Lithium and chronic kidney disease

What do we know about the effect of lithium on the kidney?

Lithium use is associated with a range of glomerular and tubular disorders resulting in chronic kidney disease and more rarely established renal failure.4 5 (see the web table on bmj.com) Nephrogenic diabetes insipidus is commonly observed and may predispose to acute lithium toxicity, but it does not directly lead to progressive renal impairment. In clinical practice some lithium users have a stable reduction in glomerular filtration rate or a slowly progressive decline, for which a biopsy is rarely carried out; hence the histopathology is poorly characterised. The existing evidence from a small cohort study shows a “creeping creatinine” phenomenon (a progressive increase in the serum creatinine concentration over time), with some evidence of improvement on discontinuation.6 It remains uncertain who is at risk of either milder degrees of renal impairment or specific renal lesions, and the influence of other factors such as age, mental illness (which may in itself be a risk factor for chronic kidney disease), hypertension, and diabetes remains unclear. Hence little evidence exists to guide prescribing at the early stages of chronic kidney disease.

Renal health in people with severe mental illness as a whole is unresearched, but given that cardiovascular risk factors, which also increase the risk of chronic kidney disease, are more prevalent in this population, chronic kidney disease is probably also more common. Once chronic kidney disease is established in the general population, individuals are more likely to develop life limiting cardiovascular disease than to develop end stage renal failure,7 so the management of cardiovascular risk factors in lithium associated chronic kidney disease may be of at least equal importance as renal monitoring for the prevention of adverse physical health outcomes. Even if it is not possible to say with certainty whether a specific case of chronic renal impairment is due primarily to lithium exposure or other factors, it remains necessary to manage those with reduced renal function appropriately. For prescribers, the clinical importance of lithium associated chronic kidney disease depends on the renal and psychiatric consequences of starting or continuing lithium compared with the consequences of choosing an alternative drug or switching from lithium.

What pretreatment screening is necessary?

Cross sectional studies showing increased rates of chronic kidney disease compared with the general population, and biopsy studies showing a range of pathology, suggest it is prudent to screen for renal risk before starting lithium therapy (figure⇓). Although measuring the albumin to creatinine ratio is not a requirement included by NICE in its guidelines on pretreatment screening for chronic kidney disease, it does provide a useful baseline for distinguishing incidental proteinuria from proteinuria that results from lithium treatment. Box 1 outlines how to asses the risk factors for chronic kidney disease and cardiovascular disease.

Flowchart for renal screening before starting lithium, after results of estimated glomerular filtration rate and ratio of albumin to creatinine

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How should renal function be monitored in lithium therapy?

Although our recommendations extrapolate evidence from high quality diagnostic studies used to develop the NICE guideline on chronic kidney disease, it remains uncertain how lithium users differ from those at risk of the disease because of hypertension, diabetes, or use of non-steroidal anti-inflammatory drugs. Well patients with stable therapeutic lithium concentrations should have annual measurement of blood pressure and calculation of estimated glomerular filtration rate, with urine analysis for blood and protein. Rising serum concentrations of lithium (monitored every three months) should prompt additional calculation of estimated glomerular filtration rate, as should clinical features of possible lithium toxicity (nausea, diarrhoea, coarse tremor, ataxia, and confusion). The onset of lithium associated nephrogenic diabetes insipidus may increase the risk of raised lithium concentrations and toxicity. Vigilance should therefore be maintained for its main features (excessive thirst and polyuria), with dose reduction or a switch to alternative treatment if symptoms are persistent, as lithium associated nephrogenic diabetes insipidus is usually reversible when detected early in the treatment.

Above a rate of 60 ml/min/1.73² body surface, the estimated glomerular filtration rate is inaccurate, but this is unimportant in this context because the recommended renal monitoring for lithium users with stage 1 or 2 of chronic kidney disease is the same as for those with normal kidney function. In these three groups, dipstick proteinuria should be quantified by measuring the ratio of albumin to creatinine on a spot urine sample, and values of >70 mg/mmol should be discussed with a nephrologist.

Increased monitoring is needed for patients with stage 3 of chronic kidney disease or worse (table⇓).2 Lithium has a narrow therapeutic index (ratio of therapeutic dose to toxic dose), and acute toxicity is more likely in those with an already diminished glomerular filtration rate.8 Full discussion of the management of lithium concentrations outside the therapeutic range and acute lithium toxicity9 is outside the remit of this article. NICE’s guidelines on bipolar disorder recommend monitoring lithium serum concentrations every three months, with additional monitoring one week after any change in dose. Concentrations should be measured 12-14 hours after the last dose to obtain a reliable estimate to guide treatment.

Which drug interactions are important?

Active management of cardiovascular risk factors, and blood pressure in particular, is just as appropriate in lithium users as in any other high risk group, but lithium’s propensity to interact with diuretics, angiotensin converting enzyme inhibitors, and non-steroidal anti-inflammatory drugs must be borne in mind (box 2). Lithium users who start taking an angiotensin converting enzyme inhibitor will become more susceptible to an acute decline in their glomerular filtration rate, which may in turn markedly increase their serum lithium concentration.10

When should lithium be stopped?

No systematic evidence exists on which to base a decision to stop lithium, particularly for moderate degrees of chronic kidney disease. We recommend not trying to decide whether progressive chronic kidney disease results specifically from lithium—and no evidence exists that renal biopsy is useful in the decision making. Box 3 outlines possible considerations in decision making about stopping lithium.

Many users believe lithium is critical to their freedom from affective episodes, and evidence is accumulating for its antisuicidal effect. Any decision to stop lithium must take into account the likely effects on both renal and mental health, neither of which can be accurately predicted. Stopping or replacing lithium should be done gradually over three to six months to reduce the risk of rebound mania in bipolar disorder, although lithium can be withdrawn over a month (if switching to another agent) or immediately (if lithium concentrations are toxic or acute renal failure is present). The other commonly used agents for bipolar disorder (such as valproate, carbamazepine, olanzapine, quetiapine, risperidone, and aripiprazole) are not nephrotoxic and so present a safer treatment, but without a guarantee that they will be similarly effective.

Conclusion

Lithium use is associated with glomerular and tubular disease resulting in chronic kidney disease and more rarely established renal failure. It remains unclear which patients will develop milder and potentially reversible degrees of reduced estimated glomerular filtration rate and which will develop more severe chronic kidney disease. NICE’s guidelines identify lithium exposure as a risk factor triggering screening for chronic kidney disease and ongoing monitoring of estimated glomerular filtration rate.

In the UK, the provision of renal monitoring of lithium varies. Traditionally, monitoring was split between secondary psychiatric care based lithium clinics and primary care, depending on local custom and preference. The introduction of the targets in the quality and outcomes framework, however, may be shifting monitoring more to primary care (figures for 2007-8 show 97% achievement on a target to measure creatinine in lithium users in the previous 15 months).12 This shift is appropriate given the increased need to manage cardiovascular risk factors and hypertension in a coordinated way. Lithium safety must be supported by good communication, recording, and action on biochemistry results, with rapid access to specialist nephrology and psychiatric advice when withdrawal is considered.

The decision to stop lithium or switch to an alternative drug remains a careful judgment of risk versus benefit, in partnership with an informed patient who is fully committed to regular monitoring and understands the need to seek help early when problems arise. No evidence exists to support hasty cessation of the drug in those with mildly reduced estimated glomerular filtration rate, and the consequence of stopping lithium is a high risk of relapse in bipolar disorder. Larger epidemiological studies are needed to offer prescribers more precise evidence on which to base these important decisions. Longer term prospective cohort studies are needed to determine which individuals are prone to develop renal impairment while on lithium.