Long-term Lithium-treated Patients Research Articles

Impact of Long-Term Lithium Treatment on Renal Function in Patients With Bipolar Disorder Based on Novel Biomarkers.

Lithium in the form of lithium carbonate (Li2CO3) has become one of the most effective and widely prescribed drugs for mood stabilization. However, lithium has adverse effects on renal tubular functions, such as decreased concentrating function of the kidneys, and even occasional symptoms of nephrogenous diabetes insipidus occur with additional evidence of glomerular disruption in lithium-treated patients. We assessed the kidney function of patients with bipolar disorder who are under long-term lithium treatment using novel markers of kidney damage such as plasma neutrophil gelatinase-associated lipocalin, cystatin C, albuminuria, estimated glomerular filtration rate, Chronic Kidney Disease-Epidemiology Investigation using creatinine and cystatin C, and serum and urinary osmolality, and compared the results with those of age-matched patients with bipolar disorder not treated with lithium. The study enrolled 120 patients with bipolar disorder, consisting of 80 (30 male and 50 female patients) who have been receiving lithium for 0.5 to 20 (mean, 7) years and 40 (10 male and 30 female patients) who had never been exposed to lithium treatment. Patients treated with lithium had significantly decreased urine osmolality (mean ± SD, 405 ± 164 vs 667 ± 174 mmol/kg) and urine-to-serum osmolality ratio (1.35 ± 0.61 vs 2.25 ± 0.96). No significant difference was found in creatinine, estimated glomerular filtration rate values calculated using the Chronic Kidney Disease-Epidemiology Investigation using creatinine and cystatin C, neutrophil gelatinase-associated lipocalin, cystatin C, and albuminuria between both groups. We found no significant difference in renal biomarkers between patients treated with lithium for 6 to 24 months and those treated for 25 to 240 months. We found significantly decreased kidney concentrating ability in the long-term lithium-treated patients compared with the control group. Other renal function markers did not indicate any significant signs of renal dysfunction.

Hippocampal subfield volumes in short- and long-term lithium-treated patients with bipolar I disorder.

Patients diagnosed with bipolar disorder (BP) may experience hippocampal atrophy. Lithium exposure has been associated with increased hippocampal volumes. However, its effects on hippocampal subfields remain to be clarified. We investigated the effects of short- and long-term lithium exposure on the hippocampus and its subfields in patients affected by bipolar I disorder (BP-I). Hippocampal subfields and total hippocampal volumes were measured in 60 subjects divided into four groups: 15 patients with BP-I who were never exposed to lithium [no-exposure group (NE)], 15 patients with BP-I exposed to lithium for < 24 months [short-exposure group (SE)], 15 patients with BP-I exposed to lithium for > 24 months [long-exposure group (LE)], and 15 healthy control subjects (HC). The SE and NE groups showed smaller total hippocampal volumes and smaller bilateral cornu ammonis CA2-3, CA4-dentate gyrus (DG), presubiculum, and subiculum volumes compared with HC. The LE group showed larger total hippocampal volumes and bilateral CA2-3, left CA4-DG, left presubiculum, and right subiculum volumes compared with the NE group, and larger volumes of the right CA2-3, left CA4-DG, left presubiculum, and right subiculum compared with the SE group. No differences were found between the LE group and HC or between the SE and NE groups. Long-term, but not short-term, exposure to lithium treatment may exert neuroprotective effects on specific hippocampal subfields linked to disease progression.

Factors associated with lithium efficacy in bipolar disorder.

About one-third of lithium-treated, bipolar patients are excellent lithium responders; that is, lithium monotherapy totally prevents further episodes of bipolar disorder for ten years and more. These patients are clinically characterized by an episodic clinical course with complete remission, a bipolar family history, low psychiatric comorbidity, mania-depression episode sequences, a moderate number of episodes, and a low number of hospitalizations in the pre-lithium period. Recently, it has been found that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. Lithium exerts a neuroprotective effect, in which increased expression of brain-derived neurotrophic factor (BDNF) and inhibition of the glycogen synthase kinase-3 (GSK-3) play an important role. The response to lithium has been connected with the genotype of the BDNF gene and serum BDNF levels. A better response to lithium is connected with the Met allele of the BDNF Val/Met polymorphism, as is a hyperthymic temperament. Excellent lithium responders have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. The preservation of cognitive functions in long-term lithium-treated patients may be connected with the stimulation of the BDNF system, with the resulting prevention of affective episodes exerting deleterious cognitive effects, and possibly also with lithium's antiviral effects. A number of candidate genes that are related to neurotransmitters, intracellular signaling, neuroprotection, circadian rhythms, and other pathogenic mechanisms of bipolar disorder were found to be associated with the lithium prophylactic response. The Consortium on Lithium Genetics (ConLiGen) has recently performed the first genome-wide association study on the lithium response in bipolar disorder.

P.2.d.008 Association study of the glycogen synthase kinase-3β gene polymorphism with kidney function in long-term lithium-treated patients

It is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment.This study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation.The study included patients aged 6–16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n = 43), obese non-asthmatic (n = 45), and non-obese non-asthmatic (control group, n = 30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups.No statistically significant differences were observed in 25(OH)-vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP-9.This is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children.

The association of glycogen synthase kinase-3beta (GSK-3β) gene polymorphism with kidney function in long-term lithium-treated bipolar patients.

BackgroundMost bipolar patients experience a reduction in urinary concentrating ability within a few weeks of starting lithium treatment. This phenomenon may be connected with the effect of lithium on the glycogen synthase kinase-3beta (GSK-3β) present in the renal tubules. The GSK-3β gene is located on chromosome 3q13 and possesses a functional -50 C/T polymorphism. In the present study, we estimated this polymorphism in a group of long-term lithium-treated patients and assessed its association with various parameters of kidney function, including novel markers of kidney injury such as serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary beta2-microglobulin (β2-MG).MethodsThe study comprised 78 patients with bipolar mood disorder (25 males, 53 females), aged 36 to 82 (60 ± 11) years. The mean duration of bipolar illness was 6 to 50 (24 ± 10) years, and the patients have been receiving lithium for 5 to 38 (16 ± 9) years. All the patients had the following features, regarded as the phenotypes of kidney functions measured: urine examination for specific gravity evaluation, serum creatinine concentration, and estimated glomerular filtration rate (eGFR) evaluation, as well as the serum concentrations of NGAL and urinary β2-MG. Genotyping of GSK-3β gene -50 C/T polymorphism was done by polymerase chain reaction analysis.Results and discussionThirty-four patients (6 males, 28 females) had the T/T genotype, 37 patients (16 males, 21 females) had the T/C genotype, and 7 patients (3 males, 4 females) had the C/C genotype. Patients homozygous for C allele had significantly higher urine specific gravities (1.019 ± 0.008) compared to the remaining genotypes (1.013 ± 0.007) (p = 0.035), with no influence of the duration of lithium treatment. Other parameters of kidney function (serum creatinine, eGFR, serum NGAL, and urinary β2-MG levels) were not different between genotypes and, again, were not affected by the duration of lithium treatment. There was no correlation between urine specific gravity and other kidney function parameters. The results of our study indicate that the GSK-3β genotype may be connected with lithium-induced impairment of renal concentrating ability in long-term lithium-treated bipolar patients. Limitations of the study include small size of the sample, small number of C/C genotype patients, and a lack of multiple testing analysis of genotypic differences in various measures of kidney function.

A Case of Renal Failure Requiring a Renal Transplant Secondary to Lithium Treatment

A Case of Renal Failure Requiring a Renal Transplant Secondary to Lithium Treatment

Screening for the markers of kidney damage in men and women on long-term lithium treatment.

SummaryBackgroundLithium is the most effective therapeutic modality for the prevention of recurrences in bipolar disorder. An important adverse effect of lithium, especially with long-term treatment, is a possibility of a toxic effect on kidney function. Therefore, the aim of the study was to assess kidney function in a group of long-term lithium-treated patients.Material/MethodsThe study comprised 80 patients with bipolar mood disorder (26 male, 54 female), aged 60±11 years. They had been receiving lithium for 5–38 (16±9) years. Random urine sample was examined for albumin and creatinine excretion, and urinary albumin to creatinine ratio (UACR) was calculated. Specific gravity of the urine sample was recorded. Serum concentration of creatinine was measured and estimated glomerular filtration rate (eGFR) was calculated. Serum concentration of albumin was also measured.ResultsDecreased eGFR values <60 ml/min/1.73 m2 were found in 23% of patients, significantly more frequently in men that in women (38% vs. 16%, p=0.04). Elevated UACR values (>30 mg/g) were found in 25% of men and 12% of women, respectively. Serum albumin concentration >52 g/l was detected in 19% of patients (17% of men and 20% of women). Specific gravity of the urine, equal to or below 1.005, was recorded in 21% of men and 14% of women.ConclusionsThe results confirm the opinion that screening for the markers of kidney damage should be performed in long-term lithium-treated patients for identification of persons with impaired kidney function. Male sex seems to be the risk factor for the development of kidney damage during long-term lithium treatment.

Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3β-positive epithelium

It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3β (pGSK-3β) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7-28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3β-immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β-, and pGSK-3β-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3β, proliferation, and microcysts.

Ultrasonically determined thyroid volume and thyroid functions in lithium‐naïve and lithium‐treated patients with bipolar disorder: a cross‐sectional and longitudinal study

This study investigated thyroid volume, hormone levels and antibodies in long-term lithium-treated and lithium-naïve bipolar patients, some of whom underwent prospective follow-up evaluations. Fourteen lithium-naïve patients, 13 long-term lithium-treated patients diagnosed with bipolar disorder and 12 healthy controls were included. Seven lithium-naïve patients were followed-up during their lithium receiving period (range 6-9 months). Thyroid volume and serum levels of thyroid hormones and antibodies were measured once in the long-term lithium-treated patients and controls, and twice in the lithium-naïve patients, i.e. before and after lithium treatment. Mean thyroid volumes in the lithium-naïve patients were significantly higher than those in the controls. Long-term lithium-treated patients had significantly higher total thyroid volume than the lithium-naïve patients and the controls. Total thyroid volume in the patients after the lithium treatment was significantly higher than that before. Serum free thyroxine (fT4) levels in the long-term lithium-treated patients were lower than those in the lithium-naïve patients and the controls. In the lithium-naïve patients, after lithium treatment, free triiodothyronine (fT3) levels were lower, and thyroid stimulating hormone (TSH) levels were higher compared to those before lithium treatment. The results suggest that thyroid enlargement and some alterations in thyroid hormones in bipolar patients may present even before lithium treatment and increase further with lithium treatment.

Lithium-induced nephropathy: Rate of progression and prognostic factors

Long-term lithium administration in humans may lead to chronic tubulointerstitial nephritis, which develops very slowly. Its progression to end-stage renal disease (ESRD) has been rarely reported. The aim of this study is to document the rate of progression of lithium-induced nephropathy and its prognostic factors, and to provide an estimation of the percentage of lithium-induced ESRD in France. Two groups have been studied: 54 patients with lithium-induced renal failure, nine of whom underwent renal biopsy; and 20 patients who were referred for systematic renal biopsy, 14 of whom were subsequently followed up. In addition, a survey of lithium-induced ESRD was conducted in French dialysis centers. The mean annual loss of creatinine clearance in patients with lithium-induced nephropathy was 2.29 mL/min. Among 74 patients, 12 reached ESRD at a mean age of 65 years. Creatinine clearance at referral and at last follow-up was inversely related to the duration of lithium therapy in both univariate and multivariate analyses adjusting for age, gender, hypertension, and proteinuria. The degree of interstitial fibrosis on renal biopsy was also related to the lithium duration and cumulative dose. It was predictive of the final creatinine clearance. About 35% of the patients tested had moderate hypercalcemia, due to hyperparathyroidism. The prevalence of lithium-related ESRD in France was estimated as two per 1000 dialysis patients. The average latency between onset of lithium therapy and ESRD was 20 years. Lithium-induced chronic renal disease is slowly progressive. Its rate of progression is related to the duration of lithium administration. Lithium-related ESRD represents 0.22% of all causes of ESRD in France. Regular monitoring of estimated creatinine clearance is mandatory in long-term lithium-treated patients.

Are thyrotropin-binding inhibiting immunoglobulins associated with lithium-induced thyroid gland dysfunction?

Although the thyroid-inhibiting effects of lithium carbonate treatment are well appreciated (Myers 1985), the exact pathogenesis of clinically significant lithium-associated thyroid dysfunction has not been determined (Crowe et al. 1973). and whereas up to 30% of long-term lithium-treated patients have abnormal thyroid function tests, only 5% develop hypothyroidism (Myers 1985). Previous explanations have suggested that preexisting thyroid gland damage is a primary factor in lithium-associated hypothyroidism, yet prospective study has not supported this hypothesis (Myers 1985). Findings of elevated thyroid microsomal and antithyroglobulin antibodies in some lithium-treated patients have led to speculation that immunological phenomena may be implicated in lithium-associated thyroid dysfunction, yet no direct thyrotoxic effect of microsomal or thyroglobulin antibodies has been demonstrated (Myers 1985 ). Recently, IgG antibodies that bind to the thyrotropin (TSH) receptor and block the binding

Lithium effects on calcium, magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion.

Calcium, magnesium and phosphate metabolism was studied in lithium-treated patients, using a metabolic balance technique. Two groups of patients participated in the study: 1) Patients who were to start on a prophylactic lithium treatment, and 2) Long-term lithium-treated patients whose treatment was to be terminated. Lithium treatment produced a positive balance in both calcium, phosphate and magnesium. By continuous lithium treatment the effect on magnesium wore off, whereas the effect on calcium and phosphate persisted. In urine, lithium induced a decrease in both calcium and phosphate excretion, whereas the excretion of magnesium was increased. Bone mineral content was measured by photon absorption, and lithium treatment resulted in a decrease in bone mineral content occurring within the first 6 months of lithium treatment. In the patients, bioavailability of the Li2CO3 preparation was found to be about 95%, and the patients contained about one 24-h dose of lithium just before the next dose of lithium was administered.

Lithium, bone and body weight studies in long-term lithium-treated patients and in the rat.

Morphometric studies were carried out on radiographs taken on separate occasions, 2 years apart, from patients receiving long-term prophylactic lithium. Similar studies were made of femora of growing rats over a 1-year period. We conclude that lithium dos not affect the size or mineralization of bone from either humans or growing or growing rats, but that it affects whole body growth in growing rats.