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Original Investigation |

Use of Lithium and Anticonvulsants and the Rate of Chronic Kidney Disease A Nationwide Population-Based Study

Lars Vedel Kessing, MD, DMSc1; Thomas Alexander Gerds, PhD2; Bo Feldt-Rasmussen, MD, DMSc3; Per Kragh Andersen, PhD, DMSc2; Rasmus W. Licht, MD, PhD4,5
[+] Author Affiliations
1Psychiatric Center Copenhagen, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
2Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3Department of Nephrology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
4Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
5Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
JAMA Psychiatry. 2015;72(12):1182-1191. doi:10.1001/jamapsychiatry.2015.1834.
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Importance  Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD).

Objective  To compare rates of CKD and in particular rates of end-stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder.

Design, Setting, and Participants  This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10 591), and all patients exposed to either lithium (n = 26 731) or anticonvulsants (n=420 959). Cohort 2 included the subgroup of 10 591 patients diagnosed as having bipolar disorder.

Main Outcomes and Measures  Possible CKD, definite CKD, and end-stage CKD (defined as long-term dialysis or renal transplantation).

Results  A total of 14 727 (0.8%), 18 762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319 (3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or end-stage CKD, respectively. Based on the total sample and not considering diagnoses, use of lithium was associated with an increased rate of definite CKD (0 prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; ≥60 prescriptions: HR = 3.65, 95% CI, 2.64-5.05; P for trend < .001) and possible CKD (0 prescriptions: HR = 1.01, 95% CI, 0.79-1.30; ≥60 prescriptions: HR = 2.88, 95% CI, 2.17-3.81; P for trend < .001), whereas use of anticonvulsants, antipsychotics, or antidepressants was not. Neither use of lithium nor use of any other drug class was associated with increasing rates of end-stage CKD. In patients with bipolar disorder, use of lithium was associated with an increased rate of definite CKD (1-2 prescriptions: HR = 0.89, 95% CI, 0.39-2.06; ≥60 prescriptions: HR = 2.54, 95% CI, 1.81-3.57; P for trend < .001) or possible CKD (1-2 prescriptions: HR = 1.26, 95% CI, 0.65-2.43; ≥60 prescriptions, HR = 2.48, 95% CI, 1.80-3.42; P for trend < .001), as was use of anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23, 95% CI, 0.76-1.99; ≥60 prescriptions, HR = 2.30, 95% CI, 1.53-3.44; P for trend < .001; possible CKD, 1-2 prescriptions: HR = 1.11, 95% CI, 0.70-1.76; ≥60 prescriptions: HR = 1.97, 95% CI, 1.34-2.90; P for trend < .001). There was no such association with antipsychotics or antidepressants. Also in patients with bipolar disorder, use of lithium was not significantly associated with an increased rate of end-stage CKD, whereas use of anticonvulsants was (1-2 prescriptions, HR = 0 [95% CI, 0.00-infinity]; 30-39 prescriptions: HR = 3.23, 95% CI, 1.26-8.27; ≥60 prescriptions: HR = 2.06, 95% CI, 0.82-5.16; P for trend = .002).

Conclusions and Relevance  Maintenance treatment with lithium or anticonvulsants as practiced in modern care is associated with an increased rate of CKD. However, use of lithium is not associated with an increased rate of end-stage CKD. The associations between use of medication and CKD may at least partly be attributed to bias.

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Figure 1.
Cumulative Incidence of Definite Chronic Kidney Disease for Patients With Bipolar Disorder Treated With Lithium

Cumulative incidence of definite chronic kidney disease for patients with bipolar disorder treated with lithium by ages 30 (A), 45 (B), 60 (C), and 75 (D) years, with the number of prescriptions (0, 1-9, and ≥10) indicating the lithium exposure history at the birthday specified in each panel. For example, patients diagnosed as having mania or bipolar disorder at age 60 years show a 10-year risk of 3.9% (95% CI, 1.7%-6.2%) when they were never before treated with lithium. The 10-year risk increased to 7.3% (95% CI, 1.0%-13.5%) in patients who had 1 to 9 lithium prescriptions before their 60th birthday and to 8.7% (95% CI, 5.9%-11.6%) in patients who had 10 or more lithium prescriptions prior to their 60th birthday.

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Figure 2.
Cumulative Incidence of Definite Chronic Kidney Disease for Patients With Bipolar Disorder Treated With Anticonvulsants

Cumulative incidence of definite chronic kidney disease for patients with bipolar disorder treated with anticonvulsants by ages 30 (A), 45 (B), 60 (C), and 75 (D) years, with the number of prescriptions (0, 1-9, and ≥10) indicating the anticonvulsant exposure history at the birthday specified in each panel.

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Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population-based study
Posted on November 30, 2015
J Elisabeth Wells, Nicholas B Cross
Population Health, University of Otago, Christchurch, New Zealand; Nephrology, Christchurch Hospital, New Zealand
Conflict of Interest: None Declared

Kessing et al. [1], in their national Danish study using registers, report a puzzling finding: the number of anticonvulsant prescriptions is associated with possible chronic kidney disease (CKD), definite CKD and end-stage CKD in bipolar patients but not in their general population cohort [2]. They acknowledge that the result in bipolar patients could be, ‘due to another kind of selection bias, for example, patients with decreased renal function will less likely begin treatment with lithium and will more likely begin treatment with anticonvulsants.’ However they could not check for this selection bias as they did not have access to laboratory data on creatinine from which to estimate glomerular filtration rates. A further selection bias mentioned by Goodwin in his editorial [2] is that patients with deteriorating renal function may be switched from lithium to anticonvulsants.

Both these selection biases could perhaps be assessed in an English study with retrospective laboratory data on renal function in general practice patients diagnosed with bipolar disorder [3]. As long as all these patients had renal function tested, this study could show to what extent 1) bipolar patients starting treatment with anticonvulsants had lower renal function than those starting on lithium, and 2) if those switched from lithium to anticonvulsants experienced a worsening of renal function prior to the switch (some of course will have been switched because of non-responsiveness to lithium). The appropriate analyses to assess these biases have not been done but it seems that the relevant data is available.

Kessing et al. [1] found that the extent of lithium use was associated with possible and definite CKD but not significantly with end-stage CKD. They note that the lithium association they observed could be due in part to detection bias because of the regular blood tests which are part of monitoring for patients on lithium. They also acknowledge that the absence of a significant association between lithium use and end-stage CKD could be due to the small number of patients with end-stage CKD. Another factor is that the duration of this study was less than 20 years whereas a small Swedish study [4] suggests that lithium-induced end-stage CKD takes 20-30 years.

It seems premature to conclude that lithium does not cause kidney damage or that anticonvulsants do, in bipolar patients.

References

1. Kessing L, Gerds T, Feldt-Rasmussen B, Andersen P, Licht RW. Use of lithium and anticonvulsants and the rate of chronic kidney disease: A nationwide population-based study [published online November 4, 2015]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.1834
2. Goodwin GM. The safety of lithium [published online November 4, 2015]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.2014
3. Close H, Reilly JL, Mason JM, Kripalani M, Wilson D, Main J, et al., Renal failure in lithium-treated bipolar disorder: A retrospective cohort study. PLoS One 2014: 9(3);e9016169.
4. Bendz H, Schon S, Attman P-O, Aurell M. Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 2010;77(3):219-24.
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