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Li-fe or death of the collecting duct?
- John A Sayer (17 July 2009)
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Lithium and renal impairment –“magnitude of risks”
- SUMEET GUPTA, Amit Agrawala (23 July 2009)
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Lithium can be toxin, not therapy
- Zekria Ibrahimi (28 July 2009)
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John A Sayer, Senior Clinical Lecturer in Nephrology Institute of Human Genetics, International Centre for Life, Newcastle University, NE1 3BZ, UK
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Kripalani and colleagues point out the necessary monitoring and required vigilance for patients receiving treatment with lithium, to ensure renal toxicity is not missed 1. It is worth noting that nephrogenic diabetes insipidus (NDI) is the most common “renal” side effect of this drug, causing reduced concentrating ability in over half of patients and leading to significant polyuria in around one fifth of patients 2. These urinary concentration defects are not always reversible upon stopping lithium. Lithium is toxic to the principal cells of the collecting duct cells (which are responsible for regulating final urinary concentration). Lithium enters and accumulates in these cells from the filtrate via apical amiloride sensitive ENaC channels. Given this known mechanism, amiloride treatment may be recommended as a specific therapy for lithium induced polyuria and NDI 3. Whether the progressive renal impairment, seen with 10 -20 years of lithium treatment, is secondary to this collecting duct toxicity alone and can therefore be largely prevented by amiloride, remains to be determined 4. 1. Kripalani M, Shawcross J, Reilly J, Main J. Lithium and chronic kidney disease. Bmj 2009;339:b2452. 2. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987;10(5):329-45. 3. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985;312(7):408-14. 4. Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009;5(5):270-6. Competing interests: None declared |
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SUMEET GUPTA, Consultant Psychiatrist Hundens Lane Rescource Centre,Darlington, Amit Agrawala
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I read the excellent review by Dr. Kriplani, et al. The article gives very practicable advice regarding monitoring of renal functions in patients taking lithium. It mentions that lithium is associated with renal disorder and renal failure, but the magnitude of risk is uncertain (1). I would like to elaborate on the issues surrounding the magnitude of risks. Lithium is one of the oldest psychotropic drugs and it has been with us for the past 50 years. It has been used extensively in psychiatry and because of risk of toxicity patients are closely monitored. As the article mentions polyuria is the commonest renal side effect, but it is considered to be a benign and reversible condition, at least early in treatment. Whether lithium causes changes in GFR and chronic renal failure remains an unsettled issue, despite more than 3 decades of studies. Over the years there have been many studies and reviews supporting or refuting the claims. The confusion is due to lack of well designed longitudinal studies. In the past studies were marred by methodological flaws like heterogeneity of the population and lack of control for the confounding variables. Despite all these limitations, majority of studies suggested that long term monitored lithium treatment does not adversely affect glomerular filtration rate. Following are some recent publications which have shed more light in this grey area. In 1999, Gitlin extensively reviewed the available literature and concluded that lithium does affect tubular dysfunction (deficits in urine concentrating ability) and it is usually reversible, but at a later stage may become structural and permanent. However, it does not cause significant change in glomerular filtration rate and in the vast majority of patients renal effects of lithium are benign. None the less, they acknowledged that a very small minority of patients’ lithium may lead to renal insufficiency, possibly in conjunction with other somatic factors (2). Lepkifker et al 2004 compared 114 psychiatric patients who were on lithium (4 to 30 years) and compared them with 94 unmedicated subjects, matched for sex and age. 21% of the patients showed creeping creatinine phenomenon. In their study renal impairment (defined by blood creatinine levels >1.5 mg/dL) was associated with episodes of lithium toxicity, associated medications and co morbid illnesses, but not with duration of lithium therapy, serum lithium concentration and cumulative lithium dose. They finally concluded that in an overwhelming majority of the patients lithium did not influence glomerular function (3). Recently, Paul et al 2009 meta-analysed the effect of lithium on serum creatinine levels. They reported that any lithium associated increase in serum creatinine is quantitatively small and of questionable significance. They also confirmed that renal changes are associated with episodes of lithium toxicity, age, concurrent illness rather than dose or time on lithium (4). From the available evidence, although we cannot predict the exact risk, yet we can certainly say that magnitude of risk is small. The above information should also be provided to service users whilst explaining the risks and benefit of lithium. It is very important to remember that if lithium use is properly monitored and if episodes of toxicity can be avoided then it can be safely used, even in patients with chronic renal disease. (1) Kripalani M, Shawcross J, Reilly J, Main J. Lithium and chronic kidney disease. Bmj 2009;339:b2452 (2) Gitlin M. Lithium and the kidney: an updated review. Drug Safety 1999;20:231-43 (3) Lepkifker E, Sverdlik A, Iancu I, Ziv R, Segev S, Kotler M. Renal insufficiency in long-term lithium treatment. J Clin Psychiatry 2004; 65:850-6. (4) Paul R,Minay J,Cardwell C,Fogarty D,Kelly C.Meta-analysis of the effect of lithium usage on serum creatinine levels. J Psychopharmacol. 2009 Apr 24. [Epub ahead of print] Competing interests: None declared |
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Zekria Ibrahimi, psychiatric patient Coombs Library, Southall, UB1 3EU
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Lithium and sodium are both alkali metals; they come from Group I of the Periodic Table, that is, they are related in terms of their chemical reactivity. It could thus be unfortunately predicted that lithium would be disruptive of sodium within the human body. Our cellular structure and our nervous system are unable to function without sodium- without its regulation of osmosis across the membrane, and of action potentials in neurons and axons. Lithium threatens the natural action of sodium. Lithium competes with sodium. Lithium would replace sodium during the production of an action potential. The subsequent problem is that lithium is not able to be readily removed from the cell. Lithium will accumulate in an inert manner until the axon is deactivated. Lithium is a neurotoxin- a potential poison. So here is the similarity between lithium and the anti-psychotics- both hamper the capacity of nerve cells to communicate with each other, albeit by different methods. Anti- psychotics block dopamine, lithium blocks sodium. Lithium is not a modern patented drug, and it does not produce large profits for the drug corporations. Thus, there appears to be openness about its side effects, as in this BMJ article (1), whereas other psychotropic drugs are not so freely discussed in terms of adverse actions. As David Healy concludes with a sad cynicism: 'The list of lithium's hazards ... seems fearsome, ... But lithium has the kind of profile all drugs should have, and has it because it has had no company support. Any symposia about lithium have typically been about its side effects, and how to manage these, while symposia for the other drugs ... have been run by companies who have often made strenuous efforts to hide any problems their drugs may have.' (2) REFERENCES: (1)Lithium and chronic kidney disease. Mukesh Kripalani, James Shawcross, Joe Reilly, John Main. BMJ 2009;339:b2452. (2) Psychiatric Drugs Explained. Fifth Edition. Elsevier. David Healy. 2009. Pg.102. Competing interests: None declared |
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