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Home , Hyperaldosteronism, Renin

Journal of Human (1999) 13, 75–78  1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh CASE REPORT High and non-suppressible plasma activity in a patient with producing adenoma: pathophysiologic and diagnostic implications

E Shyong Tai and PHK Eng Department of , Singapore General Hospital, Singapore

We describe a case of due to an possible pathophysiological causes of a rise in PRA in aldosterone producing adenoma with high and non-sup- this clinical setting and suggest that underlying arteri- pressible (PRA). She had sup- olar due to prolonged hypertension may be the pressed PRA at initial diagnosis. This rose above the cause of increased and non-suppressible PRA in pri- reference range for normal individuals over a period of mary aldosteronism. 7 years with untreated hypertension. We discuss the

Keywords: primary aldosteronism; plasma renin activity; diagnosis

Introduction Case report Primary aldosteronism is classically associated with Our patient was a 34-year-old woman who was hypertension, hypokalaemia and suppressed plasma found to have hypertension during the fifteenth renin activity (PRA). Most cases are due to an aldo- week of pregnancy. Plasma aldosterone was sterone producing adenoma (APA). We present a 2039 pmol/l, PRA Ͻ0.15 ␮g/l/h and a diagnosis of case of prolonged, untreated, primary aldosteronism primary aldosteronism was made. Following the due to an APA. She had suppressed PRA at the time delivery of her child, she defaulted follow-up and of diagnosis, which became elevated and non-sup- was not treated with any antihypertensives nor pot- pressible by intravenous salt loading. While raised assium supplements. PRA has been reported previously in primary aldo- In 1997, 7 years after the original diagnosis, she steronism,1 spontaneous rise in PRA from sup- suffered a thalamic haemorrhage resulting in hemi- pressed levels in any one patient with primary aldo- plegia. On admission, there was marked hyperten- steronism is unusual. We discuss the various sion (219/141 mm Hg) and hypokalaemia (serum pathophysiological processes that may have resulted K+ 1.4 mmol/l). in this change. Her ECG showed marked left ventricular hypertro- phy but the cardiac shadow was not enlarged on a Biochemical methods plain chest radiograph. No hypertensive retinopathy was noted. Serum aldosterone and PRA were Serum aldosterone (normal range 16.6–617.7 2334.4 pmol/l and 3.26 ␮g/l/h respectively. It pmol/l) was measured by radioimmunoassay (Coat- should be noted that she was on fluid restriction and A Count Aldosterone, Diagnostic Products Corpor- was undetectable in her at that time. ation, Los Angeles, CA, USA). PRA (normal range Twenty-four hour urinary catecholamines and cor- 0.66–3.08 ␮g/l/h) was assayed using radioimmu- tisol levels were normal. noassay (Incstar Gammacoat 1251 Plasma Renin Control of her pressure was achieved with Activity Radioimmunoassay kit, Incstar Corpor- prazosin 5 mg (6 hourly) and nifedipine 15 mg (8 ation, Stillwater, MN, USA). To calculate the hourly). Subsequently, she was put on an intra- aldosterone/renin ratio, the serum aldosterone was venous infusion of 2 L of normal saline and first divided by 27.75 to convert the concentration 80 mmols of daily for 3 days. Biochemi- from pmol/l to ng/dl before dividing by the PRA. cal data were obtained as in Table 1. Postural studies were not possible at the time due to the right hemi- paresis. A renogram was performed which Correspondence: Dr E Shyong Tai, Department of Endocrinology, Singapore General Hospital, 1, Hospital Drive, Singapore 169608 showed no evidence of renal stenosis. A CT Received 16 April 1998; revised 22 June 1998; accepted 4 Sep- scan of the abdomen revealed a 2 × 1 cm nodule in tember 1998 the left adrenal and normal sized kidneys. Adrenal High plasma renin in primary aldosteronism E Shyong Tai and PHK Eng 76 Table 1 Biochemistry performed after 3 days of salt loading. All presented during pregnancy with hypertension and tests were done with the patient supine hypokalaemia when we know that patients with pri- mary aldosteronism often become normotensive and 24-h urinary aldosterone 47.9 ␮g/day (6.0–25.0) 24-h urinary sodium 260 mmol/d (50–220) normokalaemic during pregnancy due to the spiro- Serum potassium 4.3 mmol/l (3.3–4.9) nolactone-like effect of . Perhaps of Plasma renin activity 4.66 ␮g/1/h (0.66–3.08) greater interest is the finding that the PRA, having (supine at 8 am) been suppressed early in the course of the disease Serum aldosterone 1023.4 pmol/l (16.6–617.7) has spontaneously risen to levels above the refer- ence range, even following salt loading. Non-sup- pressed PRA is not in itself an unusual finding in 1 sampling was performed 2 months after her primary aldosteronism. Bravo et al found that intracranial bleed. The results are in Table 2. 12.5% of patients with primary aldosteronism had She was subjected to laparoscopic adrenalectomy normal PRA and 15% had PRA above the 95% con- and a left adrenal cortical adenoma (confirmed on fidence intervals for normal individuals of the popu- ) was excised. Preoperatively, she required lation. However, the lack of suppression of PRA in prazosin 4 mg t.i.d., nifedipine 20 mg q.i.d., atenolol these individuals has never been fully explained 100 mg o.m. and 100 mg t.i.d. for and a rise in PRA from suppressed levels to above control. Despite this treatment, she the normal range have not been described in the continued to have hypokalaemia requiring oral pot- same patient. assium supplementation of 78 mmol per day. During There are several pathophysiological reasons why this period, captopril was briefly added to her treat- the PRA may have risen. Fluid and salt restriction 3 ment regimen for poorly controlled blood pressure could cause high PRA. This is the basis of diagnos- and hypokalaemia. This resulted in an acute deterio- tic tests using the PRA after salt depletion for the ration in renal function (serum rose from diagnosis of primary aldosteronism. Although PRA 93 ␮mol/l to 202 ␮mol/l) which resolved after with- usually does not exceed 2 ng/ml/h following salt drawal of the drug. Postoperatively, her blood press- depletion in primary aldosteronism,4 it does occur ure is controlled on atenolol 100 mg om and Adalat in 36% of patients. The PRA was even higher in the LA 30 mg o.m. Her serum potassium is now normal salt replete state and this is unusual. We believe the (4.8 mmol/l) without supplementation. Repeat PRA salt load was adequate as the 24-h urinary sodium was 0.52 ␮g/l/hour and serum aldosterone was was 260 mmol/l and took place 4 days after the fluid 308.8 pmol/l. restriction was lifted. We therefore do not feel that salt or fluid depletion was responsible for the hyper- reninaemia seen in this patient. Other causes of Discussion renal hypoperfusion such as cardiac failure, There is little doubt that this patient had primary or nephrotic syndrome were not evident. aldosteronism at the time of her initial presentation This patient did not exhibit any oedema or hypo- given the presence of hypertension, hypokalaemia, albuminaemia to suggest nephrotic syndrome. very high levels of serum aldosterone and PRA sup- Drugs can give rise to hyperreninaemia and these pressed below the limits of the assay. Even allowing would include the -converting for the rise in plasma aldosterone during normal inhibitors, the aldosterone antagonist spironolac- pregnancy, the value of 2039 pmol/l exceeds the lev- tone, or angiotensin II receptor antagonists. None of els expected in the first trimester although it could these agents were used in this patient. The calcium be considered normal in the third trimester. Further- channel blockers can raise PRA in normal indi- more, the increase in plasma aldosterone during viduals. This occurs through inhibition of calcium pregnancy is correlated with an increase in the PRA entry into juxtaglomerular apparatus cells resulting rather than suppression as seen in this case.2 Pri- in renin release. Although this patient was on nifed- mary aldosteronism is confirmed again by failure of ipine at this time, we do not feel this is sufficient to suppression of the 24-h urine aldosterone excretion explain all the current findings. below 14 ␮g/day,1 which is perhaps the most sensi- Hyperreninaemic hypertension has been reported 5 tive test for primary aldosteronism. There are sev- in association with acute pyelonephritis, unilateral 6–8 eral unusual features about this case. This patient hydronephrosis and blunt trauma to the kid- ney.9,10 It has also been reported following haemor- rhage into the perinephric space from polycystic Table 2 Results of adrenal venous sampling. The levels 11 from the right adrenal vein confirm that the right adrenal vein disease. None of these conditions were evi- was not cannulated dent in this patient. This brings us to various vascular causes of hyper- Aldosterone Cortisol reninaemic hypertension. This can be due to (pmol/l) (nmol/l) decreased renal perfusion as in sternosis12 or dissecting aneurysm of the renal Supra-renal inferior veno-cava 996.9 172 artery.13,14 Involvement of smaller vessels by sys- Right adrenal vein 2227 142 temic sclerosis15,16 and necrotising vasculitis17 can Left adrenal vein 22211 354 Right renal vein 830.1 157 also cause hyperreninaemia but these were not evi- Left renal vein 914.7 139 dent in this case. Malignant hypertension gives rise Infra-renal inferior veno-cava 956.6 153 to hyperreninaemia and this has been reported in patients with aldosterone producing adenomas.18 High plasma renin in primary aldosteronism E Shyong Tai and PHK Eng 77 We have to entertain this possibility despite the off of 50. We would like to suggest that a rise in the absence of any retinal changes to suggest malignant PRA might be part of the natural history of primary hypertension as Beevers et al19 noted the absence of aldosteronism. This may be due to prolonged hyper- these signs in two of four patients who exhibited tension resulting in arteriolar disease or hyperten- fibrinoid necrosis on renal biopsy. We do not have sive nephrosclerosis. This could be the reason why a renal biopsy from this patient. However, there was diagnostic tests, which include suppression of the no haematuria on urine microscopy, which often PRA, often fail to diagnose primary aldosteronism. accompanies fibrinoid necrosis. Finally, arteriolar The development of hypertensive nephrosclerosis damage from hypertensive nephrosclerosis can give resulting in hyperreninaemia may also explain the rise to high PRA. When we examine the results of observation that higher PRA is associated with a the adrenal vein sampling, the extremely high aldo- lower cure rate after adrenal surgery in patients with sterone concentration in the left adrenal vein and aldosterone producing adenoma.30 a ratio of aldosterone from the left adrenal vein to Although primary aldosteronism is an uncommon aldosterone in the inferior vena cava of 23.22 (Ͼ10) cause of hypertension (1%), it is an important diag- suggests a left adrenal adenoma,20 even though the nosis to make as it is potentially curable by surgery right adrenal vein was not cannulated successfully. (35–68%)30,32–35 if due to an aldosterone producing Despite this, the aldosterone secretion from the right adenoma or primary adrenal . Even if the adrenal is clearly unsuppressed as the level of aldo- cause is idiopathic , there is a sterone in the blood taken from around the right need for a rational approach to therapy, based on adrenal vein is higher than surrounding areas the underlying pathophysiology of the disease, reflecting activation of the renin angiotensin system which may differ from the usual management of similar to that seen in unilateral renal artery sten- . Surgical treatment has been osis. The same results can occur in hypertensive beneficial in this case, even at this stage of the dis- nephrosclerosis and Pettinger et al21 have used the ease, in that blood pressure, which was poorly con- term pseudo to describe this trolled on four drugs preoperatively, is now con- occurrence on a background of hypertensive nephro- trolled on two and the patient no longer requires sclerosis. potassium supplementation. We feel that hypertensive nephrosclerosis has resulted in the rise in PRA in this patient over a 7- Conclusion year period of untreated hypertension. Underlying renal arteriolar disease is suggested by the acute, This case demonstrates a spontaneous rise in PRA reversible deterioration in renal function caused by in primary aldosteronism caused by an aldosterone captopril. This can occur in bilateral renal artery producing adenoma. This rise is probably due to the stenosis, renal artery stenosis to a single kidney or development of hypertensive nephrosclerosis sec- in those with severe arteriolar disease.21,22 This ondary to prolonged hypertension. The authors feel patient had a normal captopril renogram, which that this may be part of the natural history of pri- although is not the gold standard for diagnosis of mary aldosteronism and gives rise to the lack of sen- renal artery stenosis (sensitivity 71–92%,23–26), sitivity of diagnostic tests that utilise PRA. makes this diagnosis unlikely. We would not be surprised that she has significant Acknowledgements hypertensive nephrosclerosis. Conn’s original description of a case of aldosterone producing aden- We would like to thank Dr Emmanuel L Bravo of the oma included the finding of severe arteriosclerosis Department of Nephrology and Hypertension, Cleve- in the renal biopsies.27 The development of renal land Clinic Foundation, for his invaluable help and vascular complications has been found to be as com- guidance in the preparation of this manuscript. mon in hyperaldosteronism as in other causes of hypertension.19 The extent of end-organ damage (left References ventricular hypertrophy on her ECG and haemor- rhagic stroke) would be consistent with the presence 1 Bravo E et al. The changing clinical spectrum of pri- of renal damage from prolonged hypertension. mary aldosteronism. Am J Med 1983; 74: 641–651. 2 Wilson M et al. Blood pressure, the renin-aldosterone Good blood pressure control could explain the system and sex steroids throughout normal pregnancy. suppression of the PRA after treatment. The use of Am J Med 1980; 68: 97–104. atenolol in the management of this patient’s hyper- 3 Gavras H et al. Role of reactive hyperreninemia in tension can also lower PRA.28 In a previous report blood pressure changes induced by sodium depletion of malignant hypertension with high PRA and ald- in patients with refractory hypertension. Hypertension sterone producing adenoma, a lowering of PRA to 1981; 3(4): 441–447. similar levels by drug treatment was also seen.18 4 Bravo E. Primary aldosteronism. Urologic Clin N Am The diagnosis of primary aldosteronism has been 1989; 16(3): 481–486. fraught with controversy with regards the ideal diag- 5 Kaneda H et al. Elevated plasma renin activity in nostic test.29 Tests that utilise PRA include PRA patients with acute pyelonephritis. Tohoku J Exp Med 1978; 125(2): 169–176. after salt depletion4 and the plasma aldosterone to 30,31 6 Abramson M, Jackson B. Hypertension and unilateral renin ratio. Both of these tests fail to establish hydronephrosis. J Urol 1984; 132(4): 746–748. the diagnosis in this case due to the high PRA before 7 Riehle RA Jr, Vaughan Ed, Jr. Renin participation in and after salt loading and the aldosterone/renin ratio hypertension associated with unilateral hydro- of only 7.9, which is well below the suggested cut- nephrosis. J Urol 1981; 126(2): 243–246. High plasma renin in primary aldosteronism E Shyong Tai and PHK Eng 78 8 Urata H et al. A case of hyperreninemic hypertension 21 Pettinger WA, Mitchell HC, Lee HC, Redman HC. with unilateral hydronephrosis. Jpn J Med 1985; 24(1): Pseudo renal artery stenosis (PRAS) syndrome. Am J 44–49. Hypertens 1989; 2(5 Pt 1): 349–351. 9 McCune TR, Stone WJ, Breyer JA. Page kidney: case 22 Mimran A. Renal effects of antihypertensive agents in report and review of the literature. Am J Kidney Dis parenchymal renal disease and renovascular hyperten- 1991; 18(5): 593–599. sion. J Cardiovasc Pharmacol 1992; 19 (Suppl 6): 10 Sufrin G. The Page kidney: a correctable form of S45–S50. arterial hypertension. J Urol 1975; 113(4): 450–454. 23 Distler A, Spiers K. Diagnostic procedures is renovas- 11 Bongu S, Faubert PF, Porush JG, Gulmi F. Uncon- cular hypertension. Clin Nephrol 1991; 36(4): 174– trolled hypertension and hyperreninemia after 180. hemorrhage in a patient with end-stage renal disease 24 Elliott WJ, Martin WB, Murphy MB. Comparison of and acquired renal cysts. J Am Soc Nephrol 1994; 5(1): two noninvasive screening tests for renovascular 22–26. hypertension. Arch Intern Med 1993; 153(6): 755–764. 12 Pickering TG. The role of laboratory testing in the diag- 25 Roccatello D, Picciotto G. Captopril-enhanced scinti- nosis of renovascular hypertension. Clin Chem 1991; graphy using the method of the expected renogram: 37(10 Pt 2): 1831–1837. improved detection of patients with renin-dependent 13 Esayag-Tendler B, Yamase H, Ramsby G, White WB. hypertension due to functionally significant renal Accelerated hypertension with encephalopathy due to artery stenosis. Nephrol Dial Transplant 1997; 12(10): an isolated dissection of a renal artery branch vessel. 2081–2086. Am J Kidney Dis 1994; 23(6): 869–873. 26 Kahn D et al. Captopril-enhanced 99Tcm-MAG3 renal 14 Paul M, Bear RA. Dissecting aneurysm of renal artery. scintigraphy in subjects with suspected renovascular Reversible cause of high-renin hypertension. Urology hypertension. Nucl Med Commun 1994; 15(7): 515– 1984; 24(5): 483–484. 528. 27 Conn J. Primary aldosteronism. J Lab & Clin Med 1955; 15 Gavras H et al. Is elevated plasma renin activity of (April): 661–664. prognostic importance in progressive systemic scler- 28 Sasaki Y, Arakawa K. Acute effect of atenolol on osis? Acta Intern Med 1977; 137(11): 1554–1558. hemodynamic, plasma renin activity and plasma aldo- 16 Yamanaka K et al. Scleroderma renal crisis compli- sterone concentration in the once daily oral adminis- cated by hemolytic uremic syndrome in a case of eld- tration. Jpn Circ J 1984; 48(9): 988–993. erly onset systemic sclerosis. J Dermatol 1997; 24(3): 29 Bravo E. Primary aldosteronism. Endocrinol Metabol 184–188. Clin N Am 1994; 23(2): 271–283. 17 White RH, Schambelan M. Hypertension, hyperrenine- 30 Blumenfeld JD et al. Diagnosis and treatment of pri- mia, and secondary hyperaldosteronism in systemic mary hyperaldosteronism [see comments]. Ann Intern necrotizing vasculitis. Ann Intern Med 1980; 92(2 Pt Med 1994; 121(11): 877–885. 1): 199–201. 31 Young W et al. Primary aldosteronism: diagnosis and 18 Ideishi M et al. High-renin malignant hypertension treatment. Mayo Clin Proc 1990; 65: 96–110. secondary to an aldosterone-producing adenoma. 32 Ferriss JB et al. The treatment of low-renin (‘primary’) 1990; 54(3): 259–263. hyperaldosteronism. Am J 1978; 96(1): 97–109. 19 Beevers DG et al. Renal abnormalities and vascular 33 Lim R et al. Primary aldosteronism: changing concepts complications in primary hyperaldosteronism. Evi- in diagnosis and management. Am J Surg 1987; 152: dence on tertiary hyperaldosteronism. Q J Med 1976; 116–121. 45(179): 401–410. 34 Weinberger M et al. Primary aldosteronism. diagnosis, 20 Scroggins B, Oddie C, Hare W, Coghlan J. Pre-operat- localisation and treatment. Ann Intern Med 1979; 90: ive lateralisation of aldosteron-producing tumours in 386–395. primary aldosteronism. Ann Intern Med 1972; 76: 35 Groth H et al. Adrenalectomy in primary aldosteron- 891–897. ism. Cardiology 1985; 72(Suppl 1): 107–116.