- Email: [email protected]
Long-term lithium and estimated glomerular filtration rate – Authors' reply
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
Correspondence
to Takeshi Terao’s letter6 about our work, some evidence exists (from two animal studies) for a protective effect of valproate against renal impairment (in doxorubicin-induced nephropathy and diabetes-induced fibrosis). Terao suggests a further analysis of our data to compare lithium versus valproate exposure. We think that Kessing and colleagues’ study4 addresses this question sufficiently, and suggests no difference in the effect of the two drugs in patients with bipolar disorder. From a clinical and public health perspective, it seems to be time to move on from the controversy about how rare or common these renal adverse events are. We appreciate Davis and colleagues’ call for studies of larger datasets and would be interested in future co-operations to look into the role of dosing regimens
www.thelancet.com/psychiatry Vol 3 February 2016
and prescribed preparations (other than slow-release lithium carbonate as in our study) on a patient level, and prescribing and monitoring systems on a population level, not least to optimise treatment for patients with baseline eGFR below 60 mL/min per 1·73 m² and elderly patients. PTD has received grants from Novo Nordisk, Lundbeck, and GlaxoSmithKline outside the submitted work. PTD is a member of the New Drugs Committee of the Scottish Medicines Consortium that makes decisions on prescribing in Scotland. SC and AS declare no competing interests.
1
2
3
4
5
*Stefan Clos, Alison Severn, Peter T Donnan [email protected]
6
Davis JM, Rosenbaum A, Shahinian V, Brosius FC. Prevention of lithium-associated renal failure: recent evidence. Lancet Psychiatry 2015; 2: 1045–47. 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, Sardu C, Piras D, Pani A. Long-term lithium and estimated glomerular filtration rate. Lancet Psychiatry 2015; 3: 104–05. 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; 72: 1182–91. Close H, Reilly J, Mason JM, et al. Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One 2014; 9: e90169. Terao T. Doubtful comparison group. Lancet Psychiatry 2015; 3: 104.
Community LD Psychiatry, Murray Royal Hospital, Perth, UK (SC); Renal Unit, Ninewells Hospital and Medical School, Dundee, UK (AS); and Dundee Epidemiology and Biostatistics Unit, Division of Population Health Sciences, Medical Research Institute, University of Dundee, Dundee, UK (PTD)
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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
Correspondence
to Takeshi Terao’s letter6 about our work, some evidence exists (from two animal studies) for a protective effect of valproate against renal impairment (in doxorubicin-induced nephropathy and diabetes-induced fibrosis). Terao suggests a further analysis of our data to compare lithium versus valproate exposure. We think that Kessing and colleagues’ study4 addresses this question sufficiently, and suggests no difference in the effect of the two drugs in patients with bipolar disorder. From a clinical and public health perspective, it seems to be time to move on from the controversy about how rare or common these renal adverse events are. We appreciate Davis and colleagues’ call for studies of larger datasets and would be interested in future co-operations to look into the role of dosing regimens
www.thelancet.com/psychiatry Vol 3 February 2016
and prescribed preparations (other than slow-release lithium carbonate as in our study) on a patient level, and prescribing and monitoring systems on a population level, not least to optimise treatment for patients with baseline eGFR below 60 mL/min per 1·73 m² and elderly patients. PTD has received grants from Novo Nordisk, Lundbeck, and GlaxoSmithKline outside the submitted work. PTD is a member of the New Drugs Committee of the Scottish Medicines Consortium that makes decisions on prescribing in Scotland. SC and AS declare no competing interests.
1
2
3
4
5
*Stefan Clos, Alison Severn, Peter T Donnan [email protected]
6
Davis JM, Rosenbaum A, Shahinian V, Brosius FC. Prevention of lithium-associated renal failure: recent evidence. Lancet Psychiatry 2015; 2: 1045–47. 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, Sardu C, Piras D, Pani A. Long-term lithium and estimated glomerular filtration rate. Lancet Psychiatry 2015; 3: 104–05. 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; 72: 1182–91. Close H, Reilly J, Mason JM, et al. Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One 2014; 9: e90169. Terao T. Doubtful comparison group. Lancet Psychiatry 2015; 3: 104.
Community LD Psychiatry, Murray Royal Hospital, Perth, UK (SC); Renal Unit, Ninewells Hospital and Medical School, Dundee, UK (AS); and Dundee Epidemiology and Biostatistics Unit, Division of Population Health Sciences, Medical Research Institute, University of Dundee, Dundee, UK (PTD)
107