Lithium Carbonate Therapy Causes Nephrotoxicity and its Alleviation with Ascorbic Acid in Wistar Albino Rats

Introduction

Lithium is the lightest alkali metal used effectively to treat manic disorders and in preventing recurring manic depressive episodes [1, 2] since it has a narrow therapeutic range which makes blood serum lithium levels monitoring mandatory to avoid lithium intoxication [3]. Chronic lithium treatment can produce significant changes in different organs like kidney, liver, brain and spleen [4]. Also Lithium salts cause ocular side effects [5], polyuria and polydipsia, and impaired renal concentration capacity after water deprivation [6]. Lithium is well absorbed by the stomach and doudeneum with no absorption in the large intestine, after ingestion peak serum lithium levels are seen after two and a half hour and completed within 6-8 hours [7]. Lithium does not bind to plasma protein but binds to some legend [8], as it moves slowly from extra- cellular compartment to intracellular space it may require 6-10 days to reach steady blood concentration and the desired therapeutic responses [1, 9]. Lithium effects have been investigated in details in the brain, intestine, liver and thyroid gland, and revealed many deformities and histological alteration [10, 11]. Antioxidant supplements may include a number of different free radical-fighting compounds. It is thought that antioxidants, such as vitamin C, E and beta carotene, may reduce the damage caused by free radical in the bodies by inhibiting their formation [12]. The objective of this study was to assess the nephrotoxicity by measure serum creatinine, urea and uric acid and histopathological of kidney tissue, of drug and to compare it with its use, accompanied by ascorbic acid as an antioxidant, in Wistar Albino rats.

Discussion

Since lithium carbonate is highly effective in controlling and preventing recurring of manic depressive episodes, its use in psychiatry to rehabilitate patients continues despite its complications [17]. Structural and functional effects of lithium carbonate have been studied by various workers from time to time [18]. Chronic lithium intoxication is more common. There is gradual accumulation of lithium, usually due to decreased excretion. Lithium poisoning causes impaired renal function, drug interactions, volume depletion, and concurrent illnesses such as congestive, inflammation and necrosis [18]. Lithium exerts its effects on a wide range of cellular functions by inhibiting inositol production, affects the protein kinase C signaling pathway, and inhibits glycogen synthase kinase [19]. Early recognition and management of lithium induced organ toxicity can save lives and reduce significant morbidity. In the current study the total mean of serum urea in different doses of lithium carbonate showed a highly significant increase (P=0.000) compared to the control group. This result agreed with Devesh KJ, et al. [20] who found that the concentration of serum urea was significantly increased by oral administration of lithium treatment in rats. Also this result agreed with Aziz J, et al. who reported that therapeutic doses of lithium carbonate induce nephrotoxicity reflected as increase in serum urea [21]. A similar study done by Sharma S, et al. reported that lithium therapy treatment in rats caused increased urea [2]. The results also agree Kielczykowska M, et al.

reported that lithium carbonate treated rats in the form of water solution by stomach tube for 6 weeks caused the increased serum urea [22]. A similar study conducted by Omar HE, et al. reported that different doses of lithium carbonate treated rats showed increase in all groups treated. Kidney damage was evident in the present study by histopathological findings [23]. Increasing of concentration in the serum urea provided information from cellular damage of kidney. In fact, urea is the first acute renal marker which increases when the kidney suffers any kind of injury [24]. In the present study the total mean of serum urea in different doses of lithium carbonate and L-ascorbic acid showed higher values compared to the control group. The results agreed with Kielczykowska M, et al. reported that lithium carbonate and L-ascorbic acid co administration treated rats in the form of water solution by stomach tube for 6 weeks caused the increased serum urea [22]. A similar study done by Omar HE, et al. who reported that different doses of lithium carbonate and antioxidants vitamin treated rats showed increase of urea levels in all treated groups [23]. A similar study done by Omar HE, et al. reported that different doses of lithium carbonate and other antioxidants as co administration the treated rats showed increase in urea in all treated groups [23]. This finding showed that urea levels may increase in animals treated with lithium carbonate, even when antioxidants were used. In the current study the total mean of serum creatinine in different doses of lithium carbonate showed a significant (p=0.000) increase compared to the control group except group D that was not changed. Omar HE, et al. reported that different doses of lithium carbonate treated rats showed increase of serum creatinine in all groups of the study, their results agreed with groups B and C but disagreed with group D [23]. Kielczykowska M, et al. reported that lithium carbonate treated rats in the form of water solution by stomach tube for 6 weeks caused no change in the concentration of the serum creatinine, their results agreed with group D and disagree with group C and B [22]. Also Omar HE, et al. reported that the concentration of serum creatinine was significantly increased in oral administration of different doses of lithium treatment in rats [23]. The increase of serum creatinine, can be attributed to the fact that, the increment of creatinine in blood could be related to the reabsorption of creatinine in the glomerular filtrate, lower rates of glomerular filtration, which might be expected due to perturbation of the renin-angiotensin system. This could cause reduction of renal cortical blood flow [25]. Which was evident in the present study by histopathological findings of the renal damage. On the other hand, increasing concentration of creatinine in the serum provide information from cellular damage of kidney. Sine creatinine is a known marker of renal functioning and its concentration in the serum increases as renal function decreases. The elevated creatinine levels observed in serum of lithium treated rats may be the reflection of reduced glomerular filtration capacity as reported by Joshi D, et al. [24]. In the present study the total mean of serum creatinine in different doses of lithium carbonate and L-ascorbic acid showed slight increase in group C and slight decrease in groups D and E compared to the control group. A similar study conducted by Omar HE, et al. reported that, different doses of lithium carbonate and L-ascorbic acid treated rats showed unchanged level of serum creatinine in all groups treated, this study agreed with their results with exception of groups D and E [23]. The results also agree with Kielczykowska M, et al. who reported that lithium carbonate and L-ascorbic acid in co administration, in treated rats, in the form of water solution by stomach tube for 6 weeks caused slight increase in serum creatinine this agreed with group C in this study but different than groups (D and E) [22]. Tripathi S, et al. explained this to be attributed to the fact that, the increment of creatinine in blood could be related to the reabsorption of creatinine in the glomerular filtrate, lower rates of glomerular filtration, which might be expected due to perturbation of the renin-angiotensin system [25]. This could cause reduction of renal cortical blood flow; which was evident in the present study by histopathological findings of the kidneyes. This finding suggests the L-ascorbic acid may acted as protective element. In the current study the total mean of serum uric acid in different doses of lithium carbonate showed a highly significant(p=0.000) decrease compared to the control group. Lithium carbonate well known antimanic agent, was found to decrease serum uric acid levels and produce uricosuric effect as reported by Anumonye A, et al., El- Mallakh R, et al. [26, 27]. Increased urinary excretion and decreased serum uric acid is one of the complications of lithium therapy, and has been observed in both experimental animal and human after lithium administration [26, 27, 28]. In the present study the total mean of serum uric acid in the groups treated with different doses of lithium carbonate and L-ascorbic acid showed no effect due to treatment, but the total mean of serum uric acid was significantly increased in the group received the high dose compared to group B, which received only ascorbic acid. The results agreed with Omar HE, et al. reported that, antioxidant beside lithium therapy increased the blood uric acid [23]. A similar study conducted by Kielczykowska M, et al. showed that, lithium carbonate and co administration treated rats in the form of water solution by stomach tube for 6 weeks caused changes in serum uric acid [22]. This suggested that, the increase of uric acid in blood could be related to the lower rates of glomerular filtration, which might be expected due to perturbation of the renin-angiotensin system. As it could cause reduction of renal cortical blood flow as stated by Tripathi S, et al. [25]. This was evident in the present study by the histopathological findings of the kidneys. The findings of this study reflected tubular necrosis, congestion and infiltration of inflammatory cells as common pathological lesions observed in the kidney at different doses of lithium carbonate in the first experiment. This finding was supported by Loghin F, et al. who reported that chronic lithium treatment can produce significant inflammatory and congestive changes in kidney [4]. A similar study conducted by Mohammed A, et al. reported that the histopathological observations of the kidney tissue revealed many deformities and histological alteration due to lithium treatment [29]. The development of necrosis in proximal tubules, glomerular shrinking, tubular necrosis and loss of cellular integrity due to lithium exposure has been observed earlier also during lithium therapy [30]. The results of the present study were consistent with the previous findings of Lepkifker E, et al. in which renal insufficiency in long term treatment with lithium carbonate has been reported [31]. Similar study performed by Omar HE, et al. reported that the morphological examination of kidney revealed the finding that cellular architecture was disturbed following lithium treatment [23]. Several histopathological examinations revealed congestive or degenerative lesions, large areas of lesions and accumulations of leukocytes, glomerulosclerosis, peritubular infiltration with lymphocytes and mononuclear cells in the kidney of lithium treated rats and co-treatment with antioxidant improved those changes [32]. The study agreed with Sharma S, et al., as they reported congestive changes in kidney during long term of lithium therapy treatment in human and rats respectively [2]. The morphological examination of kidney revealed that cellular architecture was disturbed following lithium treatment. These findings are concomitant with the findings of Weiner D, et al. [33]. The present study agreed with Aziz J who reported that therapeutic doses of lithium carbonate induced nephrotoxicity in the form of necrosis of the renal tubules, alteration of cellular structures, degeneration, and glomerulosclerosis with congestion were observed [21]. The study agreed also with Kanfer A, et al. [34] and was supported by the finding of, Sharma S, et al. as they detected chronic tubule-interstitial nephropathy after long term of lithium therapy treatment in human and rats respectively [2]. The pathogenies mechanism by which lithium causes alteration in kidney are not well understood and also lithium therapy induced renal damage [35]. Lithium plays a role as a modulator of pathway for inositol monophosphate, which results in decreased inositol concentrations and inhibition of cell cycle ,Thus, accumulation of lithium in cells of distal nephron can cause Tubular damage revealed that the modulation of the phosphoinositol pathway may play a role in kidney pathological changes after lithium treatment [35, 10]. In the current study the protective effect of L-ascorbic acid on kidney tubules was compatible with lithium carbonate doses. L-ascorbic acid reduce infiltration of inflammatory cells seen when lithium carbonate was applied alone. Antioxidant supplements may include a number of different free radical-fighting compounds. It is thought that antioxidants, such as vitamin C may reduce the damage caused by free radical in the bodies by inhibiting their formation [12]. This finding supported by Frei B, et al. who showed that histopathological examination revealed congestive or degenerative lesion, large areas of lesions and accumulations of leukocytes, glomerulosclerosis, peritubular of infiltration with lymphocytes and mononuclear cells in the kidney of lithium treated rats and co-treatment with antioxidant improved those changes [12]. The present study also revealed that the L-ascorbic acid may protect against lithium toxicity in kidney cells.

Conclusions

In conclusion, the present results suggested that lithium carbonate induced renal toxicity in rats at physiological and histopathological levels. It has also potentials of inducing adverse effects in rat blood values although, the precise mechanism of lithium carbonate toxicity still remains incompletely understood, the clinical use of lithium needs a carful and caution attention. And also, the data from the present study showed that L- ascorbic acid alone or it’s the interaction with lithium carbonate is effective in protection against lithium renal toxicity in rats. Lithium carbonate exposure caused a histological and biochemical changes and lithium accumulation but co-treatment with L-ascorbic acid showed clear protect on against lithium toxicity.