LETTERS TO THE EDITOR
Blunted Natriuretic Responses in Norm :ensive Men With Positive Family Histories of Hypertension REFERENCES
1
2
1. Widgren BR, Herlitz H, Hedner T, et al: Blunted sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension. Am J Hypertens 1991;4:570-578. 2.
Cuche JL, Kuchel O, Barbeau A, et al: Relationship between the adrenergic nervous system and renin during adaptation to upright posture: a possible role or 3,4dihydroxyphenethylamine (dopamine). Clin Sci 1972; 43:481-489.
3.
Alexander RW, Gill JR, Jr., Yamabe H, et al: Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excretion and adrenergic activity in man. J Clin Invest 1974;54:194-200.
4.
Kuchel O, Buu NT, Racz K, Gutkowska J: Hormonal correlates of the inadequate natriuretic response to salt loading in idiopathic edema. Clin Invest Med 1987;10:71-77.
5.
Gill JR, Jr., Grossman E, Goldstein DS: High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension. Hypertension 1991;18:614-621.
6.
Kuchel O, Kuchel G: Peripheral dopamine in pathophysiology of hypertension: interaction with aging and lifestyle. Hypertension 1991;18:709-721.
7.
Saito I, Takeshita E, Saruta T, et al: Urinary dopamine excretion in normotensive subjects with or without family history of hypertension. J Hypertens 1986;4:57-60.
8.
Kinoshita S, Sidhu A, Felder RA: Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest 1989;84:1849-1856.
9.
Sunuhara RK, Niznik HB, Weiner DM, et al: Human DI dopamine receptor encoded by an intronless gene on chromosome 5. Nature 1990;347:80-83.
3
4
5
6
7
8
9
O T T O KUCHEL From the Clinical Research Institute of Montreal, Hotel-Dieu Hospital, University of Montreal, Montreal, Quebec, Canada. Address correspondence and reprint requests to Otto Kuchel, MD, ScD, Clinical Research Institute of Montreal, Hotel-Dieu Hospital, University of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Blunted Sodium Excretion During Acute Saline Loading in Subjects With Positive Family Histories of Hypertension: A Multifactorial Relationship In this issue of the journal Dr. Kuchel gives an interesting opinion and a correct interpretation of our finding of blunted renal sodium excretion during acute saline loading in subjects with positive family histories of hypertension. We speculated that this finding may be due 1
to an inherited failure of the renal dopaminergic system in nonhypertensive subjects with positive family histories of hypertension. It is well known from both clinical practice and experimental data that stimulation of intrarenal dopamine receptors will increase the renal blood
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
The study by B.R. Widgren and coworkers presents interesting findings suggesting a blunted renal sodium excretion and increased pressor response to an acute saline load in normotensive men with positive family histories of hypertension. The possible interpretation of this finding is however incomplete since it does not take into account accumulating evidence suggesting a potential natriuretic role of endogenous dopamine. Since the findings of a positive relationship between urinary sodium and dopamine excretions under physiological maneuvers such as orthostatism and excessive salt intake or saline infusion, a blunted natriuretic and increased pressor response to sodium loading was found in idiopathic edema, in parallel with an inadequate urinary dopamine response to saline. Recent evidence suggests an association between a defective natriuretic response and a decreased decarboxylation of dihydroxyphenylalanine (DOPA) to dopamine as reflected by a high D O P A : dopamine ratio in urine in salt-sensitive hypertension and in plasma following DOPA administration in stable hypertension. Even more to the point, Saito et al demonstrated that the significant urinary dopamine-sodium relationship in normotensive subjects without a family history of hypertension becomes disturbed in subjects with a positive family history of hypertension. This raises the possibility of an additional dopamine-related abnormality in hypertension, a defective tubular dopamine-1 receptor adenylate cyclase coupling, which has already been demonstrated in spontaneously hypertensive rats. Two distinct dopamine-related abnormalities may thus contribute to the blunted natriuretic response of normotensive subjects with a family history of hypertension. The later possibility attracts interest to the genetics of hypertension because of the recent cloning and chromosome mapping of the dopamine-1 receptor.
420
AJH-JUNE 1992-VOL 5, NO. 6, PART 1
LETTERS TO THE EDITOR
2
3
tem and the development of primary hypertension. Rather, altered dopaminergic activity is likely to be an abnormality associated with sodium handling and renal hemodynamics, which should be further studied in carefully selected nonhypertensive subjects predisposed to primary hypertension. Studies of renal hemodynamics, tubular function, and sodium excretion and the role of the dopaminergic system in such individuals would be an interesting area of primary hypertension for future investigation. 14
4
5
REFERENCES 1.
Widgren BR, Herlitz H, Hedner T, et al: Blunted renal sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension. Am J Hypertens 1991;4:570-578.
2.
Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical application. Pharmacol Rev 1972;24:1-28.
3.
Herlitz H, Lundin S, Henning M, et al: Hormonal pattern during development of hypertension in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 1982;4:915-935.
4.
Hedge S, Lokhandwala M: Renal dopamine and sodium excretion. Am J Hypertens 1990;3:78S-81S.
5.
Felder R, Kinoshita S, Sidhu A, et al: A renal dopamine-1 receptor defect in two genetic models of hypertension. Am J Hypertens 1990;3:96S-99S.
6.
van den Buuse M, Versteg DHG, Dejung W: Brain catecholamines and the development of hypertension in spontaneously hypertensive rats. J Hypertens 1986;4(suppl 3):S159-S161.
7.
Sabouni MH, Alkadhi KA, Lokhandwala MF: Effect of dopamine receptors activation on ganglionic transmission and cyclic AMP levels in the stellate ganglia and renal arteries of the dog. J Pharmacol Exp Ther 1987;240:93-98.
8.
Lefevre-Borg F, Lorrian J, Lechaire J, et al: Cardiovascular characterization of the DA dopamine receptor agonist quinpirole in rats. Fundam Clin Pharmacol 1987;1:179-200.
6
7
8
2
9
1
10
11
12
2
9.
Judy WV, Watanabe AM, Henry DP, et al: Effect of Ldopa on sympathetic nerve activity and blood pressure ' in the spontaneously hypertensive rat. Circ Res 1978;43:24-28.
10.
Widgren BR, Hedner T, Hedner J, et al: Resting and volume-stimulated circulating atrial nartiuretic peptide in young normotensive men with positive family histories of hypertension. J Hypertension 1991;9:139-146.
11.
Widgren BR, Herlitz H, Aurell M, et al: Increased systemic and renal sensitivity to angiotensin II in normotensive men with positive family histories of hypertension. Am J Hypertens (in press).
12.
Stenvinkel P, Saggar-Malik AK, Wahrenberg H, et al: Impaired intrarenal dopamine production following intravenous sodium chloride infusion in Type-1 (insulindependent) diabetes mellitus.
13.
Iimura O, Shimamoto K, Ura N: Dopaminergic activity and water-sodium handling in the kidneys of essential
1
13
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
flow, inhibit the sodium reabsorbtion and increase the natriuresis in animals and both normotensive and hypertensive humans. It is well known that dopamine has dose-dependent systemic hemodynamic effects with a vasodilatory action on renal, mesenteric, and coronary vascular beds and vasoconstriction in arterial vessels. During the development of hypertension an increased dopamine urinary excretion has been reported in young spontaneously hypertensive rats (SHR) and an activation of dopamine receptors was shown to be related to the diuresis and natriuresis in Sprague-Dawley rats. In SHR as well as in Dahl salt sensitive rats a defect in proximal tubular dopamine receptor function was reported as early as 3 to 4 weeks of age. In hypertensive rats, evidence of central dopaminergic mechanisms has also been reported. Dopamine is also known to decrease ganglionic transmission in the sympathetic nervous sytem and to inhibit norepinephrine release from sympathetic nerve endings, through stimulation of presynaptic dopamine -receptors. In SHR a central inhibition of renal sympathetic nervous activity by dopa entering the brain has been suggested. As correctly pointed out by Dr. Kuchel, all mechanisms underlying the blunted renal sodium excretion in subjects with positive family histories of hypertension were not completely assessed in our study. Interestingly, a blunted atrial natriuretic peptide response to a volume load has been found and an increased systemic and renal sensitivity to angiotensin II infusion in low doses has been observed in subjects with positive family histories of hypertension. Another very elegant study by Stenvinkel et a l has reported that patients with type 1 diabetes mellitus were characterized by blunted sodium excretion and blunted increase in atrial natriuretic peptide, as well as impaired intrarenal dopamine production during sodium/volume loading. These findings may support the hypothesis of a common pathogenetic pathway in primary hypertension and diabetes mellitus. It has to be pointed out that renal sodium excretion during an acute volume load is regulated by a great number of both hormonal, hemodynamic, and neurogenic mechanisms more or less related to each other and closely related to sodium homeostasis, volume state, and the activity in the sympathetic nervous system. However, one of the possible mechanisms behind the blunted natriuretic response could be an inherited failure of the intrarenal dopaminergic system responsible in part or in conjunction with other mechanisms. An interesting study by Iimura et a l showed a decreased renal dopaminergic activity and increased renal sensitivity to dopamine in normotensive subjects with positive family histories of hypertension. It has to be remembered that these findings of altered dopaminergic activity in primary hypertension are not evidence of a relationship between the dopamine sys-
hypertensive subjects: is renal dopaminergic activity suppressed at the prehypertensive stage? J Cardiovasc Pharmacol 1990;16(suppl 7):S56-S58. 14.
Watt G: Design and interpretation of studies comparing individuals with and without a family history of high blood pressure. J Hypertens 1986;4:1-7.
BENGT
R.
WIDGREN
From the Division of Angiology, Hypertension Unit, Department of Medicine, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden. Address correspondence and reprint requests to Dr. Bengt R. Wid gren, Department of Medicine, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden.
Comments on Postma et al's "The Effect of Caffeine on Renal Vein Renin Concentration in Patients With Renal Arterial Disease" 1
larged study is impossible to say. However, a power analysis of the data in Table 1 indicated that even if on average caffeine had increased the renal vein PRA ratio in RVH patients by as much as one ratio unit more than it increased the renal vein PRA ratio in patients with a nonfunctional stenosis, the power of the data (0.06) in Table 1 would have been far too low to have detected the difference. In fact, from the variance of the data in Table 1, it can be calculated that if caffeine increases the mean PRA ratio in RVH by an incredible four ratio units more than it increases the PRA ratio in stenotic but nonRVH patients, 20 patients in each group would have to be studied to achieve even a power of 0.75. The major point is that the hypothesis that caffeine increases the PRA ratio more in patients with RVH versus patients with a nonfunctional stenosis must be tested in a much larger study. Another important point is that although not all kid neys with a functional renal artery stenosis increase their secretion of renin in response to caffeine, it is quite possible that a sizable percentage do respond to caf feine. Postma et al collected renal vein PRAs from a total of 22 kidneys (11 patients), four of which were con nected to a renal artery with a functionally significant stenosis. Of the 18 kidneys that were not supplied by a renal artery with a functionally significant stenosis, caf feine did not on average increase renal vein PRA (caffeine-induced change = —1.4 ± 5.0 n m o l / L / h ; mean ± SD). However, in two of the four kidneys with a functionally significant stenosis, renal vein PRA levels increased markedly following administration of caf feine ( + 2 5 . 5 n m o l / L / h in one kidney and + 1 6 nmol/ L / h in another). The fact that the caffeine-induced change in these two kidneys was three to five standard deviations from the mean change induced by caffeine in kidneys not connected to a functionally significant ste nosis argues strongly that caffeine may greatly enhance renin release from some kidneys with a functionally significant renal artery stenosis. Since this may have clinical significance with regard to blood pressure con trol in RVH patients, these data reinforce the need for additional studies. Although the number of patients involved in the
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
Postma et al recently published a very interesting study in the American Journal of Hypertension in which they tested the hypothesis that caffeine (an adenosine recep tor antagonist) might increase the sensitivity and speci ficity of the renal vein renin ratio test for the detection of renovascular hypertension (RVH). The hypothesis was based on work in animals that supports a role for aden osine as an endogenous inhibitor of renin release in duced by unilateral renal artery clipping. In their study, Postma et al described the effects of caffeine on plasma renin activity (PRA) in the renal veins of 11 hyperten sive patients who underwent arteriography of the renal arteries. Unilateral renal artery stenosis was identified in seven patients, but only four of these seven patients had RVH as demonstrated by a blood pressure reduction following correction of the renal artery stenosis. The authors concluded that "caffeine did not induce any consistent effect on PRA in the renal veins, either on the stenotic side or on the contralateral side in patients with RVH." Although I fully agree with the authors' conclusion that caffeine did not produce a "consistent effect" on renal vein PRA or renal vein PRA ratio in RVH, I believe their results should encourage, rather than discourage, additional studies. From the data presented in Table 1 of the article by Postma et al, it can be seen that in all four patients with RVH, caffeine increased the renal vein PRA ratio. On the other hand, in the three patients with a nonfunctional stenosis, caffeine increased the renal vein PRA ratio in one patient, decreased the ratio in another patient, and did not affect the ratio in the third patient. Using the data presented in Table 1,1 calculated the change in renal vein PRA ratio induced by caffeine for each patient, and compared these changes in pa tients with a nonfunctional stenosis (—0.67 ± 0 . 8 3 ; η = 3) versus patients with RVH (3.95 ± 3.2; η = 4). When these results were subjected to a nonparametric Mann-Whitney test, Ρ = .11. Therefore, despite the ex tremely small sample size and the variability in both groups, a trend was observed for caffeine to increase the renal vein PRA ratio more in the RVH group compared with the stenotic but non-RVH group. Whether this trend will prove significant in an en
Blunted Natriuretic Responses in Norm :ensive Men With Positive Family Histories of Hypertension REFERENCES
1
2
1. Widgren BR, Herlitz H, Hedner T, et al: Blunted sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension. Am J Hypertens 1991;4:570-578. 2.
Cuche JL, Kuchel O, Barbeau A, et al: Relationship between the adrenergic nervous system and renin during adaptation to upright posture: a possible role or 3,4dihydroxyphenethylamine (dopamine). Clin Sci 1972; 43:481-489.
3.
Alexander RW, Gill JR, Jr., Yamabe H, et al: Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excretion and adrenergic activity in man. J Clin Invest 1974;54:194-200.
4.
Kuchel O, Buu NT, Racz K, Gutkowska J: Hormonal correlates of the inadequate natriuretic response to salt loading in idiopathic edema. Clin Invest Med 1987;10:71-77.
5.
Gill JR, Jr., Grossman E, Goldstein DS: High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension. Hypertension 1991;18:614-621.
6.
Kuchel O, Kuchel G: Peripheral dopamine in pathophysiology of hypertension: interaction with aging and lifestyle. Hypertension 1991;18:709-721.
7.
Saito I, Takeshita E, Saruta T, et al: Urinary dopamine excretion in normotensive subjects with or without family history of hypertension. J Hypertens 1986;4:57-60.
8.
Kinoshita S, Sidhu A, Felder RA: Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest 1989;84:1849-1856.
9.
Sunuhara RK, Niznik HB, Weiner DM, et al: Human DI dopamine receptor encoded by an intronless gene on chromosome 5. Nature 1990;347:80-83.
3
4
5
6
7
8
9
O T T O KUCHEL From the Clinical Research Institute of Montreal, Hotel-Dieu Hospital, University of Montreal, Montreal, Quebec, Canada. Address correspondence and reprint requests to Otto Kuchel, MD, ScD, Clinical Research Institute of Montreal, Hotel-Dieu Hospital, University of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Blunted Sodium Excretion During Acute Saline Loading in Subjects With Positive Family Histories of Hypertension: A Multifactorial Relationship In this issue of the journal Dr. Kuchel gives an interesting opinion and a correct interpretation of our finding of blunted renal sodium excretion during acute saline loading in subjects with positive family histories of hypertension. We speculated that this finding may be due 1
to an inherited failure of the renal dopaminergic system in nonhypertensive subjects with positive family histories of hypertension. It is well known from both clinical practice and experimental data that stimulation of intrarenal dopamine receptors will increase the renal blood
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
The study by B.R. Widgren and coworkers presents interesting findings suggesting a blunted renal sodium excretion and increased pressor response to an acute saline load in normotensive men with positive family histories of hypertension. The possible interpretation of this finding is however incomplete since it does not take into account accumulating evidence suggesting a potential natriuretic role of endogenous dopamine. Since the findings of a positive relationship between urinary sodium and dopamine excretions under physiological maneuvers such as orthostatism and excessive salt intake or saline infusion, a blunted natriuretic and increased pressor response to sodium loading was found in idiopathic edema, in parallel with an inadequate urinary dopamine response to saline. Recent evidence suggests an association between a defective natriuretic response and a decreased decarboxylation of dihydroxyphenylalanine (DOPA) to dopamine as reflected by a high D O P A : dopamine ratio in urine in salt-sensitive hypertension and in plasma following DOPA administration in stable hypertension. Even more to the point, Saito et al demonstrated that the significant urinary dopamine-sodium relationship in normotensive subjects without a family history of hypertension becomes disturbed in subjects with a positive family history of hypertension. This raises the possibility of an additional dopamine-related abnormality in hypertension, a defective tubular dopamine-1 receptor adenylate cyclase coupling, which has already been demonstrated in spontaneously hypertensive rats. Two distinct dopamine-related abnormalities may thus contribute to the blunted natriuretic response of normotensive subjects with a family history of hypertension. The later possibility attracts interest to the genetics of hypertension because of the recent cloning and chromosome mapping of the dopamine-1 receptor.
420
AJH-JUNE 1992-VOL 5, NO. 6, PART 1
LETTERS TO THE EDITOR
2
3
tem and the development of primary hypertension. Rather, altered dopaminergic activity is likely to be an abnormality associated with sodium handling and renal hemodynamics, which should be further studied in carefully selected nonhypertensive subjects predisposed to primary hypertension. Studies of renal hemodynamics, tubular function, and sodium excretion and the role of the dopaminergic system in such individuals would be an interesting area of primary hypertension for future investigation. 14
4
5
REFERENCES 1.
Widgren BR, Herlitz H, Hedner T, et al: Blunted renal sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension. Am J Hypertens 1991;4:570-578.
2.
Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical application. Pharmacol Rev 1972;24:1-28.
3.
Herlitz H, Lundin S, Henning M, et al: Hormonal pattern during development of hypertension in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 1982;4:915-935.
4.
Hedge S, Lokhandwala M: Renal dopamine and sodium excretion. Am J Hypertens 1990;3:78S-81S.
5.
Felder R, Kinoshita S, Sidhu A, et al: A renal dopamine-1 receptor defect in two genetic models of hypertension. Am J Hypertens 1990;3:96S-99S.
6.
van den Buuse M, Versteg DHG, Dejung W: Brain catecholamines and the development of hypertension in spontaneously hypertensive rats. J Hypertens 1986;4(suppl 3):S159-S161.
7.
Sabouni MH, Alkadhi KA, Lokhandwala MF: Effect of dopamine receptors activation on ganglionic transmission and cyclic AMP levels in the stellate ganglia and renal arteries of the dog. J Pharmacol Exp Ther 1987;240:93-98.
8.
Lefevre-Borg F, Lorrian J, Lechaire J, et al: Cardiovascular characterization of the DA dopamine receptor agonist quinpirole in rats. Fundam Clin Pharmacol 1987;1:179-200.
6
7
8
2
9
1
10
11
12
2
9.
Judy WV, Watanabe AM, Henry DP, et al: Effect of Ldopa on sympathetic nerve activity and blood pressure ' in the spontaneously hypertensive rat. Circ Res 1978;43:24-28.
10.
Widgren BR, Hedner T, Hedner J, et al: Resting and volume-stimulated circulating atrial nartiuretic peptide in young normotensive men with positive family histories of hypertension. J Hypertension 1991;9:139-146.
11.
Widgren BR, Herlitz H, Aurell M, et al: Increased systemic and renal sensitivity to angiotensin II in normotensive men with positive family histories of hypertension. Am J Hypertens (in press).
12.
Stenvinkel P, Saggar-Malik AK, Wahrenberg H, et al: Impaired intrarenal dopamine production following intravenous sodium chloride infusion in Type-1 (insulindependent) diabetes mellitus.
13.
Iimura O, Shimamoto K, Ura N: Dopaminergic activity and water-sodium handling in the kidneys of essential
1
13
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
flow, inhibit the sodium reabsorbtion and increase the natriuresis in animals and both normotensive and hypertensive humans. It is well known that dopamine has dose-dependent systemic hemodynamic effects with a vasodilatory action on renal, mesenteric, and coronary vascular beds and vasoconstriction in arterial vessels. During the development of hypertension an increased dopamine urinary excretion has been reported in young spontaneously hypertensive rats (SHR) and an activation of dopamine receptors was shown to be related to the diuresis and natriuresis in Sprague-Dawley rats. In SHR as well as in Dahl salt sensitive rats a defect in proximal tubular dopamine receptor function was reported as early as 3 to 4 weeks of age. In hypertensive rats, evidence of central dopaminergic mechanisms has also been reported. Dopamine is also known to decrease ganglionic transmission in the sympathetic nervous sytem and to inhibit norepinephrine release from sympathetic nerve endings, through stimulation of presynaptic dopamine -receptors. In SHR a central inhibition of renal sympathetic nervous activity by dopa entering the brain has been suggested. As correctly pointed out by Dr. Kuchel, all mechanisms underlying the blunted renal sodium excretion in subjects with positive family histories of hypertension were not completely assessed in our study. Interestingly, a blunted atrial natriuretic peptide response to a volume load has been found and an increased systemic and renal sensitivity to angiotensin II infusion in low doses has been observed in subjects with positive family histories of hypertension. Another very elegant study by Stenvinkel et a l has reported that patients with type 1 diabetes mellitus were characterized by blunted sodium excretion and blunted increase in atrial natriuretic peptide, as well as impaired intrarenal dopamine production during sodium/volume loading. These findings may support the hypothesis of a common pathogenetic pathway in primary hypertension and diabetes mellitus. It has to be pointed out that renal sodium excretion during an acute volume load is regulated by a great number of both hormonal, hemodynamic, and neurogenic mechanisms more or less related to each other and closely related to sodium homeostasis, volume state, and the activity in the sympathetic nervous system. However, one of the possible mechanisms behind the blunted natriuretic response could be an inherited failure of the intrarenal dopaminergic system responsible in part or in conjunction with other mechanisms. An interesting study by Iimura et a l showed a decreased renal dopaminergic activity and increased renal sensitivity to dopamine in normotensive subjects with positive family histories of hypertension. It has to be remembered that these findings of altered dopaminergic activity in primary hypertension are not evidence of a relationship between the dopamine sys-
hypertensive subjects: is renal dopaminergic activity suppressed at the prehypertensive stage? J Cardiovasc Pharmacol 1990;16(suppl 7):S56-S58. 14.
Watt G: Design and interpretation of studies comparing individuals with and without a family history of high blood pressure. J Hypertens 1986;4:1-7.
BENGT
R.
WIDGREN
From the Division of Angiology, Hypertension Unit, Department of Medicine, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden. Address correspondence and reprint requests to Dr. Bengt R. Wid gren, Department of Medicine, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden.
Comments on Postma et al's "The Effect of Caffeine on Renal Vein Renin Concentration in Patients With Renal Arterial Disease" 1
larged study is impossible to say. However, a power analysis of the data in Table 1 indicated that even if on average caffeine had increased the renal vein PRA ratio in RVH patients by as much as one ratio unit more than it increased the renal vein PRA ratio in patients with a nonfunctional stenosis, the power of the data (0.06) in Table 1 would have been far too low to have detected the difference. In fact, from the variance of the data in Table 1, it can be calculated that if caffeine increases the mean PRA ratio in RVH by an incredible four ratio units more than it increases the PRA ratio in stenotic but nonRVH patients, 20 patients in each group would have to be studied to achieve even a power of 0.75. The major point is that the hypothesis that caffeine increases the PRA ratio more in patients with RVH versus patients with a nonfunctional stenosis must be tested in a much larger study. Another important point is that although not all kid neys with a functional renal artery stenosis increase their secretion of renin in response to caffeine, it is quite possible that a sizable percentage do respond to caf feine. Postma et al collected renal vein PRAs from a total of 22 kidneys (11 patients), four of which were con nected to a renal artery with a functionally significant stenosis. Of the 18 kidneys that were not supplied by a renal artery with a functionally significant stenosis, caf feine did not on average increase renal vein PRA (caffeine-induced change = —1.4 ± 5.0 n m o l / L / h ; mean ± SD). However, in two of the four kidneys with a functionally significant stenosis, renal vein PRA levels increased markedly following administration of caf feine ( + 2 5 . 5 n m o l / L / h in one kidney and + 1 6 nmol/ L / h in another). The fact that the caffeine-induced change in these two kidneys was three to five standard deviations from the mean change induced by caffeine in kidneys not connected to a functionally significant ste nosis argues strongly that caffeine may greatly enhance renin release from some kidneys with a functionally significant renal artery stenosis. Since this may have clinical significance with regard to blood pressure con trol in RVH patients, these data reinforce the need for additional studies. Although the number of patients involved in the
Downloaded from http://ajh.oxfordjournals.org/ at Monash University on November 29, 2015
Postma et al recently published a very interesting study in the American Journal of Hypertension in which they tested the hypothesis that caffeine (an adenosine recep tor antagonist) might increase the sensitivity and speci ficity of the renal vein renin ratio test for the detection of renovascular hypertension (RVH). The hypothesis was based on work in animals that supports a role for aden osine as an endogenous inhibitor of renin release in duced by unilateral renal artery clipping. In their study, Postma et al described the effects of caffeine on plasma renin activity (PRA) in the renal veins of 11 hyperten sive patients who underwent arteriography of the renal arteries. Unilateral renal artery stenosis was identified in seven patients, but only four of these seven patients had RVH as demonstrated by a blood pressure reduction following correction of the renal artery stenosis. The authors concluded that "caffeine did not induce any consistent effect on PRA in the renal veins, either on the stenotic side or on the contralateral side in patients with RVH." Although I fully agree with the authors' conclusion that caffeine did not produce a "consistent effect" on renal vein PRA or renal vein PRA ratio in RVH, I believe their results should encourage, rather than discourage, additional studies. From the data presented in Table 1 of the article by Postma et al, it can be seen that in all four patients with RVH, caffeine increased the renal vein PRA ratio. On the other hand, in the three patients with a nonfunctional stenosis, caffeine increased the renal vein PRA ratio in one patient, decreased the ratio in another patient, and did not affect the ratio in the third patient. Using the data presented in Table 1,1 calculated the change in renal vein PRA ratio induced by caffeine for each patient, and compared these changes in pa tients with a nonfunctional stenosis (—0.67 ± 0 . 8 3 ; η = 3) versus patients with RVH (3.95 ± 3.2; η = 4). When these results were subjected to a nonparametric Mann-Whitney test, Ρ = .11. Therefore, despite the ex tremely small sample size and the variability in both groups, a trend was observed for caffeine to increase the renal vein PRA ratio more in the RVH group compared with the stenotic but non-RVH group. Whether this trend will prove significant in an en
