders in whom it was measured. Neither group had suppressed plasma prorenin levels, indicat ing no suppression of renin gene expression. These results indicate that many hyperkalemic patients do not have suppressed PRA. Further, a majority of patients with suppressed PRA have high levels of ANP and can respond to diuretic therapy with a rise in PRA and a fall in ANP, suggesting physiologic suppression of the renin system by volume expansion. A minority of hyperkalemic patients with suppressed PRA had PRA that did not increase under these study conditions. (J Lab Clin Med 1998; 132:229-35)

Abbreviations: ANP = atrial natriuretic peptide; PRA = plasma renin activity

H yperkalemia may be observed in a variety of clinical circumstances. 1 It occurs with little or no increase in total body potassium in such

conditions as insulinopenia or metabolic acidosis when

From the Nephrology Section, Department of Medicine, Lenox Hill Hospital, and the Cardiovascular Center, New York Hospital-Cornell University Medical College. Supported by National Institutes of Health Grant HL 18323SCR and by grants from the Starr and Maxwell Foundations. Submitted for publication February 25, 1998; accepted April 26, 1998. Reprint requests: Richard Chan, MD, 130 East 77th Street, New York, NY 10021. Copyright © 1998 by Mosby, Inc. 0022-2143/98 $5.00 + 0 5/1/91584

potassium shifts from intracellular to extracellular fluid. 2-4 Hyperkalemia usually develops, however, when renal potassium excretion is impaired.I, 5 The major route of potassium elimination is the distal nephron of the kidney, where luminal sodium is reab- sorbed in exchange for potassium, a mechanism facili- tated by aldosterone. 6

Disorders of renin or aldosterone production, or defi- ciencies in renal tubular function, may therefore result in hyperkalemia. Examples of such conditions are the syndrome of hyporeninemic hypoaldosteronism, Addi- son's disease, and renal tubular dysfunction caused by tubulointerstitial disease. 7-tl Inhibition of aldosterone- stimulated renal tubular potassium excretion also occurs during angiotensin-converting enzyme inhibi-

229

J Lab Clin Med 230 Chanet al September 1998

HYPERKALEMIA AND THE RENIN-ALDOSTERONE SYSTEM

34 PATIENTS WITH HYPERKALEMIA

19 (56%) 15 (44%) PRA > 1.5 ng/m~hr PRA < 1.5 ng/mL/hr

. /?-. . . 8 (67%) 4 (33%) 3

responsive* not responsive not available for further study

PRA = plasma renin activity *responsive = PRA increased after furosemide treatment

Fig 1. Results of plasma renin activity measurements in 34 patients with hyperkalemia.

tion. 12 Decreased PRA or plasma aldosterone and hyperkalemia may also occur in association with the use of nonsteroidal anti-inflammatory drugs and cyclosporine A, and infection with Mycobacterium avium intracellularae and cytomegalovirus virus and the use of heparin. 13-16 Changes in other variables such as age and body potassium stores may also influence levels of renin and aldosterone. 17,18

The syndrome of hyporeninemic hypoaldosteronism is characterized by low levels of PRA and plasma aldosterone in association with hyperkalemia and mild-to- moderate renal insufficiency. It may occur as part of a variety of disorders including infection with human immunodeficiency virus, systemic lupus erythematosus with renal involvement, and--most frequently--in patients with diabetic nephropathy.6j4j 9-23

The pathogenesis of the low plasma renin levels in diabetic patients remains uncertain, although a deficiency of prorenin processing to renin has been postulated. 24 Plasma prorenin levels are normally 10 times higher than those of renin but can be as much as 100- fold higher in patients with diabetic nephropathy. 25 Wil- son and Luetscher have shown that the increase in plasma prorenin precedes the development of diabetic nephropathy in teenaged patients. We have observed a relationship between high plasma prorenin levels and increased blood flow to kidneys and reproductive organs, leading us to postulate that high prorenin levels may actually predispose to hyperperfusion and thus be the cause of renal injury in diabetic patients. 26

However, other pathophysiologic events can lead to suppression of plasma renin and aldosterone levels. 27 An increase in intravascular volume may result in volume-induced increases in ANR which can suppress plasma levels of both PRA and plasma aldosterone. %-32 The production of ANP increases in states of volume

16--

14--

12--

10--

8 - -

6 - -

4 - -

2 - -

[ ] precaptopril

IM postcaptopril

._ i_11 baseline furosemide

PRA (ng/mL./hr)

8

baseline l

furosemide aldosterone

(no/dE)

8 0 _

7 0 _

6 0 -

5 0 - 40_ 30_ 20_ 10_

['7 baseline

[ ] furosemide

40

3 0 _

2 0 _

1 0 _

prorenin (ng/mL)

m

l ANP

(fmol/mL)

baseline vs. furosemide * p=0.06 ** p<0.01

Fig 2. Responses before and after captopril, before and after furosemide administration, for PRA, plasma aldosterone, prorenin, and ANP, in 8 hyperkalemic hyporeninemic patients responsive to furosemide.

excess as the result of distention of stretch receptors in atrial myocytes. 33 With increased intravascular volume, increased perfusion of the juxtaglomerular apparatus may also suppress PRA.

Therapy for hyperkalemic hyporeninemic hypoaldosteronism has included such diverse approaches as the oral administration of potassium-binding resins, the administration of agents with mineralocorticoid activity, and the use of diuretic therapy. 9,21 Because PRA and plasma aldosterone have been noted to decrease with age,17,34, 35 and because hyperkalemia is not uncommon in older patients, 6,~6 we investigated hormone levels and responses in a group of patients with hyperkalemia, many of whom were elderly. Our hypothesis concerned possible interrelationships between hyporeninemic hypoaldosteronism and the intravascular volume status of patients with this disorder. For this reason, responses of PRA, plasma aldosterone, and ANP to short-term

J Lab Clin Med Volume 132, Number 3 Chan et al 231

diuretic administration were also evaluated. This study proposed to determine the frequency of decreased plasma renin and aldosterone and increased ANP in patients with hyperkalemia and to determine whether PRA and aldosterone would increase and ANP would fall with pharmacologically induced volume depletion.

METHODS

Patients from inpatient and outpatient services of the Lenox Hill Hospital, New York, NY, were screened for serum potassium levels >5.0 mEq/L. Subjects receiving potassium sup- plements, potassium-sparing diuretics, nonsteroidal anti- inflammatory drugs, angiotensin-converting enzyme inhibitors, beta-blocking agents, or heparin were excluded. Patients with advanced renal insufficiency, as demonstrated by serum creatinine >5.0 mg/dL, were also excluded. After informed consent was obtained, baseline levels of PRA and plasma aldosterone were measured. A standard captopril stimulation test was then performed as follows to measure the responsiveness of the renin-aldosterone axis. 37 Captopril (25 mg), crushed and dissolved in water, was administered to the patient after 30 minutes of quiet rest in a seated position. Blood samples were obtained at time 0 (T = 0) and 60 minutes (T = 60). Blood pressure was measured in triplicate every 15 miuutes, and the average values were recorded. Blood was immediately centrifuged at room temperature (for PRA, plasma aldosterone, prorenin, and electrolytes) or in the cold (4 ° C) (for ANP) and then frozen.

Patients with plasma renin activity below 1.5 ng/mL/h before and after captopril administration were included for further study. They were given furosemide, 20 mg daily by mouth, for 2 weeks. Changes in body weight were recorded, and a second captopril stimulation test was then performed. Plasma electrolytes, blood urea nitrogen, and plasma creatinine were analyzed by standard laboratory methods with an autoanalyzer (Ektachem; Eastman Kodak, Rochester, NY). PRA and prorenin 38 were measured by radioimmunoassay. ANP was measured as previously described. 39 Plasma aldosterone was measured with a kit from ICN.

Statistical analysis was performed by using Student's t test with the Microsoft Excel statistical analysis program. Com- parisons of data obtained were made before and after capto- pill and furosemide administration. Differences were consid- ered to be significant at P < .05.

RESULTS

Thirty-four patients were enrolled in the study. Their mean serum potassium value was 5.7 + 0.1 mEq/L. Their mean age was 65.3 +- 3.3 years (range 24 to 90 years). Of the initial 34 patients, 19 (56%) did not have hyporeninemia (Fig 1), defined as plasma renin activity <1.5 ng/mL/h. Their PRA and plasma aldosterone averaged 9.3 + 3.7 ng/mL/h and 7.8 + 2 ng/dL, respectively, and they were excluded from further study.

The remaining 15 of 34 (44%) had an initial PRA <1.5 ng/mL/h. Their mean PRA was 0.6 + 0.1 ng/mL/h before

captopril and 0.6 + 0.1 ng/mL/h after captopril (not significant). Plasma aldosterone was borderline low at 5.0 +_ 1.6 ng/dL and did not increase after captopril, 4.0 +_ 1.1 ng/dL (not significant). These subjects could be consid- ered to have hyperkalemic hyporeninemic hypoaldosteronism that was unresponsive to stimulation by captopril.

Of these 15 patients, 12 subjects agreed to a 2-week course of furosemide, 20 mg daily. After furosemide therapy, 4 patients continued to have low baseline (T = 0) PRA and plasma aldosterone (0.4 + 0.1 ng/mL/h and 4.3 + 1.7 ng/dL, respectively [Table I]). In these subjects, body weight did not fall significantly with furosemide (59.6 + 5.5 kg to 58.4 + 5.6 kg [-2%][not significant]), and serum creatinine also did not increase significantly (2.3 + 0.7 to 2.7 _+ 0.8 mg/dL [not significant]). Moreover, after furosemide, PRA and plasma aldosterone did not increase after captopril (PRA, 0.4 +_ 0.1 ng/mL/h; plasma aldosterone, 2.4 + 0.7 ng/mL [not significant]). Serum potassium did not fall in 3 of these 4 patients after furosemide. Furthermore, plasma ANP levels were 22 and 17 fmol/mL before furosemide and 13 and 55 fmol/mL after furosemide in the 2 patients in whom it was measured (not significant). Plasma prorenin averaged 27 _+ 6 ng/mL/h before furosemide and 31 + 7 ng/mL/h after furosemide (not significant). Plasma prorenin increased in 2 patients (from 15 to 23 ng/mL/h and from 29 to 46 ng/mL/h) and fell slightly in the other 2 (from 43 to 39 ng/mL/h and from 19 to 15 ng/mL/h).

In contrast, furosemide increased PRA in the remaining 8 patients after furosemide (Fig 2 and Table II), from 0.6 -+ 2 ng/mL/h to 5.5 _+ 3.4 ng/mL/h. Plasma aldosterone also increased, but not significantly, from 5.8 _+ 2.5 ng/mL to 8.7 +_ 2.5 ng/mL. Serum potassium fell in only 2 of 7 patients in which it was measured. Before fnrosemide, PRA after captopril was 0.5 + 0.2 ng/mL/h, whereas after furosemide, PRA after captopril was 15.3 _+ 8.4 ng/mL/h (P < .06). After furosemide, plasma aldosterone did not fall after captopril (8.7 + 2.5 ng/dL to 5.0 _+ 1.3 ng/dL, not significant). In these renin responders, body weight decreased during furosemide, from 74.4 _+ 6.0 kg to 72.9 + 6.1 kg (-2%)(P = .05). Serum creatinine increased significantly, from 2.2 + 0.3 mg/dL to 2.6 _+ 0.5 mg/dL (P < .05). ANP levels were initially elevated at 36 -+ 6 fmol/mL, and after furosemide, fell in every patient to an average of 16 + 2 fmol/mL (P < .003) (Fig 2).

The average plasma prorenin was higher than in all of the nonresponders and increased from 42 + 18 ng/mL to 61 _+ 16 ng/mL after furosemide (P < .05). Both of these values are above the normal range for prorenin, and prorenin increased in 6 of 6 patients with paired data. Ten of 19 (55%) of the hyperkalemic patients without suppressed renin had diabetes melli-

J Lab Clin M e d 232 C h a n e t al Sep tember 1998

T a b l e I. L o w - r e n i n n o n r e s p o n d e r s

Diabetes Pt Sex mellitus

PRA (ng/mL/h) Precaptopril Postcaptopril

ANP (fmol/mL) Precaptopril Postcaptopril Reninrrotal renin*

Prefurosemide

1 F N 0.2 0.2 22 24 1.3% 2 F N 0.3 0.2 17 30 1.0% 3 M N 0.8 0.7 - - - - 1.9% 4 M N 0.2 0.2 - - - - 1.0% Mean - - - - 0.3 0.3 20 27 1.3%

SEM - - - - 0.1 0.1 3 3 0 .2% Postfurosemide

1 F N 0.2 0.3 13 11 0.9% 2 F N 0.5 0.4 55 45 1.1% 3 M N 0,6 0.5 - - - - 1.5% 4 M N 0.3 0,3 - - - - 2.0% Mean ~ - - 0.4 0.4 34 28 1 .4%

SEM - - - - 0.1 0.1 21 17 0 .2%

P t - - - - 0.55 0.59 0.65 0.95 0.27

*Total renin = renin + prorenin. tPrefurosemide versus postfurosemide values,

T a b l e II. L o w - r e n i n r e s p o n d e r s

Diabetes Patient Sex mellitus

PRA (ng/mL/h) ANP (fmol/mL) Precaptopril Postcaptopril Precaptopril Postcaptopril Reninrrotal renin*

Prefurosemide

1 F Y 1.4 1.3 37 41 1.1% 2 F Y 0.5 0.6 37 14 - - 3 M Y 0.5 0.5 32 13 1.0% 4 F Y 0.4 0.4 26 16 1.0% 5 F Y 1.2 1.0 45 39 - - 6 F Y 0.1 0.1 21 17 1.0% 7 M Y 0.2 0.2 17 24 1.3% 8 F N 0.1 0.1 70 64 0.8% Mean - - - - 0.6 0.5 36 28 1 .0%

SEM - - - - 0.2 0.2 6 6 0 .1% Postfurosemide

1 F Y 2.8 3.2 20 16 2.1% 2 F Y 1.3 1.7 23 25 - - 3 M Y 1.4 1.2 15 10 1.9% 4 F Y 2,8 7,8 11 10 4.8% 5 F Y 29.0 49.0 18 23 - - 6 F Y 5.6 58.0 15 11 11.0% 7 M Y 0.9 1.1 5 4 2.7% 8 F N 0.5 0.8 23 22 2.0% Mean - - - - 5.5 15.3 16 15 4 .1%

SEM - - m 3,4 8.4 2 3 1 .5%

P t - - ~ 0.09 0.06 0.003 0.05 0.05

*Total renin = renin + prorenin, -~Prefurosemide versus postfurosemide values,

tus. Moreover, 7 of 8 (87%) of the hyporeninemic renin responders had diabetes mellitus, but none of the 4 renin nonresponders had diabetes mellitus. The renin nonresponder patients were 50% female, whereas the renin responder patients were 75% female. Although they were 75% female, body weight was 15 kg higher in the renin responder group.

D I S C U S S I O N

Hyperkalemia can occur more frequently as patients age. The reasons include age-related decreases in the levels of plasma renin and aldosterone, 34 diseases such as diabetes mellitus, and the use of a variety of drugs often prescribed for the aged including potassium-spar-

J Lab Clin M e d Volume 132, Number 3 Chan et al 233

Prorenin ALDO (ng/dL) K (nglml.) P r e c a p t o p r i l Postcaptopril (mEq/L)

BUN Cr Wt (mg/dL) (mgldL) (kg)

15 5,0 4.0 5.6 20 2.5 52.9 29 1,1 0.7 4.8 10 1.4 75.9 43 - - - - 4.6 13 1,1 56.4 19 4,3 3.1 5.3 88 4,2 53.2 27 3.5 2.6 5.1 33 2.3 59.6 6 1.2 1.0 0.2 19 0,7 5.5

23 5.2 3.5 4.9 22 3.5 49.9 46 1.1 1.0 4.9 29 1.8 75.0 39 - - - - 4.7 15 1,1 54.5 15 6.6 2.6 5.7 87 4,4 54.1 31 4.3 2.4 5.0 38 2.7 58.4 7 1.7 0.7 0.2 16 0.8 5.6

0,47 0.37 0.47 0.92 0.31 0.16 0.24

Prorenin ALDO (ng/dL) K (ng/mL) Precaptopr i l Postcaptopril (mEq/L)

BUN Cr Wt (mgldL) (mgldL) (kg)

124 1.8 1.5 5.3 59 3.1 93.1

- - 3.7 . . . . 68.2 48 3.8 1.9 4.9 42 2.3 65.2 41 2.7 2.0 5.9 32 1.1 48.0 - - 23.0 14.0 4.0 28 1.7 99.2 10 3.7 7.2 5.1 15 1.2 83.4 15 1.1 - - 4.4 19 2.3 75.5 12 6.4 5.4 5.4 45 3.5 62.3 42 5.8 5.3 5.0 34 2.2 74.4 18 2.5 2.0 0.2 6 0.3 6.0

133 1.6 1.9 5.3 93 3.8 89.1 - - 2.0 . . . . 67.3 74 1.6 0.9 5.4 57 2.9 64.5 55 20.0 9.7 5.4 37 1.3 45.7 - - 13.0 6.1 2.8 66 1.8 98,9 47 15.0 6.4 5.0 23 1.2 85.0 32 5.3 - - 5.1 23 2.6 73.6 25 11.0 5.1 5.3 64 4.6 59.1 61 8.7 5.0 4.9 52 2.6 72.9 16 2.5 1.3 0.4 10 0.5 6.1 0.01 0.36 0.88 0.69 0,01 0.03 0.05

ing diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, beta blockers, and the newer angiotensin II receptor antagonists, which can impair potassium excretion.6,21, 40 The patients included in our study were not receiving any of the above pharmacologic agents, but they were older and did include many diabetic patients. We evaluated hyper-

kalemic patients with regard to the status of their renin and aldosterone systems and their level of intravascular volume as indicated by measurement of plasma atrial natriuretic peptide. Further, the response to 2 weeks of furosemide administration was quantitated.

Thirty-four hyperkalemic patients were investigated. They had a mean age of 65.3 + 3.3 years. Because sev-

J Lab Clin Med 234 Chan et al September 1998

eral studies have suggested that there is a tendency for plasma renin activity and plasma aldosterone to decrease with age, 17,34,35 and because hyperkalemia is often associated with hyporeninemia, 21 we expected that many of our patients would have subnormal renin levels. Surpris- ingly, more than half (56%) of the patients evaluated demonstrated normal or elevated levels of PRA. It is obvious, therefore, that high levels of serum potassium can occur in other than low-renin states and that many elderly patients do not necessarily have low renin levels, as has also been previously noted. 41

When patients with low PRA were given furosemide, 66% responded with an increase in PRA into the normal range. Further, when captopril stimulation testing was performed after furosemide administration and weight loss in such responders, brisk increases in PRA occurred, in contrast to the lack of response to captopril before the furosemide. These observations are consistent with ear- lier studies in patients with chronic renal failure that demonstrate that patients with low renin activity that is unresponsive to stimulation can be made to increase their PRA to normal levels after fluid removal and that their PRA will then respond to stimulatory procedures. 42 These data would suggest, at least in some cases of hyporeninism, that low PRA is not an irreversible phe- nomenon and that it can be restored to normal levels by volume manipulation. It should also be noted that most of these responder patients had diabetes mellitus, whereas none of the nonresponders had diabetes.

Increased intravascular volume has previously been implicated in the development of hyporeninemic hypoaldosteronism.2L 43 Our data are consistent with that premise, because increased levels of ANP were found in the responders with hyporeninemia, and ANP fell in all of them in association with the rise in PRA. It could be postulated that as patients age, some may experience a decrease in renal function 44 and an increase in intravascular volume with suppression of the renin-aldosterone system. As intravascular volume increases, plasma ANP would also be expected to become elevated. Because ANP also suppresses PRA and plasma aldosterone, it could follow that a constel- lation of low PRA, low plasma aldosterone, and high ANP might occur. These patients would be expected to respond to fluid loss with increases in PRA and plasma aldosterone and a decrease in ANR Such changes occurred in 2 thirds of our low-renin patients.

Thirty-three percent of our study patients with low PRA levels and hyperkalemia did not respond to the administration of furosemide or captopril. None of these patients were diabetics. This group may indeed have an abnormal- ity in renin secretion such that it no longer responds to the usual stimuli. Such patients may be said to have true hyporeninemic hypoaldosteronism, whereas the former

patients may exhibit a pseudo hyporeninemic hypoaldosteronism related to intravascular volume excess. It is possible, however, that the degree of net fluid loss attained in this subgroup may have been insufficient to provoke the renin-aldosterone system. There was no difference in the degree of weight loss in the low-renin responders as com- pared with the nonresponders (1.4 _+ 0.7 kg vs 1.3 _+ 0.9 kg, P > .05), but additional diuresis might have increased renin-aldosterone responsiveness in the latter patients. Caution must be exercised with such manipulations in clinical practice, however, because excessive diuresis could result in an excessive decrease in intravascular volume that could compromise renal excretory function, especially with regard to potassium excretion. 45-47

The prorenin measurements are also of interest. None of the renin responders or the renin nonresponders had low prorenin levels. In fact, all of them had prorenin levels that were high in proportion to renin, such that the renin averaged only 1% in contrast to the usual 10% of total plasma renin (rehin plus prorenin). This shows that in neither group was the low renin caused by an inabil- ity to express the renin gene. Moreover, the responders increased the processing of prorenin to renin such that the ratio of renin to total plasma renin increased from 1% to 4.1% after furosemide treatment. It is also likely that much of their plasma prorenin was of renal origin, because it increased with furosemide. Plasma prorenin levels have been noted to be elevated in patients with diabetes mellitus, especially those with diabetic vascu- lar disease.24, 25 Of interest, plasma prorenin levels tend- ed to be higher in the renin responder group. This may reflect the high percentage (87.5%) of diabetic patients.

In summary, a group of elderly hyperkalemic patients was identified, and PRA and plasma aldosterone levels were characterized. Forty-four percent of patients had subnormal PRA levels. Twelve of them permitted physiologic evaluation of PRA, plasma aldosterone, and ANP with captopril testing before and after 2 weeks of furosemide. In 2 thirds of them, furosemide increased PRA into the normal range, and a normal PRA response to captopril stimulation testing developed that had not been present before furosemide; prorenin levels were elevated and increased during furosemide. These were predominantly diabetic patients. ANP was high initially in this group and fell into the normal range after furosemide. The data suggest that at least some elderly patients with hyperkalemia and suppressed PRA can respond to diuretic administration, with reversal of both low PRA and increased ANP levels.

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renin-aldosterone system can respond to furosemide in patients with hyperkalemic hyporeninism

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