Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.

T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.

A comparison of plasma cystatin C and plasma creatinine for the screening of renal function in lithium-treated patients.

BACKGROUND: Renal insufficiency is a serious complication of lithium treatment. Therefore, regular monitoring of plasma (P) creatinine is always part of lithium treatment safety routines. Recently P-cystatin C-estimated glomerular filtration rate (cystatin C-eGFR) had been launched as a preferable alternative to P-creatinine. AIMS: To find out which of the two alternatives to prefer in the safety routines for lithium-treated patients. MATERIAL: All 201 patients on lithium treatment at the Department of Psychiatry in Lund, Sweden. METHODS: During 14 months P-cystatin C was included in the safety routines besides routine P-creatinine every 4 months. At the end of the study period, 182 patients were eligible for analysis. With iohexol clearance as reference for GFR (performed in 111/182 patients) we calculated positive and negative predictive values (PPV, NPV) for P-creatinine and for creatinine-eGFR and cystatin C-eGFR, obtained by prediction equations. We also calculated the agreement between the measures of GFR (including repeatability). RESULTS: PPV for cystatin C-eGFR (65%) was better than for creatinine-eGFR (48%). Combining the two resulted in a PPV of 56% and marginally increased NPV to 95%. The average of cystatin C-eGFR and creatinine-eGFR yielded PPV 67% and NPV 92%. The agreement between creatinine-eGFR and GFR was better than the agreement between cystatin C-eGFR and GFR, but both were clinically unacceptable. The repeatability of P-creatinine was acceptable for psychiatric purposes. The repeatability of cystatin C-eGFR was inferior to that of P-creatinine. CONCLUSION: Our results do not justify replacing P-creatinine by cystatin C-eGFR in the lithium treatment safety routines.

A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed.

BACKGROUND: Insufficient knowledge on the longitudinal fate of renal function in lithium patients incited this retrospective study of 149 patients. METHOD: Medical record review of a lithium cohort (N = 149), 8--12 years after an initial renal function study. RESULTS: Twenty-one patients had died, one from uremia probably not caused by lithium, and 42 had discontinued lithium. Reduced urinary concentrating capacity (Umax) or glomerular filtration rate (GFR) was not more frequent among deceased or off-lithium patients than among the 86 patients who were on lithium at follow-up. In 63 of the latter patients, Umax had been re-examined after the initial study, and GFR in 29 patients. Reduced Umax and GFR had become twice as common, and average Umax and GFR had decreased significantly. The reduction of GFR was associated with lithium treatment duration and age, and reduced Umax with treatment duration only. CONCLUSIONS: Reduced renal function is not a major cause of treatment discontinuation but becomes increasingly common with treatment duration.Limitations. Missing data rendered the interpretation difficult in some respects. Clinical relevance. The increased proportion of patients with reduced GFR and Umax with time implies an increased risk of potentially lethal dehydration and lithium intoxication. Continued surveillance of urinary output and GFR is therefore necessary.

Drug-induced diabetes insipidus: incidence, prevention and management.

Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified antidiuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization's adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10). Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indomethacin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders. In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications.

Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal.

OBJECTIVES: To assess in patients with long-term lithium treatment the incidence and prevalence of hypercalcaemia and hyperparathyroidism, and to evaluate the relationship between parathyroid function and renal function: also, to examine the effect of treatment discontinuation. DESIGN: Part 1. An epidemiological cross-sectional study covering defined catchment areas. Part 2. A lithium withdrawal study in a subgroup of the patients who were examined after a mean of 8.5 (4-16) weeks off lithium. Comparisons were made with a group of psychiatric non-lithium patients matched for sex and age. SETTING: Outpatient treatment at nine psychiatric departments in southern Sweden. SUBJECTS: Inclusion criterion was 15 years or more on lithium. Excluded from Part 2 were patients with a high risk of relapse. Out of 215 identified patients. 142 (66%) entered and completed Part 1, while 13 of the latter entered and completed Part 2. RESULTS: The point prevalence of persistent hypercalcaemia was 3.6% and of surgically verified hyperparathyroidism 2.7%. The observed incidence of hyperparathyroidism over 19 years was 6.3%. It was significantly higher than expected in females. In the withdrawal group serum calcium was significantly increased compared to controls, and did not change during 8.5 weeks without lithium. Isostenuria was significantly more common among patients with than without hyperparathyroidism. CONCLUSIONS: The point prevalence, and the 19-year incidence of hyperparathyroidism, were increased. The point prevalence of hypercalcaemia was also increased, and not reversible during 8.5 weeks off lithium. The findings support the hypothesis of a causal relationship between lithium treatment and hyperparathyroidism. Hypercalcaemia and hyperparathyroidism are sometimes aetiologically related to reduced renal function in long-term lithium patients.

Renal function on and off lithium in patients treated with lithium for 15 years or more. A controlled, prospective lithium-withdrawal study.

BACKGROUND: Controversy remains over the magnitude and reversibility of reduced renal function in long-term lithium patients. METHODS: Thirteen patients with 18 years (range 15-24) on lithium discontinued the treatment, and were re-examined twice after 5 and 9 weeks (4-16) off lithium. They were compared to a non-lithium psychiatric control group, matched for age and sex. RESULTS: Glomerular filtration rate (GFR) tended to improve from 69 (39-96) to 74 (39-94) ml/min/1.73 m2 BSA, P = 0.057, which was not significantly different from 78 (61-106 ml/min per 1.73 m2 BSA in the controls. Reduced GFR was found in only two of the lithium patients off lithium, and in none of the controls. Maximal urinary concentrating capacity did not improve at all. It was 637 (130-875) mOsm/kg H2O in the lithium patients, which was lower than 856 (705-1.035) mOsm/kg H2O (P < 0.01) in the controls. Two of the lithium patients had isosthenuria. CONCLUSIONS: Lithium patients often have an irreversible, clinically important reduction of Umax, sometimes progressing to nephrogenic diabetes insipidus, while GFR is well preserved in most patients.

Kidney damage in long-term lithium patients: a cross-sectional study of patients with 15 years or more on lithium.

The renal risks associated with long-term lithium treatment are a growing concern. We have therefore studied renal function by means of glomerular filtration rate (GFR) and maximum urinary concentrating capacity (Umax) in 142 of 215 patients with more than 15 years of lithium treatment in nine psychiatric clinics. Data on psychiatric and somatic diseases, hospital admissions, cumulative lithium doses, and other psychotropic treatments were extracted from the medical records. The patients were investigated according to a standardized protocol. GFR was measured as 51Cr EDTA clearance and Umax using the DDAVP test. Thirteen patients had had signs of lithium intoxication. GFR was reduced in 21% of the patients and Umax in 44%. Nephrogenic diabetes insipidus was present in 12%. Umax but not GFR was inversely correlated to the cumulative lithium dose. Kidney function was more reduced in patients on lithium combined with psychotropic treatment and/or concomitant treatment for somatic disorders. Thirst was a complaint of 53% of the patients, predominantly those with additional psychotropics. We conclude that kidney damage is common in patients on long-term lithium treatment and that both glomerular and tubular function are affected.

Kidney function in a selected lithium population. A prospective, controlled, lithium-withdrawal study.

Forty-six lithium (Li) patients who had been on Li for about 1-11 years were studied while on Li and after about 3 months (7 weeks-26 months) off Li. Kidney function was compared between patients on Li and the same patients off Li, and, in 32 matched pairs, between patients on and off Li and psychiatric controls. Urine osmolality (U-osmol) was significantly lower, urine volume higher in patients on Li than in controls. Measures of both glomerular and tubular function improved when Li-patients discontinued medication. U-osmol remained somewhat lower than in controls and was negatively correlated with time-on-Li. Although serum creatinine was somewhat higher in Li-patients off Li than in controls, clearance values were not different between the two groups. Long-term lithium treatment causes a permanent reduction of tubular function. Time-on-Li is a risk factor. In this population the reduction was clinically insignificant. In addition, Li treatment causes a reversible reduction of both tubular and glomerular function. The results can probably be generalized to other outpatient Li populations with the same time-on-Li and with U-osmol below 800 mOsm/kg during ongoing treatment.

Kidney function in an unselected lithium population. A cross-sectional study.

We studied kidney function in 124 short-term and long-term lithium outpatients from a population of 127 patients. Glomerular and distal tubular function were measured and correlated with a number of demographic and treatment variables. There was a significant negative correlation between age and glomerular filtration rate. There were no other significant correlations. Tubular function was below normal in 51% of the patients. Glomerular function was below normal in 3% of the patients. We conclude that lithium treatment in non-toxic dose affects kidney function and that tubular function is more affected than glomerular function. Tubular function probably is better than our figures indicate, glomerular function not as good. Types of lithium preparation do not affect kidney function differently nor does combined treatment with neuroleptics.

Kidney function in lithium-treated patients. A literature survey.

UNLABELLED: Twenty-three studies of the effect of lithium treatment on tubular and glomerular function are reviewed. They include about 1,450 patients from a total population of more than 2,000. One hundred and thirty-two patients were kidney biopsied. In addition, two specific questions are reviewed: 1) Does combined treatment lithium/neuroleptics affect the kidneys adversely? 2) Do different lithium preparations or treatment schedules affect the kidneys differently? CONCLUSIONS: In a small proportion of patients long-term lithium treatment causes morphological changes of a tubulointerstitial type and partly irreversible reduction of tubular function. Glomerular function is reduced secondary to tubular atrophy. Combined treatment with neuroleptics does not increase the risk of kidney damage. Types of lithium preparation do not affect kidneys differently. Multiple-dose schedules may be associated with a higher urinary output than one-dose schedule. Reduced renal function may in the future become a problem in an increasing number of patients.