- Email: [email protected]
Long-term lithium and estimated glomerular filtration rate
Correspondence
of diabetes in this dataset. We encourage researchers with datasets that include all past and current antipsychotic drug treatment, family history of diabetes, and diabetes assigned by testing not clinical detection, to do other analyses that track the effect of natural variation in treatment trajectories, including patients who stop using antipsychotic drugs altogether, stratified by family history. Second, the issue of confounding by indication, or prescribing in response to adverse side-effects or other factors that might affect the observed pattern of association, was also discussed in this paper and a previous report.2 Those with pre-diabetes or diabetes might have preferentially been taken off olanzapine. However, we still see the same pattern of results for olanzapine as for other commonly prescribed antipsychotics when we stratify our results by family history of diabetes. Our findings might be surprising to some and do require replication in other informative samples, but it remains possible that risk factors for diab etes in people with psychosis are non-additive. Our findings could therefore be a clue to mechanisms of risk. We encourage stratification of family history, not only in observational datasets but also in clinical trial datasets, to further test this possibility. We declare no competing interests.
*Debra Foley, Andrew Mackinnon [email protected] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, VIC, Australia (DF); and Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia (AM) 1
2
Foley DL, Mackinnon A, Morgan VA, et al. Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. Lancet Psychiatry 2015; 2: 1092–98. Foley DL, MacKinnon A, Morgan VA, et al. Predictors of type 2 diabetes in a nationally representative sample of adults with psychosis. World Psychiatry 2014; 13: 176–83.
www.thelancet.com/psychiatry Vol 3 February 2016
Doubtful comparison group
I declare no competing interests.
Takeshi Terao [email protected]
I read with much interest the recent article by Stefan Clos and colleagues 1 in which the authors identified an annual decline in estimated glomerular filtration rate (eGFR) in patients receiving lithium maintenance therapy of 1·3 mL/min per 1·73 m² (adjusted for age, sex, and baseline eGFR) and by 1·0 mL/min per 1·73 m² (after further adjustment for comorbidities, co-prescriptions, and episodes of lithium toxicity). In this group of patients, which included both those receiving lithium alone and those receiving lithium and the comparator drug, the rate of decline in eGFR was non-significantly greater than the respective rate of eGFR decline in the comparator group of patients receiving quetiapine, olanzapine, or valproate. However, as Clos and colleagues pointed out, recent data have linked atypical antipsychotic use with acute kidney injury. 2,3 Therefore, their findings suggest that both the lithium group and the comparator group might induce renal impairment to almost the same degree, although they suggested no harmful effect of stable lithium maintenance therapy on the rate of change in eGFR over time. Additionally, valproate has been reported to protect against renal impairment,4,5 although the authors did not mention this effect. If there is no significant difference in the rate of eGFR change between lithium and valproate, then the authors’ view is sufficiently supported that lithium maintenance therapy does not increase the risk of renal dysfunction. I recommend that the authors reanalyse their present data by comparing the lithium group consisting of patients receiving lithium alone and the comparator group consisting of patients receiving valproate alone.
Department of Neuropsychiatry, Oita University Faculty of Medicine, Idaigaoka 1-1, Hasamamachi, Yufu, Oita, 879-5593, Japan 1
2
3
4
5
Clos, S, Rauchhaus, P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry 2015; 2: 1075–83. Rej, S, Shulman, K, Herrmann, N et al. Prevalence and correlates of renal disease in older lithium users: a population-based study. Am J Geriatr Psychiatry 2014; 22: 1075–82. Hwang YJ, Dixon SN, Reiss JP et al. Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study. Ann Intern Med 2014; 161: 242–48. Van Beneden K, Geers C, Pauwels M, et al. Valproic acid attenuates proteinuria and kidney injury. J Am Soc Nephrol 2011; 22: 1863–75. Khan S, Jena G, Tikoo K. Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat. Exp Mol Pathol 2015; 98: 230–39.
Long-term lithium and estimated glomerular filtration rate We read with great interest the population-based cohort study by Stefan Clos and colleagues1 assessing the long-term effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in patients with affective disorders. The authors conclude that there is “no effect of stable lithium maintenance therapy on the rate of change in eGFR over time.” We have reached the following apparently opposite conclusion in a recent paper: “duration of lithium treatment is to be added to advancing age as a risk factor for reduced glomerular filtration rate.” 2 Our study was based on a cohort of 953 patients with affective disorders registered from 1980 to 2012 at a lithium clinic. In a crosssectional evaluation of the last available measurement, we found 105
Correspondence
that eGFR was lower in women (by 3·47 mL/min/1·73 m²), in older patients (0·73 mL/min/1·73 m² per year of age), and in patients who had a longer duration of lithium treatment (0·73 mL/min/1·73 m² per year). Half of the patients treated with lithium for longer than 20 years had an eGFR lower than 60 mL/min per 1·73 m², which corresponds to the upper end of stage G3a of chronic kidney disease, 3 whereas 40% of patients treated for longer than 25 years had an eGFR lower than 45 mL/min per 1·73 m², which corresponds to the upper end of stage G3b and is often considered a point of no return of chronic kidney disease.3 The median time on lithium taken to enter G3a was 25 years, whereas it took a median of 31 years to enter G3b. By contrast with Clos and colleagues’ study, 1 our study was not population based and we acknowledge many other limitations. We did not include in the model renal risk factors (diabetes, hypertension, use of non-steroidal anti-inflamamtory drugs, etc), baseline eGFR, mean lithium levels, and acute intoxications, which were proven to be significant predictors for eGFR decline in Clos and colleagues’ study.1 Moreover, we did not have the comparator group of patients with recurrent mood disorder exposed to alternative drugs. The latter might be relevant with regard to chronic kidney disease, as also suggested by the Danish nationwide populationbased study that has recently been published.4 In any case, our estimate that renal dysfunction tends to appear after decades of lithium treatment merits a comment on Clos and colleagues’ study. In particular, mean duration of exposure to lithium in their patients was only 55 months. We wonder whether the difference between the annual decline in eGFR for the lithium group (1·0 mL/min/1·73 m²) and that in the comparator group 106
(0·4 mL/min/1·73 m²) will remain non-significant after a longer duration of exposure. We declare no competing interests.
*Alberto Bocchetta, Claudia Sardu, Doloretta Piras, Antonello Pani [email protected] Department of Biomedical Sciences, University of Cagliari, “San Giovanni di Dio” Hospital, Via Ospedale 54, 09124 Cagliari, Italy (AB); Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy (CS); and Nephrology, Dialysis and Transplantation Unit, ‘Giuseppe Brotzu’ Hospital, Cagliari, Italy (DP, AP) 1
2
3
4
Clos S, Rauchhaus P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry 2015; 2: 1075–83. Bocchetta A, Ardau R, Fanni T, et al. Renal function during long-term lithium treatment: a cross-sectional and longitudinal study. BMC Med 2015; 13: 12–18. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1–150. Kessing LV, Gerds TA, Feldt-Rasmussen B, Andersen PK, Licht RW. Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population-based study. JAMA Psychiatry 2015; published online Nov 4. DOI:10.1001/jamapsychiatry.2015.1834.
Authors’ reply In their Comment in The Lancet Psychiatry, John Davis and colleagues1 raise several points about the causes of lithium-associated renal failure and the conclusions of our study.2 They refer to diabetic nephropathy and suggest that “virtually all chronic kidney diseases develop over a long period and substantial renal pathology occurs many years before a decline in eGFR”. But can (the common) diabetic nephropathy and (the rare) cases of a chronic progressive nephropathy in lithium-exposed patients really be compared? The aim of our study was to quantify the factors leading to renal decline in patients on lithium maintenance therapy. Admittedly, other studies such as those cited by Davis and colleagues1 have longer follow-up than ours. Equally,
Alberto Bocchetta and colleagues highlight in their letter3 relating to our study that renal dysfunction tends to develop after decades of lithium treatment. But might not the confounding factors and the drivers for a decline in renal function remain the same in the second or third decade of lithium exposure? Repetition of a misleading study design with a larger sample size and longer follow-up will not necessarily produce any different results. Of the studies cited by Davis and colleagues, two do not include an appropriate comparator group (and to compare an exposed group to the rest of the population does not qualify as a comparative cohort study) and two have no comparator group at all. In a Marx Brothers film, when a friend asked Groucho Marx “How is your wife?” he replied “Compared to what?” We had this question in mind when we designed our study. Recent longitudinal studies with an appropriate comparator group are those by Kessing and colleagues4 and Close and colleagues.5 Kessing and colleagues’ work supports the view that bipolar disorder is associated with an increased rate of chronic kidney disease independent of drug treatment, with no difference between maintenance treatment with lithium or anticonvulsants. Close and colleagues’ finding of a fall in renal function after 5–10 years in their lithium-exposed group doesn’t necessarily contradict our results (since they had only a limited ability to adjust for confounders, especially episodes of acute lithium toxicity). Kessing and colleagues4 also reported that use of lithium was not associated with an increased rate of end-stage chronic kidney disease, whereas use of anticonvulsants was. Do we want to continue this research now ad absurdum and start addressing the subject of anticonvulsant-associated end-stage chronic kidney disease in patients with bipolar disorder? According www.thelancet.com/psychiatry Vol 3 February 2016
of diabetes in this dataset. We encourage researchers with datasets that include all past and current antipsychotic drug treatment, family history of diabetes, and diabetes assigned by testing not clinical detection, to do other analyses that track the effect of natural variation in treatment trajectories, including patients who stop using antipsychotic drugs altogether, stratified by family history. Second, the issue of confounding by indication, or prescribing in response to adverse side-effects or other factors that might affect the observed pattern of association, was also discussed in this paper and a previous report.2 Those with pre-diabetes or diabetes might have preferentially been taken off olanzapine. However, we still see the same pattern of results for olanzapine as for other commonly prescribed antipsychotics when we stratify our results by family history of diabetes. Our findings might be surprising to some and do require replication in other informative samples, but it remains possible that risk factors for diab etes in people with psychosis are non-additive. Our findings could therefore be a clue to mechanisms of risk. We encourage stratification of family history, not only in observational datasets but also in clinical trial datasets, to further test this possibility. We declare no competing interests.
*Debra Foley, Andrew Mackinnon [email protected] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, VIC, Australia (DF); and Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia (AM) 1
2
Foley DL, Mackinnon A, Morgan VA, et al. Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. Lancet Psychiatry 2015; 2: 1092–98. Foley DL, MacKinnon A, Morgan VA, et al. Predictors of type 2 diabetes in a nationally representative sample of adults with psychosis. World Psychiatry 2014; 13: 176–83.
www.thelancet.com/psychiatry Vol 3 February 2016
Doubtful comparison group
I declare no competing interests.
Takeshi Terao [email protected]
I read with much interest the recent article by Stefan Clos and colleagues 1 in which the authors identified an annual decline in estimated glomerular filtration rate (eGFR) in patients receiving lithium maintenance therapy of 1·3 mL/min per 1·73 m² (adjusted for age, sex, and baseline eGFR) and by 1·0 mL/min per 1·73 m² (after further adjustment for comorbidities, co-prescriptions, and episodes of lithium toxicity). In this group of patients, which included both those receiving lithium alone and those receiving lithium and the comparator drug, the rate of decline in eGFR was non-significantly greater than the respective rate of eGFR decline in the comparator group of patients receiving quetiapine, olanzapine, or valproate. However, as Clos and colleagues pointed out, recent data have linked atypical antipsychotic use with acute kidney injury. 2,3 Therefore, their findings suggest that both the lithium group and the comparator group might induce renal impairment to almost the same degree, although they suggested no harmful effect of stable lithium maintenance therapy on the rate of change in eGFR over time. Additionally, valproate has been reported to protect against renal impairment,4,5 although the authors did not mention this effect. If there is no significant difference in the rate of eGFR change between lithium and valproate, then the authors’ view is sufficiently supported that lithium maintenance therapy does not increase the risk of renal dysfunction. I recommend that the authors reanalyse their present data by comparing the lithium group consisting of patients receiving lithium alone and the comparator group consisting of patients receiving valproate alone.
Department of Neuropsychiatry, Oita University Faculty of Medicine, Idaigaoka 1-1, Hasamamachi, Yufu, Oita, 879-5593, Japan 1
2
3
4
5
Clos, S, Rauchhaus, P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry 2015; 2: 1075–83. Rej, S, Shulman, K, Herrmann, N et al. Prevalence and correlates of renal disease in older lithium users: a population-based study. Am J Geriatr Psychiatry 2014; 22: 1075–82. Hwang YJ, Dixon SN, Reiss JP et al. Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study. Ann Intern Med 2014; 161: 242–48. Van Beneden K, Geers C, Pauwels M, et al. Valproic acid attenuates proteinuria and kidney injury. J Am Soc Nephrol 2011; 22: 1863–75. Khan S, Jena G, Tikoo K. Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat. Exp Mol Pathol 2015; 98: 230–39.
Long-term lithium and estimated glomerular filtration rate We read with great interest the population-based cohort study by Stefan Clos and colleagues1 assessing the long-term effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in patients with affective disorders. The authors conclude that there is “no effect of stable lithium maintenance therapy on the rate of change in eGFR over time.” We have reached the following apparently opposite conclusion in a recent paper: “duration of lithium treatment is to be added to advancing age as a risk factor for reduced glomerular filtration rate.” 2 Our study was based on a cohort of 953 patients with affective disorders registered from 1980 to 2012 at a lithium clinic. In a crosssectional evaluation of the last available measurement, we found 105
Correspondence
that eGFR was lower in women (by 3·47 mL/min/1·73 m²), in older patients (0·73 mL/min/1·73 m² per year of age), and in patients who had a longer duration of lithium treatment (0·73 mL/min/1·73 m² per year). Half of the patients treated with lithium for longer than 20 years had an eGFR lower than 60 mL/min per 1·73 m², which corresponds to the upper end of stage G3a of chronic kidney disease, 3 whereas 40% of patients treated for longer than 25 years had an eGFR lower than 45 mL/min per 1·73 m², which corresponds to the upper end of stage G3b and is often considered a point of no return of chronic kidney disease.3 The median time on lithium taken to enter G3a was 25 years, whereas it took a median of 31 years to enter G3b. By contrast with Clos and colleagues’ study, 1 our study was not population based and we acknowledge many other limitations. We did not include in the model renal risk factors (diabetes, hypertension, use of non-steroidal anti-inflamamtory drugs, etc), baseline eGFR, mean lithium levels, and acute intoxications, which were proven to be significant predictors for eGFR decline in Clos and colleagues’ study.1 Moreover, we did not have the comparator group of patients with recurrent mood disorder exposed to alternative drugs. The latter might be relevant with regard to chronic kidney disease, as also suggested by the Danish nationwide populationbased study that has recently been published.4 In any case, our estimate that renal dysfunction tends to appear after decades of lithium treatment merits a comment on Clos and colleagues’ study. In particular, mean duration of exposure to lithium in their patients was only 55 months. We wonder whether the difference between the annual decline in eGFR for the lithium group (1·0 mL/min/1·73 m²) and that in the comparator group 106
(0·4 mL/min/1·73 m²) will remain non-significant after a longer duration of exposure. We declare no competing interests.
*Alberto Bocchetta, Claudia Sardu, Doloretta Piras, Antonello Pani [email protected] Department of Biomedical Sciences, University of Cagliari, “San Giovanni di Dio” Hospital, Via Ospedale 54, 09124 Cagliari, Italy (AB); Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy (CS); and Nephrology, Dialysis and Transplantation Unit, ‘Giuseppe Brotzu’ Hospital, Cagliari, Italy (DP, AP) 1
2
3
4
Clos S, Rauchhaus P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry 2015; 2: 1075–83. Bocchetta A, Ardau R, Fanni T, et al. Renal function during long-term lithium treatment: a cross-sectional and longitudinal study. BMC Med 2015; 13: 12–18. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1–150. Kessing LV, Gerds TA, Feldt-Rasmussen B, Andersen PK, Licht RW. Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population-based study. JAMA Psychiatry 2015; published online Nov 4. DOI:10.1001/jamapsychiatry.2015.1834.
Authors’ reply In their Comment in The Lancet Psychiatry, John Davis and colleagues1 raise several points about the causes of lithium-associated renal failure and the conclusions of our study.2 They refer to diabetic nephropathy and suggest that “virtually all chronic kidney diseases develop over a long period and substantial renal pathology occurs many years before a decline in eGFR”. But can (the common) diabetic nephropathy and (the rare) cases of a chronic progressive nephropathy in lithium-exposed patients really be compared? The aim of our study was to quantify the factors leading to renal decline in patients on lithium maintenance therapy. Admittedly, other studies such as those cited by Davis and colleagues1 have longer follow-up than ours. Equally,
Alberto Bocchetta and colleagues highlight in their letter3 relating to our study that renal dysfunction tends to develop after decades of lithium treatment. But might not the confounding factors and the drivers for a decline in renal function remain the same in the second or third decade of lithium exposure? Repetition of a misleading study design with a larger sample size and longer follow-up will not necessarily produce any different results. Of the studies cited by Davis and colleagues, two do not include an appropriate comparator group (and to compare an exposed group to the rest of the population does not qualify as a comparative cohort study) and two have no comparator group at all. In a Marx Brothers film, when a friend asked Groucho Marx “How is your wife?” he replied “Compared to what?” We had this question in mind when we designed our study. Recent longitudinal studies with an appropriate comparator group are those by Kessing and colleagues4 and Close and colleagues.5 Kessing and colleagues’ work supports the view that bipolar disorder is associated with an increased rate of chronic kidney disease independent of drug treatment, with no difference between maintenance treatment with lithium or anticonvulsants. Close and colleagues’ finding of a fall in renal function after 5–10 years in their lithium-exposed group doesn’t necessarily contradict our results (since they had only a limited ability to adjust for confounders, especially episodes of acute lithium toxicity). Kessing and colleagues4 also reported that use of lithium was not associated with an increased rate of end-stage chronic kidney disease, whereas use of anticonvulsants was. Do we want to continue this research now ad absurdum and start addressing the subject of anticonvulsant-associated end-stage chronic kidney disease in patients with bipolar disorder? According www.thelancet.com/psychiatry Vol 3 February 2016