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Why does chloroquine impair renal function?: Chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide
Medical Hypotheses (2007) 68, 140–143
http://intl.elsevierhealth.com/journals/mehy
Why does chloroquine impair renal function?: Chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide Mohamed H. Ahmed
a,*
, Meissa M. Osman
b
a
Chemical Pathology Department, Southampton General Hospital, Tremona Road, Southampton, Hamphshire SO16 6YD, UK b Paediatric and Child health Department, Southampton General Hospital, Southampton, UK Received 3 June 2006; accepted 7 June 2006
Summary Chloroquine is one of the antimalaria drugs, also used to treat rheumatoid arthritis and systemic lupus erythematosus (SLE). Although well tolerated in most individuals, it was suggested that chloroquine can exert a profound influence on renal function, especially in individuals with compromised body fluid status. However, epidemiological studies are still lacking. The renal actions of chloroquine are further exacerbated by co-administration of other commonly used drugs such as paracetamol. The following discussion will focus on the evidence that chloroquine is a stimulator of nitric oxide (NO), which mediates many of its renal actions (diuresis, natriuresis and an increase in both glomerular filtration rate (GFR) and plasma vasopressin). Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO. c 2006 Elsevier Ltd. All rights reserved.
Introduction Chloroquine is well absorbed when administered orally, subcutaneously and intramuscularly. Bioavailability was found to be 78–80%. It has an extensive volume of distribution which allows the * Corresponding author. Tel.: +44 2380 793465; fax: +44 2380 796339. E-mail address: [email protected] (M.H. Ahmed).
drug to bind to different body tissues especially cellular components of the blood [2].The rate of clearance is much greater than the GFR, implying that a significant proportion of chloroquine is secreted into the nephron. Therefore, the dose need to be modified in renal failure [3]. Administration of chloroquine with other medications which are metabolised through cytochrome P450 may lead to significant increase in these medications (cimetidine, cyclosporine) [1–3].
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.06.012
Why does chloroquine impair renal function?
Effect of chloroquine on renal function Effect on electrolyte and blood pressure Acute and chronic administration of chloroquine appeared to have different effects. Ngaha [4] suggested that acute chloroquine administration in rat showed an increase in both UFR and protein excretion. Ahmed et al. [2] concluded that chloroquine induced significant increase in GFR, UFR and urinary excretion of monovalent and divalent ions (mediated through NO). The possible mechanisms behind such an increase in sodium excretion may be attributable to both NO and other factors and in large part is likely to reflect the increase in GFR and thus filtered Na+ load. NO has been shown to increase renal blood flow, GFR and urine flow rate. Chloroquine induced-NO may modulate renal function; however both NO and chloroquine have inhibitory effect on kidney Na+-K+-ATPase and in cAMP production in isolated inner medullary collecting ducts [2,3]. It seem that chloroquine is operating through different mechanisms which lead to an increase in sodium excretion. Chronic chloroquine administration in the rat lead to the retention of Na+ and Cl and a significant reduction in both GFR and blood pressure [5]. The reduction in blood pressure despite Na+ retention may partially be explained by the extensive vasodilation [2].
Effect of chloroquine on vasopressin Ahmed et al. showed that [2] acute chloroquine administration stimulated a significant increase in plasma vasopressin secretion. L-NAME (nitric oxide blocker) administration with chloroquine completely abolished the increase in vasopressin. Musabayane et al. [6] reported that acute chloroquine administration increased plasma vasopressin concentration, as well as increasing Na+ excretion. These renal effects of chloroquine were not observed in Brattleboro (vasopressin deficient) rats, which suggest that vasopressin may have direct effect on renal Na+ excretion. Musabayane et al. [7] further showed that the chloroquine-induced increase in Na+ excretion was mediated by AVP via V1 receptors. This could suggest that chloroquine induced increases in vasopressin are interfering with the main sites of regulated Na+ reabsorption, like the proximal tubule and the ascending limb of the loop of Henle. This would be consistent with the suggestion made by Grider et al. [8] that luminal vasopressin can inhibit NaCl transport in the
141 medullary thick ascending limb of the rat via vasopressin V1 receptors. In addition, V1 receptors stimulation was also shown to increase renal blood flow especially in the medullary region. Administration of a V1 receptors agonist increased UFR in normal rats [7]. From the above observations, the increase in plasma vasopressin following chloroquine may be another factor contributing to the associated increase in urinary sodium excretion. Despite this effect on plasma vasopressin concentration, Musabayane et al. [6] did not observe any change in UFR, while we [2] reported significant diuresis. This may be explained, in part, by the observation that chloroquine at 10 6 M significantly suppressed the AVP-stimulated increase in cAMP production in isolated inner medullary collecting ducts, suggesting that chloroquine may interfere with the normal antidiuretic response to AVP by reducing cAMP formation [9]. On the other hand chloroquine-induced NO may have inhibitory effect on cAMP production in isolated inner medullary collecting ducts. It is likely that choloroquine increased plasma vasopressin secretion and chloroquine induced-NO rendered the collecting tubule unresponsive to the action of vasopressin.
Can chloroquine causes renal failure? Renal failure in falciparum malaria is attributed to the effect of the parasitized erythrocyte in addition to the physiological factors that contribute to conditions of fluid-imbalance. Presence of malaria parasites inside erythrocytes lead to formation of knobs which adhere to vascular endothelial cells, impeding the microcirculation of the kidney [10]. Other physiological conditions associated with malaria (hypovolaemia, intravascular coagulation, hyperviscosity, intravascular haemolysis, catecholamine release and jaundice) may lead to reduction in renal blood flow [10] The kidney in our studies [2,3] was challenged by treatment of paracetamol for 30 days and then exposed to acute chloroquine treatment, which induced antidiuresis followed by diuresis. This was due to a marked increase in plasma vasopressin and a block of the protective effect of PG by paracetamol treatment. This pattern of antidiuresis followed by diuresis appeared to be mediated through a pathway involving NO. Currently there is growing interest in the role of NO and renal failure [2,3,11]. Chronic consumption of NSAIDs, malaria infection treated with chloroquine
142
Ahmed and Osman Aldosterone
Adrenaline
RBF
AVP
microcirculatory ischaemia
Renin
Malaria
Alcohol
Kidney
chloroquine
Nitric oxide
Free radical
NSAIDs
PG
PG RBF UFR Na excretion proteinuria
Na & K retention RBF NO
Increase suceptibility to vasoconstrictors
Risk of fluid imbalance
RENAL FAILURE
Figure 1
Possible mechanism that lead to impaire renal function with chloroquine administration.
collectively, in addition to factors mentioned above may put an individual at risk of reducing renal blood flow and tubular necrosis (Fig. 1).
Conclusion Chloroquine is a stimulator of NO, which mediates many of its renal actions. Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO. Further studies are needed to establish whether there is link between chloroquine administration and renal failure.
References [1] Ducharme J, Farinotti R. Clinical pharmacokientics and metabolism of chloroquine. Clin Pharmacokinet 1996;31: 257–74.
[2] Ahmed MH, Ashton N, Balment RJ. The effect of chloroquine on renal function and vasopressin secretion: a nitric oxide-dependent effect. J Pharmacol Exp Ther 2003;304: 156–61. [3] Ahmed MH, Ashton N, Balment RJ. Renal function in a rat model of analgesic nephropathy: effect of chloroquine. J Pharmacol Exp Ther 2003;305:123–30. [4] Ngaha EO. Some biochemical changes in the rat during repeated chloroquine administration. Toxicol Lett 1982;10:145–9. [5] Musabayane CT, Ndhlovu CE, Balment RJ. The effect of oral chloroquine administration in renal function. Ren Fail 1994;16:221–8. [6] Musabayane CT, Windle RJ, Forsling ML, Balment RJ. Arginine vasopressin mediates the chloroquine induced increase in renal sodium excretion. Trop Med Int Health 1996;1:542–50. [7] Musabayane CT, Forsling ML, Balment RJ. Arginine vasopressin increases renal sodium excretion in anesthetized rat through v1 receptors. Ren Fail 1997;19:23–32. [8] Grider J, Falcone J, Kilpatrick E, Ott C, Jackson B. Effect of luminal vasopressin on NaCl transport in the medullary thick ascending limb of the rat. Eur J Pharmacol 1996;313: 115–8. [9] Musabayane CT, Wargent ET, Balment RJ. Chloroquine inhibits arginine vasopressin production in isolated rat inner
Why does chloroquine impair renal function? medullary segments induced cAMP collecting duct. Ren Fail 2000;22:27–37. [10] Cameron Stewart, Davision Alex M, Grunfeld JeanPierre, Kerr David, Ritz Eberhard. Oxford textbook of
143 clinical nephrology. Oxford: Oxford University Press; 1992. [11] Kone BC. Nitric oxide in renal health and disease. Am J Kidney Dis 1997;30(3):311–33.
http://intl.elsevierhealth.com/journals/mehy
Why does chloroquine impair renal function?: Chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide Mohamed H. Ahmed
a,*
, Meissa M. Osman
b
a
Chemical Pathology Department, Southampton General Hospital, Tremona Road, Southampton, Hamphshire SO16 6YD, UK b Paediatric and Child health Department, Southampton General Hospital, Southampton, UK Received 3 June 2006; accepted 7 June 2006
Summary Chloroquine is one of the antimalaria drugs, also used to treat rheumatoid arthritis and systemic lupus erythematosus (SLE). Although well tolerated in most individuals, it was suggested that chloroquine can exert a profound influence on renal function, especially in individuals with compromised body fluid status. However, epidemiological studies are still lacking. The renal actions of chloroquine are further exacerbated by co-administration of other commonly used drugs such as paracetamol. The following discussion will focus on the evidence that chloroquine is a stimulator of nitric oxide (NO), which mediates many of its renal actions (diuresis, natriuresis and an increase in both glomerular filtration rate (GFR) and plasma vasopressin). Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO. c 2006 Elsevier Ltd. All rights reserved.
Introduction Chloroquine is well absorbed when administered orally, subcutaneously and intramuscularly. Bioavailability was found to be 78–80%. It has an extensive volume of distribution which allows the * Corresponding author. Tel.: +44 2380 793465; fax: +44 2380 796339. E-mail address: [email protected] (M.H. Ahmed).
drug to bind to different body tissues especially cellular components of the blood [2].The rate of clearance is much greater than the GFR, implying that a significant proportion of chloroquine is secreted into the nephron. Therefore, the dose need to be modified in renal failure [3]. Administration of chloroquine with other medications which are metabolised through cytochrome P450 may lead to significant increase in these medications (cimetidine, cyclosporine) [1–3].
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.06.012
Why does chloroquine impair renal function?
Effect of chloroquine on renal function Effect on electrolyte and blood pressure Acute and chronic administration of chloroquine appeared to have different effects. Ngaha [4] suggested that acute chloroquine administration in rat showed an increase in both UFR and protein excretion. Ahmed et al. [2] concluded that chloroquine induced significant increase in GFR, UFR and urinary excretion of monovalent and divalent ions (mediated through NO). The possible mechanisms behind such an increase in sodium excretion may be attributable to both NO and other factors and in large part is likely to reflect the increase in GFR and thus filtered Na+ load. NO has been shown to increase renal blood flow, GFR and urine flow rate. Chloroquine induced-NO may modulate renal function; however both NO and chloroquine have inhibitory effect on kidney Na+-K+-ATPase and in cAMP production in isolated inner medullary collecting ducts [2,3]. It seem that chloroquine is operating through different mechanisms which lead to an increase in sodium excretion. Chronic chloroquine administration in the rat lead to the retention of Na+ and Cl and a significant reduction in both GFR and blood pressure [5]. The reduction in blood pressure despite Na+ retention may partially be explained by the extensive vasodilation [2].
Effect of chloroquine on vasopressin Ahmed et al. showed that [2] acute chloroquine administration stimulated a significant increase in plasma vasopressin secretion. L-NAME (nitric oxide blocker) administration with chloroquine completely abolished the increase in vasopressin. Musabayane et al. [6] reported that acute chloroquine administration increased plasma vasopressin concentration, as well as increasing Na+ excretion. These renal effects of chloroquine were not observed in Brattleboro (vasopressin deficient) rats, which suggest that vasopressin may have direct effect on renal Na+ excretion. Musabayane et al. [7] further showed that the chloroquine-induced increase in Na+ excretion was mediated by AVP via V1 receptors. This could suggest that chloroquine induced increases in vasopressin are interfering with the main sites of regulated Na+ reabsorption, like the proximal tubule and the ascending limb of the loop of Henle. This would be consistent with the suggestion made by Grider et al. [8] that luminal vasopressin can inhibit NaCl transport in the
141 medullary thick ascending limb of the rat via vasopressin V1 receptors. In addition, V1 receptors stimulation was also shown to increase renal blood flow especially in the medullary region. Administration of a V1 receptors agonist increased UFR in normal rats [7]. From the above observations, the increase in plasma vasopressin following chloroquine may be another factor contributing to the associated increase in urinary sodium excretion. Despite this effect on plasma vasopressin concentration, Musabayane et al. [6] did not observe any change in UFR, while we [2] reported significant diuresis. This may be explained, in part, by the observation that chloroquine at 10 6 M significantly suppressed the AVP-stimulated increase in cAMP production in isolated inner medullary collecting ducts, suggesting that chloroquine may interfere with the normal antidiuretic response to AVP by reducing cAMP formation [9]. On the other hand chloroquine-induced NO may have inhibitory effect on cAMP production in isolated inner medullary collecting ducts. It is likely that choloroquine increased plasma vasopressin secretion and chloroquine induced-NO rendered the collecting tubule unresponsive to the action of vasopressin.
Can chloroquine causes renal failure? Renal failure in falciparum malaria is attributed to the effect of the parasitized erythrocyte in addition to the physiological factors that contribute to conditions of fluid-imbalance. Presence of malaria parasites inside erythrocytes lead to formation of knobs which adhere to vascular endothelial cells, impeding the microcirculation of the kidney [10]. Other physiological conditions associated with malaria (hypovolaemia, intravascular coagulation, hyperviscosity, intravascular haemolysis, catecholamine release and jaundice) may lead to reduction in renal blood flow [10] The kidney in our studies [2,3] was challenged by treatment of paracetamol for 30 days and then exposed to acute chloroquine treatment, which induced antidiuresis followed by diuresis. This was due to a marked increase in plasma vasopressin and a block of the protective effect of PG by paracetamol treatment. This pattern of antidiuresis followed by diuresis appeared to be mediated through a pathway involving NO. Currently there is growing interest in the role of NO and renal failure [2,3,11]. Chronic consumption of NSAIDs, malaria infection treated with chloroquine
142
Ahmed and Osman Aldosterone
Adrenaline
RBF
AVP
microcirculatory ischaemia
Renin
Malaria
Alcohol
Kidney
chloroquine
Nitric oxide
Free radical
NSAIDs
PG
PG RBF UFR Na excretion proteinuria
Na & K retention RBF NO
Increase suceptibility to vasoconstrictors
Risk of fluid imbalance
RENAL FAILURE
Figure 1
Possible mechanism that lead to impaire renal function with chloroquine administration.
collectively, in addition to factors mentioned above may put an individual at risk of reducing renal blood flow and tubular necrosis (Fig. 1).
Conclusion Chloroquine is a stimulator of NO, which mediates many of its renal actions. Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO. Further studies are needed to establish whether there is link between chloroquine administration and renal failure.
References [1] Ducharme J, Farinotti R. Clinical pharmacokientics and metabolism of chloroquine. Clin Pharmacokinet 1996;31: 257–74.
[2] Ahmed MH, Ashton N, Balment RJ. The effect of chloroquine on renal function and vasopressin secretion: a nitric oxide-dependent effect. J Pharmacol Exp Ther 2003;304: 156–61. [3] Ahmed MH, Ashton N, Balment RJ. Renal function in a rat model of analgesic nephropathy: effect of chloroquine. J Pharmacol Exp Ther 2003;305:123–30. [4] Ngaha EO. Some biochemical changes in the rat during repeated chloroquine administration. Toxicol Lett 1982;10:145–9. [5] Musabayane CT, Ndhlovu CE, Balment RJ. The effect of oral chloroquine administration in renal function. Ren Fail 1994;16:221–8. [6] Musabayane CT, Windle RJ, Forsling ML, Balment RJ. Arginine vasopressin mediates the chloroquine induced increase in renal sodium excretion. Trop Med Int Health 1996;1:542–50. [7] Musabayane CT, Forsling ML, Balment RJ. Arginine vasopressin increases renal sodium excretion in anesthetized rat through v1 receptors. Ren Fail 1997;19:23–32. [8] Grider J, Falcone J, Kilpatrick E, Ott C, Jackson B. Effect of luminal vasopressin on NaCl transport in the medullary thick ascending limb of the rat. Eur J Pharmacol 1996;313: 115–8. [9] Musabayane CT, Wargent ET, Balment RJ. Chloroquine inhibits arginine vasopressin production in isolated rat inner
Why does chloroquine impair renal function? medullary segments induced cAMP collecting duct. Ren Fail 2000;22:27–37. [10] Cameron Stewart, Davision Alex M, Grunfeld JeanPierre, Kerr David, Ritz Eberhard. Oxford textbook of
143 clinical nephrology. Oxford: Oxford University Press; 1992. [11] Kone BC. Nitric oxide in renal health and disease. Am J Kidney Dis 1997;30(3):311–33.