View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Kidney International, Vol. 38 (1990), pp. 1159—1163

Hyperkalemia in acute glomerulonephritis due to transient hyporeninemic hypoaldosteronism

BURL R. DON and MORRIS SCHAMBELAN

Medical Service, San Francisco General Hospital Medical Center, and Department of Medicine, University of California, San Francisco, California, USA

Hyperkalemia in acute glomerulonephritls due to transient hyporenin- hyperkalemia could be ameliorated with [8] and/or ernie hypoaldosteronism. Transient hyperkalemia has been reported to mineralocorticoid therapy [9]. occur in patients with acute glomerulonephritis, but the pathogenetic mechanism has not been investigated systematically. We studied the mechanism of hyperkalemia (5.7 to 6.7 mmollliter) in four men with Methods post-infectious glomerulonephritis. All four patients had clinical find- Patients ings consistent with acute glomerulonephritis (, , proteinuria, hematuria, and an elevated ASO titer) and a renal biopsy Four men who developed hyperkalemia in association with performed in three of the patients confirmed the diagnosis. In compar- acute post-infectious glomerulonephritis were studied. Table 1 ison to normal subjects (N =18),plasma aldosterone (5.4 1.6vs. 22,8 summarizes the clinical characteristics of the study group. All 2.6ng/dl, P <0.005) and plasma renin activity (0.3 0.2vs. 4.30.6 ng/ml/hr, P <0.005)were reduced. Hyperkalemia resolved within one patients had hypertension, edema, hematuna and proteinuria to two weeks in two patients as the nephritis resolved and diuresisand red cell casts were noted in two. Plasma volume was ensued, and aldosterone and renin levels obtained at follow-up visits increased in two of the three patients in whom this determina- were normal. Hyperkalemia persisted despite furosemide-induced di- tion was made (normal range, 35 to 44 mI/kg body wt). The ASO uresis in the other two patients, but resolved with fludrocortisonetiter was elevated in all, and in the three patients in whom treatment. Thus, hyperkalemia in patients with acute glomerulonephri- tis is a manifestation, in part, of hyporeninemic hypoaldosteronism. It complement levels were measured, serum C-3 was reduced. A is ameliorated by mineralocorticoid therapy and improves spontane- renal biopsy was performed in patients 2, 3 and 4 which ously with resolution of the glomerulonephritis. demonstrated findings confirming the diagnosis of acute prolif- erative glomerulonephritis, including hypercellularity of the glomeruli with a neutrophilic infiltrate, and intramembranous and subepithelial deposits. Serum concentration Hyperkalemia due to impaired renal excretion of potassiumranged from 5.7 to 6.7 mmol/liter despite only a mild to has been reported to occur transiently in patients with acutemoderate reduction in the clearance of creatinine, which ranged glomerulonephritis [1], but the pathogenetic mechanism ac-from 24 to 65 ml per minute (Table 1). Three of the four patients counting for this phenomenon has not been investigated sys-has subnormal serum levels of total CO2 and hyperchloremia, tematically. Impaired renal excretion of potassium generallyand arterial blood gases performed in patients 2 and 3 indicated results from severe renal insufficiency, decreased levels of orthe presence of a mild metabolic acidosis. Plasma cortisol level tubular resistance to mineralocorticoid hormone, a primarywas normal (14.5, 9.7, and 9.4 jsg/dl) in the three patients (1, 2, potassium secretory defect in the collecting tubule or a combi-and 3) in whom the measurement was performed. nation of these abnormalities [2]. Inasmuch as acute glomeru- Plasma aldosterone levels and plasma renin activity (PRA) lonephritis is usually associated with only a moderate reductionwere measured after the patients had been recumbent over- in glomerular function, renal insufficiency per se appears to benight, and after two hours of upright activity. Urine aldosterone an unlikely cause. In patients with mild to moderate renalexcretion rates were also measured in patients 1, 2, and 3. insufficiency, hyperkalemia is often due to hyporeninemic hy-Dietary intake for patients 1, 3 and 4 was 23, 99 and 87 mmol per day, respectively, and was ad libitum in patient 2. poaldosteronism, a syndrome recognized with increasing fre- quency in the past two decades [3—7]. The purpose of the Active clinical glomerulonephritis and the associated hyper- present study was to evaluate the renin-aldosterone axis inkalemia resolved rapidly (within 1 to 2 weeks) in patients 1 and patients who developed hyperkalemia in the course of acute2, whereas a protracted course of glomerulonephritis and per- post-infectious glomerulonephritis and to determine if thesistent hyperkalemia were observed in patients 3 and 4. Patient 3 was transferred to the General Clinical Research Center at San Francisco General Hospital Medical Center where he was placed on a constant metabolic diet containing 1.8 mmol Received for publication March 16, 1990 sodium, 1.0 mmol potassium and 40 kcal per kg body weight per and in revised form June 22, 1990 day. After four days of baseline observations, furosemide Accepted for publication June 28, 1990 treatment was begun, initially at a dose of 40mg per day for four © 1990 by the International Society of days and then at a dose of 80 mg per day for six additional days.

1159 1160 Don andSchambeian:Hyperkalemiainacute giomeruionephritis

Table 1.Clinical characteristics and laboratory data in patients with acute glomerulonephritis

ASO Arterial Plasma titer Urine Creatinine NaK Cl TCO2 pH BP volume RBC Todd C3 protein clearance Pt Age mm Hg Edema mi/kg casts units mg/di g/24 hr mi/mm mmoi/liter

1 34 166/108 +++ 61.6 + 960 63 3.1 65 137 6.7 109 19 ND 2 47 135/90 +++ ND — 680 ND 7.5 39 137 6.0 112 18 7.34 3 46 158/103 ++ 61.3 + 480 49 6.1 24 128 5,7 105 13 7.36 4 17 170/100 ++ 38.0 — 680 74 15.5 35 142 6.4 107 28 ND ND =Not determined

Because of persistent hyperkalemia despite furosemide ther- Table 2. Plasma aldosterone concentration and renin activity in apy, fludrocortisone, 100 g per day, was addedtothe treat- patients with acute glomerulonephritis ment regimen and observations were continued for six addi- Plasma aldosterone Plasma renin activity tional days. Venous blood samples were obtained each morning ng/di ng/mI/hr prior to breakfast and urine was collected in 24 hour pools for Pt RecumbentUprightRecumbentUpright measurement of sodium and potassium concentrations. In ad-Patients with acute dition, blood was obtained after overnight recumbency and two glomerulonephritis hours of upright activity every two to three days for measure- 1 4.9 8.3 0.2 0.2 ment of aldosterone and renin levels. 2 7.4 5.9 0.7 0.9 Patient 4 also failed to undergo a spontaneous diuresis during 3 1.3 0.6 0.1 0.1 4 ND 6.6 ND 0.1 nine days of observation. He was then treated sequentially withMean 4.5' 54C 03b 0.3C furosemide (40 to 240 mg per day) and fludrocortisone (100 per day) for six and 18 days, respectively. Normal control Laboratory methods subjects (N =18) Mean 8.9 22.8 1.8 4.3 Sodium and potassium concentrations were measured using a flame photometer. Serum and urine creatinine concentrations Comparisons between the patient group and the normal control were measured by enzymatic techniques on an automatedsubjects were made by one-way ANOVA. ND, Not determined. chemical analyzer. Plasma volume was determined by measur- aP< 0.03 ing the volume of distribution of radiolabelled 1251 human serum bP< 0.01 albumin and expressed as ml per kg ideal body weight. Plasma P <0.005 renin activity [10] and plasma and urine aldosterone were measured by radioimmunoassay [11]. phase of their acute glomerulonephritis. In patient 2, attendant Statistics with the diuresis (weight loss 2.5 kg), hyperkalemia was ame- Datain the patients were compared to values in 18 normalliorated (4.2 mmol/liter), and PRA (2.3 ng/ml/hr) and plasma men ranging in age from 22 to 57 years old by one-way analysisaldosterone concentration (11.8 ng/dl) returned to normal lev- of variance and linear regression analysis as indicated. Differ-els. However, in patient 1, PRA (0.1 ng/ml/hr) and aldosterone ences were considered to be statistically significant at a P valueconcentration (2.0 ng/dl) remained reduced despite a diuresis <0.05. (13.5 kg weight loss) and a return of plasma potassium concen- tration to normal levels (4.2 mmol/liter). On a subsequent Results outpatient follow-up visit three months later, patient 1 had a Both plasma aldosterone levels and PRA were significantlynormal PRA (1.2 ng/ml/hr). lower in the patients with acute glomerulonephritis than in the In patient 3, hyperkalemia persisted despite treatment with control subjects (Table 2). Similarly, urine aldosterone excre-furosemide and a concomitant diuresis (4.4 kg weight loss). tion was markedly reduced (2.0, 1.4, and 2.0 ttg/24 hr, normal 5Eventually a steady state ensued during which plasma potas- to 20 g/24 hr) in the three patients (1, 2, and 4) in whom it wassium averaged 5.7 mmol/liter and urinary sodium (136 5 measured. We have reported previously that urinary aldoste-mmolld) and potassium (33 Immol/day) excretion were rone excretion correlates positively with serum potassiumconstant (Fig. 2). Because of the failure of furosemide to concentration in patients with hyporeninemic hypoaldosteron-ameliorate hyperkalemia, fludrocortisone was added. Urinary ism, albeit at a reduced level in comparison to subjects withsodium excretion decreased and potassium excretion increased normal plasma renin levels [5]. As is evident in Figure 1, whenresulting in positive sodium and negative potassium balance, analyzed in this fashion, aldosterone excretion rates in therespectively. Plasma potassium concentration decreased rap- patients with acute glomerulonephritis were significantly re-idly in response to this therapy. Throughout both treatment duced in comparison to normal subjects and indistinguishableperiods urinary aldosterone excretion and PRA levels remained from those with hyporeninemic hypoaldosteronism. low. The patient was discharged from the hospital on fludro- Plasma aldosterone and PRA were also measured in samplescortisone therapy and was subsequently lost to follow-up. obtained from patients 1 and 2 during the natriuretic/recovery Patient 4 demonstrated a similar pattern in that his hyperkale- Don and Schambelan: Hyperkalemia in acute glomerulonephritis 1161

15 I Furosemide I 0 Fludrocortisone - I E 0 E 10

C0 0 0 E 0 a- 30 20

10 E 0 I I I I > 4.0 4.5 5.0 5.5 6.0 6.5 Serum potassium, mmo///iter Fig.1. Relationship between urinary aldosterone excretion and serum ::° potassium concentration in patients with acute glomerulonephritis (•), hyporeninemichypoaldosteronism (0). and normal control subjects (0). Urinary aldosterone excretion rates correlated positively with ° plasma potassium concentration in the patients with HH (r =0.58,P < 0.01)[5]. Urinary aldosterone excretion in three patients with acute > —150 glomerulonephritiswas similar to that in the patients with HH.

—250 mia (5.5 to 6.4 mmol/liter) was resistant to furosemide at a dose of 240 mg/day despite a 3.1 kg weight loss, but was ameliorated with 100 g of fludrocortisone (5.0 mmol/liter). Subsequently, >0 after his acute nephritis resolved, he was normokalemic (4.2 mmol/liter) and had a normal urinary aldosterone excretion rate (30.3 gIday). 1 2 3 4 56 78 Discussion Time,days Fig.2Plasmapotassium concentration, urinary potassium, sodium The results of this study demonstrate that, in patients whoand aldosterone excretion, and plasma renin activity in response to develop hyperkalemia during the course of acute post-infec-treatment with furosemide alone and in combination with fludrocorti- tious glomerulonephritis, the renin-aldosterone axis is sup-sone in patient 3. Hyperkalemia persisted despite treatment with pressed. The magnitude of the reduction in aldosterone levelsfurosemide at a dose of 80 mg per day. Eventually, a steady state ensued during which the daily urinary potassium and sodium excretion observed in these patients is even more striking when consid-rates were constant (days I to 3). Values of A urine potassium and ered in light of the markedly elevated levels of plasma potas-sodium excretion represent the daily differences from the mean value sium, inasmuch as potassium directly stimulates aldosteroneduring these three days and those of I the accumulated sum of the biosynthesis [12, 13]. Aldosterone deficiency despite hyperkale-daily differences during the period of fludrocortisone treatment. In mia could result from a primary abnormality in adrenocorticalresponse to fludrocortisone, urinary sodium excretion decreased and potassium excretion increased resulting in positive sodium and negative function such as Addison's disease, which seems an unlikelypotassium balance, respectively. Plasma potassium decreased rapidly possibility in view of the normal levels of cortisol and thein response to this therapy while plasma renin activity and urinary absence of markedly elevated levels of PRA that are character-aldosterone excretion rates remained low. istically seen in this disorder [14, 15]. Rather, aldosterone deficiency despite hyperkalemia in these patients can be ac- counted for by impaired renin secretion, in view of the evidence that indicates a primary role of angiotensin II in the mainte-perkalemia was ameliorated during the recovery phase despite nance of aldosterone biosynthesis [16, 171. The degree ofpersistent hypoaldosteronism (patient 1) indicates that factors suppression of both aldosterone and renin noted in thesein addition to mineralocorticoid deficiency must be contributing patients is comparable to that we [3, 5] and others [6, 7] haveto the impaired renal potassium secretion that is present during reported to occur in patients with hyporeninemic hypoaldoste-the acute nephritic phase. This is not surprising, inasmuch as ronism. Yet, hyporeninemia hypoaldosteronism is usually seenmineralocorticoid deficiency alone (such as, in patients with in the setting of chronic renal disease and tends to persist. ToAddison's disease who are maintained on glucocorticoid re- our knowledge, acute glomerulonephritis is the only disorder inplacement therapy) does not ordinarily result in significant which hyporeninemia and hypoaldosteronism are transient inhyperkalemia if renal function is normal, dietary sodium is nature and are ameliorated with resolution of the nephritis. adequate, and potassium intake is not excessive [14]. A reduc- As illustrated by patients 3 and 4, impaired renal potassiumtion in delivery of filtrate to the distal consequent to excretion in patients with acute glomerulonephritis is mm-impaired glomerular filtration rate [18] might well be an addi- eralocorticoid responsive. However, the observation that hy-tional factor that limits potassium secretion during the acute 1162 DonandSchambelan: Hyperkalemiain acute glomerulonephritis phase of glomerulonephritis, given the flow dependence of Acknowledgments potassium secretion in distal segments of the nephron [19]. This work was supported by U.S. Public Health Service Research Hyperkalemia has also been described in patients with sys- Grant HL-1 1046 from the National Heart, Lung and Blood Institute. temic lupus erythematosus in both the acute nephritic andThe studies were carried out in the General Clinical Research Center chronic stages of this disorder. The pathogenesis of this phe- (RR-83) at San Francisco General Hospital with support by the National nomenon is unclear. On the basis of an impaired kaliUreticCenter for Research Resources of the National Institutes of Health. Dr. Don is a Clinical Associate Physician of the General Clinical Research response to sodium and mineralocorticoid therapyCenter at San Francisco Hospital, supported by a grant from the in a single patient with acute lupus nephritis, Hadler, Gill andNational Center for Research Resources (RR-83). Gardner [20] suggested that renal tubular potassium secretion is impaired in this disorder. However, renin and aldosterone data Reprint requests to Burl R. Don, M.D., Building 100, Room 286, San were not provided in that report. DeFronzo et al. [211 studiedFrancisco General Hospital, San Francisco, California 94110, USA. two patients with lupus nephritis and noted that they had a normal renin-aldosterone axis, but that the kaliuretic response References to treatment with mineralocorticoid or acetazolamide plus bicarbonate was impaired. They also concluded that these I. GLAssocK Ri, ADLER SG, WARD Hi, COHEN AH: Primary glomer- patients had a primary defect in renal tubular potassium secre- ular diseases, in The , edited by BRENNER BM, RECTOR FJ tion. In contrast to these findings, Lee et al [22] screened a large iR, Philadelphia; W.B. Saunders Company, 1986, pp. 929—1013 2. SEBASTIAN A, SCHAMBELAN M: Renal hyperkalemia. Semin Neph- population of patients with systemic lupus erythematosus and rol 7:223—237, 1987 noted that those with hyperkalemia had reduced levels of PRA 3. SCHAMBELAN M, STOCKIGT JR, BIGLIERI EG: Isolated hypoaldo- and plasma aldosterone which failed to respond appropriately steronism in adults. A renin-deficiency syndrome. N Engl J Med to either furosemide or captopril stimulation. They concluded 287:573—578, 1972 4. PHELPS KR, LIEBERMAN RL, OH MS, CARROLL Hi: Pathophysi- that hyporeninemic hypoaldosteronism plays an important role ology of the syndrome of hyporeninemic hypoaldosteronism. Me- in the pathogenesis of hyperkalemia in systemic lupus erythe- tabolism 29:186—198, 1980 matosus. 5. SCHAMBELAN M, SEBASTIAN A, BIGLIERI EG: Prevalence, patho- It is possible that, in addition to impaired aldosterone secre- genesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency. Kidney mt tion, patients with hyperkalemic post-infectious glomerulone- 17:89—101, 1980 phritis may have a component of tubular unresponsiveness to 6. DEFRONZO RA: Hyperkalemia and hyporeninemic hypoaldoste- mineralocorticoid hormone to account for the hyperkalemia. ronism. Kidney mt 17:118—134, 1980 Often with acute glomerulonephntis, there is an associated 7. WEIDMANN P. REINHART R, MAXWELL MH, ROWE P, COBURN interstitial nephritis [23] and this may impair distal tubular JW, MASSRY SG: Syndrome of hyporreninemic hypoaldosteronism and hyperkalemia in renal disease. J Clin Endocrinol Metab 36:965— function. Rubini, Sanford and Meroney [24], in a report of a 977, 1973 patient with acute post-infectious glomerulonephritis, attrib- 8. SEBASTIAN A, SCHAMBELAN M, SurroN JM: Amelioration of uted the hyperkalemia to a primary potassium secretory defect hyperchloremic acidosis with furosemide therapy in patients with because the patient's aldosterone excretion rates were normal chronic renal insufficiency and type 4 . Am J or increased. However, the patient did have an appropriate Nephrol 4:287—300, 1984 9. SEBASTIAN A, SCHAMBELAN M, LINDENFELD S, MORRIS RC iR: kaliuresis after treatment with sodium bicarbonate or acetazol- Amelioration of metabolic acidosis with fludrocortisone therapy in amide. Thus, it seems unlikely that this patient had a true hyporeninemic hypoaldosteronism. N Engl J Med 297:576—583, primary tubular defect resulting in impaired secretion of potas- 1977 sium, but rather tubular resistance to mineralocorticoid hor- 10. STOCKIGT JR, COLLINS RD, NOAKES CA, SCHAMBELAN M, Bio- LIERI EG: Renal-vein renin in various forms of renal hypertension. mone. Lancet 1:1194—1197, 1972 The pathogenesis of hyporeninemia in acute glomerulone- II. MAYES D, FURUYAMA S. KEM DC, NUGENT CA: A radioimmuno- phritis is unknown. Both damage to the juxtaglomerular appa- assay for plasma aldosterone. J Clin Endocrinol Metab 30:682—685, ratus with impaired release of renin as well as physiologic 1970 suppression of renin secretion by volume expansion, which 12. HIMATHONGKAM T, DLUHY RG, WILLIAMS GH: Potassium-aldo- sterone-renin interrelationships. J Clin Endocrinol Metab 41:153— have been proposed as possible pathogenetic factors in patients 159, 1975 with chronic renal diseases and hyporeninemic hypoaldoste- 13. WILLIAMS Gil, BRALEY LM: Effects of dietary sodium and potas- ronism [4, 25, 261, may be operative in acute glomerulone- sium intake and acute stimulation on aldosterone output by isolated phritis. Artenolitis can occur in acute glomerulonephritis [27] human adrenal cells. J Clin Endocrinol Metab 45:55—64, 1977 14. SEBASTIAN A, SUTTON iM, HUTLER HN, SCHAMBELAN M, POLER so that an inflammatory process affecting juxtaglomerular ap- SM: Effect of mineralocorticoid replacement therapy on renal paratus might impair renin release. Glassock et al [1] have acid-base homeostatis in adrenalectomized patients. Kidney mt proposed that PR.Aissuppressed in patients with acute glomer- 18:762—773, 1980 ulonephritis as a consequence of volume expansion [28, 29] IS. SMITH SG, MARKANDU ND, BANKS RA, DORRINOTON-WARD P, resulting from the primary renal sodium and water retention MACGREGOR GA, BAYLE55 J, PRENTICE MG, WISE P: Evidence that patients with Addison's disease are undertreated with fiudro- characteristic of this disorder [18]. Intravascular volume expan- cortisone. Lancet 1:11—14, 1984 sion was present in two of the three patients in whom plasma16. PRArT JH: Role of angiotensin II in pottassium-mediated stimula- volume determinations were obtained. In addition to volume tion of aldosterone secretion in the dog. J Clin Invest 70:667—672, medicated suppression of renin secretion, were the primary 1982 17. YOUNG DB: Quantitative analysis of aldosterone's role in potas- renal sodium reabsorption to occur in the macula densa seg- sium regulation. Am J Physiol 255:F81 l—F822, 1988 ment of the nephron, the secretion of remn might be suppressed 18. GLASSOCK Ri: Sodium homeostasis in acute glomerulonephritis and by a non-baroreceptor mechanism [30]. the nephrotic syndrome. Contr Nephrol 23:181—203, 1980 Don and Schambelan: Hyperkalemia in acute glomerulonephritis 1163

19. GooD DW, WRIGHT FS: Luminal influences on potaasium secre-25. SCHINDLER AM, SOMMERS SC: Diabetic sclerosis of the renal tion: Sodium concentration and fluid flow rate. AmJ Physiol 236: juxtaglomerular apparatus. LabInvest 15:877—884,1966 F192—F205, 1979 26. OH MS, CARROLL Hi, CLEMMONS JE, VAGNUCCI AH, LEvisoN 20. HADLER NM, GILL JR, GARDNER JD: Impaired renal tubular SP, WHANG ESM: A mechanism for hyporeninemic hypoaldoste- secretion of potassium, elevated sweat sodium chlroide concentra- ronism in chronic renal disease. Metabolism23:1157—1166,1874 tion and plasma inhibition of erythrocyte sodium outfiux as complica- 27. INGELFINGER JR. MCCLUSKEY RT, SCHNEEBERGER EE, GRUPE tions of systemic lupus erythematosus. ArthRheum 15:515—523, 1972 WE: Necrotizing arteritis in acute poststreptococcal glomerulone- 21. DEFRONZO RA, COOKE CR, GOLDBERG M, Cox M, MYERS AR, phritis. JPediatr 91:228—232,1977 Acus ZS: Impaired renal tubular potassium secretion in systemic 28. POWELL HR, R0TENBERG E, WILLIAMS AL, MCCREDIE DA: Intern Med 86:268—271,1977 lupus erythematosus. Ann Plasma renin activity in acute poststreptococcal glomerulonephritis 22. LEE FO, QUISM0RI0 FP, TROUM OM, ANDERSON PW, Do YS, HSUEH WA: Mechanisms of hyperkalemia in systemic lupus and the haemolytic-uraemic syndrome. ArchDis in Child 49:802— erythematosus. ArchIntern Med 148:397—401,1988 807, 1974 23. GRUNFELD i-P., KLEINKNECHT D, DROZ D: Acute interstitial 29. BIRKENHAGER WH, SCHALEKAMP MADH, SCHALEKAMP-KUYKEN nephritis, in Diseasesof the Kidney, editedby ScURIER RW, MPA, KOLSTERS G, DIuss XH: Interrelations between arterial GOTTSCFIALK CW, Boston/Toronto, Little, Brown, 1988, pp. 1461— pressure, fluid-volumes, and plasma-renin concentration in the 1488 course of acute glomerulonephritis. Lancet1:1086—1087,1970 24. RuBINI ME, SANFORD JP, MERONEY WH: Studies of potassium 30. SKorr 0, BRIGGS JP: Direct demonstration of macula densa- secretion in glomerulonephritis. AmJ Med 17:790-797.1957 mediated renin secretion, Science237:1618-1620,1987