Lifetime risk of severe kidney disease in lithium-treated patients: a retrospective study.

BACKGROUND: Lithium is an essential psychopharmaceutical, yet side effects and concerns about severe renal function impairment limit its usage. AIMS: Our objectives were to quantify the occurrence of chronic kidney disease stage 4 or higher (CKD4 +) within a lithium-treated population, using age- and time-specific cumulative incidence and age-specific lifetime risk as measures of disease occurrence. Additionally, we aimed to investigate the association between the duration of lithium treatment and the risk of CKD4 + . METHODS: We identified patients from the Sahlgrenska University Hospital's laboratory database. We conducted a retrospective cohort study employing cumulative incidence functions that account for competing deaths to estimate cumulative and lifetime risk of CKD4 + . A subdistribution hazards model was employed to explore baseline covariates. For measuring the association between the duration of lithium treatment and CKD4 + occurrence, we used a matched 1:4 case-control study design and logistic regression. RESULTS: Considering a 90-year lifetime horizon, the lifetime risk of CKD4 + for patients initiating lithium treatment between ages 55 and 74 ranged from 13.9% to 18.6%. In contrast, the oldest patient group, those starting lithium at 75 years or older, had a lower lifetime risk of 5.4%. The 10-year cumulative risk for patients starting lithium between ages 18 and 54 was minimal, ranging from 0% to 0.7%. Pre-treatment creatinine level was a predictive factor, with a hazard ratio of 4.6 (95% CI 2.75-7.68) for values within the upper third of the reference range compared to the lower third. Moreover, twenty or more years of lithium exposure showed a strong association with an increased risk of CKD4 + compared to 1-5 years of lithium use, with an odds ratio of 6.14 (95% CI 2.65-14.26). CONCLUSIONS: The risk of CKD4 + among lithium-treated patients exhibited significant age-related differences. Patients under 55 years old had negligible 10-year risk, while the lifetime risk for those aged 75 and older was limited. Duration of lithium treatment, especially exceeding 20 years, emerged as a significant risk factor. For individual risk assessment and prediction, consideration of age, pre-treatment creatinine levels, and the chosen time horizon for prediction is essential.

The low risk for early renal damage during lithium treatment has not changed over time.

BACKGROUND: Modern lithium management guidelines were introduced to improve the renal prognosis of lithium patients. AIMS: To examine whether prospects for severe renal impairment (defined as chronic kidney disease at least stage 4 (CKD4)), in long-term lithium patients, have changed over time after the introduction of lithium monitoring guidelines. METHODS: The time to and hazard for CKD4 were compared between three patient cohorts who started long-term lithium in three consecutive decades: 1980s, 1990s and 2000s. The follow-up time was 10 years after completion of 1-year treatment. The data were collected from Sahlgrenska University Hospital's laboratory database. RESULTS: In all, 2169 patients were included: 623 in Cohort 1 (started lithium during 1980s), 874 in Cohort 2 (1990s) and 672 in Cohort 3 (2000s). Compliance with lithium monitoring guidelines improved, and mean serum lithium decreased, through the cohorts. In all, 22 patients developed CKD4 during follow-up. The time to CKD4 was the same in all three cohorts (overall: 10.96 years, 95% confidence interval: 10.94-11 years). Age and serum creatinine concentration at start were significant risk factors, while sex had no prognostic value. After adjusting for the significant covariates, there was no statistically significant difference in the hazard for CKD4 between the three cohorts. CONCLUSION: The risk for severe renal damage during the first decade of long-term lithium is low, but has not changed over time. Our data suggest that improved compliance with lithium guidelines is not reflected in less risk for severe renal damage.

Starting lithium in patients with compromised renal function - is it wise?

BACKGROUND: Little is known of the risks involved for patients who, at the start of lithium treatment, already have compromised renal function. AIMS: To assess the risk of developing severe renal impairment (chronic kidney disease (CKD) 4-5) among those patients and to explore predictors for the progression. METHODS: A retrospective longitudinal cohort study using data from Sahlgrenska University Hospital's laboratory database 1981-2017. We compared the risk of developing CKD 4-5 in two patient cohorts: an exposed cohort of 83 patients who had high serum creatinine prior to start of lithium and a reference cohort of 83 patients with normal serum creatinine, matched by gender, duration of lithium treatment and age at the start of lithium treatment. The patients' medical charts were reviewed and the Swedish Renal Registry was used to identify patients with renal replacement therapy. RESULTS: There were no significant differences between the exposed and reference cohorts with respect to our matching criteria. Almost half the patients in the exposed cohort versus only 10% of the reference patients progressed to CKD 4-5 (HR 6.7, 95%CI 3.1-14.3, p < 0.001) during a mean observation time of more than 10 years. The progressors were older at the start of lithium treatment and were characterised by a higher burden of comorbid somatic diseases, in particular cardiovascular diseases. CONCLUSIONS: Compromised renal function prior to initiating lithium treatment increases the risk of developing severe renal impairment. Monitoring of renal function should include somatic comorbidity among older patients.

Cardiovascular comorbidity increases the risk for renal failure during prophylactic lithium treatment.

BACKGROUND: The development of lithium-associated kidney damage is still a matter of controversy. We have addressed this question by investigating the role of somatic comorbidity for developing kidney failure in lithium treated patients. METHODS: The study group comprised of 1741 adult patients with normal creatinine levels at the start of lithium treatment. Patients who developed severe renal failure (CKD stages 4-5, n = 109), were matched by sex, time on lithium and age at start of lithium, with 109 controls (CKD stages 1-2) that did not develop severe renal failure. RESULTS: Patients in CKD 4-5 did not differ significantly from controls (CKD 1-2) in sex (females/males were 76/33 in both groups), time on lithium (mean 9.8 years, SD 6.4; vs. 9.6, SD 6.2) or age at start of lithium (mean 61.6 years, SD 13.4; vs. 60.5 years, SD 12.3), respectively. However, comparisons between groups showed a significantly higher prevalence of somatic comorbidity (p < 0.001), especially cardiovascular diseases (p < 0.003), among patients in CKD 4-5. LIMITATIONS: Patients in our study group were relatively old and the findings are therefore not generalizable to patients starting lithium at an early age. The retrospective design, relying on available charts, did not allow to grade severity of comorbid conditions other than need for hospitalisation or chronic drug treatment. CONCLUSIONS: Our findings emphasize the role of somatic comorbidity for renal damage in lithium treated patients and especially the role of cardiovascular comorbidity. Monitoring of somatic comorbidity should be taken into account in treatment recommendations and safety routines in long-term prophylactic lithium treatment.

Compliance with the safety guidelines for long-term lithium treatment in Sweden.

BACKGROUND: Lithium has been used for more than 50 years and guidelines for treatment monitoring have been documented in Sweden since the beginning of the 1980s. AIMS: The aim of this study was to describe compliance over time with the Swedish guidelines for long-term lithium treatment. METHODS: The study material was obtained from Sahlgrenska University Hospital's laboratory database. We analysed data (serum lithium and serum creatinine) of adult patients treated with lithium between 1981 and 2010, and determined compliance with guidelines and serum lithium levels over time. RESULTS: Our study material included 2841 patients and 25,300 treatment-years. The compliance with guidelines' recommendations regarding lithium and creatinine monitoring increased from 36% in 1981 to 68% in 2010. Women were on average 2% more compliant than men ( p < 0.01). Most lithium samples (87-94%) were within recommended intervals throughout the study period. The average lithium level decreased from 0.70 mmol/L in 1981 to 0.58 mmol/L in 2001, and remained stable thereafter. CONCLUSIONS: Compliance with lithium monitoring guidelines improved slowly but steadily over time. It took three decades to reach a compliance rate of just below 70%. Gender differences were small, but with a significantly better compliance rate for women. Serum lithium was kept within the recommended target interval to a large extent, throughout the study period.

A practical approach to low protein diets in Sweden- 45 years of clinical use.

This review provides an overview of the development, implementation and practise of low protein diets (LPD) in Sweden. While the current practice is discussed in general terms emphasizing the interplay between nephrologists and dieticians, the "self-selected" LPD model is explained as a practical approach to facilitated patient's adherence to the nutritional therapy. This model is currently implemented in most clinics of the country and gives considerable flexibility regarding variation in meal planning, food selection, amounts consumed, cooking methods as well as adaptations to day-to-day changes. Current LPD use in Sweden is presented through analysis of the Swedish Renal Registry. Finally two patient cases are illustrated, with examples on their diets, attempts to reduce the protein content to the desired thresholds and their clinical course.

Effects of 10 to 30 years of lithium treatment on kidney function.

Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10-29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function.

End-stage renal disease associated with prophylactic lithium treatment.

The primary aim of this study was to estimate the prevalence of lithium associated end-stage renal disease (ESRD) and to compare the relative risk of ESRD in lithium users versus non-lithium users. Second, the role of lithium in the pathogenesis of ESRD was evaluated. We used the Swedish Renal Registry to search for lithium-treated patients with ESRD among 2644 patients with chronic renal replacement therapy (RRT)-either dialysis or transplantation, within two defined geographical areas in Sweden with 2.8 million inhabitants. The prevalence date was December 31, 2010. We found 30 ESRD patients with a history of lithium treatment. ESRD with RRT was significantly more prevalent among lithium users than among non-lithium users (p<0.001). The prevalence of ESRD with RRT in the lithium user population was 15.0‰ (95% CI 9.7-20.3), and close to two percent of the RRT population were lithium users. The relative risk of ESRD with RRT in the lithium user population compared with the general population was 7.8 (95% CI 5.4-11.1). Out of those 30 patients, lithium use was classified, based on chart reviews, as being the sole (n=14) or main (n=10) cause of ESRD in 24 cases. Their mean age at the start of RRT was 66 years (46-82), their mean time on lithium 27 years (12-39), and 22 of them had been on lithium for 15 years or more. We conclude that lithium-associated ESRD is an uncommon but not rare complication of lithium treatment.

The impact of modern treatment principles may have eliminated lithium-induced renal failure.

We have previously shown that lithium can cause end-stage renal disease (ESRD): however, this serious side-effect of lithium in prophylactic treatment of mood disorders may reflect the treatment regime of the 1960s and 1970s. Today's modern treatment routines, intended to reduce or eliminate lithium-induced ESRD (Li-ESRD), were introduced in Sweden in the early 1980s. The aim of the present study was to test the hypothesis that these routines have eliminated the risk of Li-ESRD. We used the Swedish Renal Registry to identify patients on renal replacement therapy (RRT), treated with dialysis or renal transplantation, with suspected Li-ESRD in two regions of Sweden with altogether about three million inhabitants. We reviewed their medical records to verify the exposure to lithium treatment, the diagnosis of Li-ESRD and the date of starting the lithium treatment. We found 32 RRT patients in whom lithium treatment was the sole or main contributing cause of ESRD. The starting year of their lithium treatment was between 1965-1980 in all patients. No patient started lithium treatment later than 1980. Modern lithium treatment may have eliminated the risk of Li-ESRD. Our findings support the continued use of lithium as a safe drug for the long-term treatment of mood disorders.

Oxidative stress and inflammation in renal patients and healthy subjects.

The first goal of this study was to measure the oxidative stress (OS) and relate it to lipoprotein variables in 35 renal patients before dialysis (CKD), 37 on hemodialysis (HD) and 63 healthy subjects. The method for OS was based on the ratio of cholesteryl esters (CE) containing C18/C16 fatty acids (R2) measured by gas chromatography (GC) which is a simple, direct, rapid and reliable procedure. The second goal was to investigate and identify a triacylglycerol peak on GC, referred to as TG48 (48 represents the sum of the three fatty acids carbon chain lengths) which was markedly increased in renal patients compared to healthy controls. We measured TG48 in patients and controls. Mass spectrometry (MS) and MS twice in tandem were used to analyze the fatty acid composition of TG48. MS showed that TG48 was abundant in saturated fatty acids (SFAs) that were known for their pro-inflammatory property. TG48 was significantly and inversely correlated with OS. Renal patients were characterized by higher OS and inflammation than healthy subjects. Inflammation correlated strongly with TG, VLDL-cholesterol, apolipoprotein (apo) C-III and apoC-III bound to apoB-containing lipoproteins, but not with either total cholesterol or LDL-cholesterol.In conclusion, we have discovered a new inflammatory factor, TG48. It is characterized with TG rich in saturated fatty acids. Renal patients have increased TG48 than healthy controls.

Lipoprotein abnormalities in patients with atherosclerotic renovascular disease.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) have a high risk of cardiovascular death. The primary aim was to characterize abnormalities in apolipoprotein (Apo)-defined lipoprotein (Lp) subclasses in patients with ARVD. METHODS: Baseline measurements were performed on 42 patients with ARVD 4 weeks after renal angioplasty (PTRA). All patients were on statin treatment. Twenty age-matched healthy subjects without medications served as controls. Subsequently, patients were randomized to treatment with either candesartan (n = 21), or antihypertensive treatment without inhibitors of the renin-angiotensin-aldosterone system (n = 21) and followed for 11 months. RESULTS: At baseline, ApoC-III (12.7 ± 4.6 vs. 8.8 ± 2.6 (SD) mg/dl, p < 0.05), LpB:C:E (13.3 ± 5.4 vs. 8.4 ± 4.3 mg/dl, p < 0.05), and the sum of ApoC-III-containing lipoproteins, i.e. LpB:C + LpB:C:E + LpA-II:B:C:D:E (46 ± 15 vs. 37 ± 8 mg/dl, p < 0.05), were significantly elevated in ARVD patients versus healthy controls. Multiple regression analyses showed that only plasma renin activity was independently associated with ApoC-III levels at baseline (p < 0.05, r = 0.74). Treatment with candesartan did not correct abnormalities. CONCLUSIONS: Patients with ARVD treated with statins have an atherogenic lipoprotein profile characterized by elevated levels of ApoC-III-containing, triglyceride-rich lipoproteins that could accelerate atherosclerotic disease.

The effect of decreasing renal function on lipoprotein profiles.

BACKGROUND: Progressive chronic kidney disease (CKD) is accompanied by dyslipidemia that is characterized by increased concentrations of intact and partially metabolized ApoB and ApoC-III-containing triglyceride-rich lipoproteins in very low-density lipoprotein, intermediate density lipoprotein (IDL) and low-density lipoprotein. The purpose of the present study was to characterize the distribution of individual discrete lipoprotein subclasses in relation to the glomerular filtration rate (GFR) in nondiabetic CKD subjects. METHODS: Fifty-one subjects (33 patients with CKD and 18 asymptomatic subjects) with GFR ranging from 12 to 120 mL/min were studied. Individual ApoA- and ApoB-containing lipoprotein subclasses (Lp) were determined in plasma by sequential immunoaffinity chromatography and subsequent determination of apolipoprotein composition by electroimmunoassays. GFR was measured as plasma clearance of iohexol or (51)Cr-ethylenediaminetetraacetic acid. RESULTS: There were no changes in concentrations of ApoA-containing lipoproteins with decreasing GFR. The levels of ApoB-containing lipoproteins increased significantly with decreasing GFR. There was a moderate increase of cholesterol-rich LpB and a 3-fold increase of ApoB- and ApoC-III-containing lipoproteins in subjects in the two lowest quintiles of GFR. This was accompanied by a significant increase of plasma ApoC-III. CONCLUSIONS: Reduced renal function is associated with a complex alteration of the lipoprotein profile that is predominantly characterized by increased concentrations of triglyceride-rich lipoprotein subclasses containing both ApoB and ApoC-III.

Renal failure occurs in chronic lithium treatment but is uncommon.

We sought to establish the prevalence of lithium-induced end-stage renal disease in two regions of Sweden with 2.7 million inhabitants corresponding to about 30% of the Swedish population. Eighteen patients with lithium-induced end-stage renal disease were identified among the 3369 patients in the general lithium-treated population, representing a sixfold increase in prevalence compared with the general population for renal replacement therapy. All lithium-treated patients were older than 46 years at end-stage renal disease with a mean lithium treatment time of 23 years with ten patients having discontinued lithium treatment an average of 10 years before the start of renal replacement therapy. The prevalence of chronic kidney disease (defined as plasma creatinine over 150 micromol/l) in the general lithium-treated population was about 1.2% (excluding patients on renal replacement therapy). Compared with lithium-treated patients without renal failure, those with chronic kidney disease were older and most were men but, as groups, their mean serum lithium levels and psychiatric diagnoses did not differ. We found that end-stage renal disease is an uncommon but not rare consequence of long-term lithium treatment and is more prevalent than previously thought. Time on lithium was the only identified risk factor in this study, suggesting that regular monitoring of renal function in these patients is mandatory.

Dyslipidemia of kidney disease.

PURPOSE OF REVIEW: Chronic kidney disease is associated with specific alterations of lipoprotein metabolism that may be linked to accelerated atherosclerosis and cardiovascular disease. This review summarizes current knowledge of the pathophysiology of renal dyslipidemia and the therapeutic options. RECENT FINDINGS: The renal dyslipidemia is characterized by accumulation of intact and partially metabolized triglyceride-rich apoB-containing and apoC-containing lipoproteins. Increased concentrations of atherogenic apoC-III rich lipoproteins, the hallmark of renal dyslipidemia, may result from disturbances of insulin metabolism and action in chronic kidney disease. Novel findings strongly suggest that apoC-III triggers a cascade of pro-inflammatory events, which ultimately can result in endothelial dysfunction and vascular damage. Disappointingly, recently reported intervention trials with statins have failed to show any benefit on cardiovascular disease in patients with advanced renal failure. SUMMARY: During recent years, our understanding of the character and biological significance of the dyslipidemia of chronic kidney disease, and its link to cardiovascular disease, has increased. However, our knowledge about its proper management is still very limited.

Positive effects of protein restriction in patients with chronic kidney disease.

OBJECTIVES: The potential benefit or harm of low-protein diets (LPDs) for patients with chronic kidney disease has been debated. This study sought to investigate the effects of treatment with LPDs on nutritional markers, morbidity, and survival during subsequent dialysis. A second objective was to evaluate the effect of LPDs on renal function and the start of dialysis. DESIGN: This was a retrospective study of medical records. SETTING: The setting was an outpatient nephrology and dialysis clinic. PATIENTS: One-hundred twenty-two renal patients were recruited from the central dialysis registry of one clinic. The patients had been followed by a nephrologist for > or =6 months before dialysis. Sixty-one patients were treated with LPDs, and an equal number of control patients not treated with LPDs were matched for sex, age, dialysis modality, diabetes, and start of dialysis. MAIN OUTCOME MEASURES: Main outcome measures included weight and weight change, serum albumin, glomerular filtration rate, morbidity, and mortality. RESULTS: There was less mean weight loss in the LPD group the year before dialysis (0.14 kg/month, compared with the control group at 0.36 kg/month, P < .05). The level of serum albumin was higher in the LPD group at the start of dialysis (P < .01). The mean rate of progression during the 6 months before dialysis was lower in the LPD group (4.1 mL/min/year) than in the control group (13.4 mL/min/year) (P < .001). The LPD group had fewer days of hospitalization at the start of dialysis than the control group (8.2 vs 15.4 days, respectively, P < .01). There was no difference in mortality between groups 1, 2, or 5 years after starting dialysis. CONCLUSIONS: Low-protein diets can reduce patient morbidity, preserve renal function, relieve uremic symptoms and improve nutritional status. The results suggest that LPDs can postpone the start of dialysis for 6 months, and entail substantial cost-savings. Low-protein diets should be used more generally in the renal community.

Protein restriction and body composition in renal disease.

OBJECTIVE: To study the effect of low-protein diet (LPD) on body composition (BC). STUDY DESIGN: A systematic review of the literature investigating BC during LPD treatment using total body potassium, dual energy X-ray absorptiometry, bioelectrical impedance analysis, and anthropometry. PATIENTS: Studies reporting data of patients treated with LPD 0.3-0.75 g/kg/day and a renal function of glomerular filtration rate (GFR) < or =20 mL/min, creatinine clearance < or =25 mL/min, on serum creatinine > or =500 micromol/L were included in the review. Fourteen studies with a total number of 666 subjects were found eligible. RESULTS: All studies except two concluded that treatment with LPD does not affect BC negatively. However, LPD should not be introduced in patients with a complicating disease, e.g., acidosis, septicaemia, and surgical treatment; neither should it be continued in patients who are unable to adhere to a diet prescription. Furthermore, LPD should be introduced with great caution in patients with an expected time to dialysis of < or =4 months due to an initial reduction of body weight and/or fat-free mass. Monitoring of treatment with LPD must be emphasized, including BC measurements and evaluation of protein and energy intake. These conclusions do not apply to patients with diabetes mellitus, because this diagnosis was excluded in a majority of reviewed studies. CONCLUSION: There is no strong evidence that LPD impairs BC in patients with GFR < or =20 mL/min.

Prevention of clot formation during haemodialysis using the direct thrombin inhibitor melagatran in patients with chronic uraemia.

BACKGROUND: This study assessed the feasibility of replacing intravenous (i.v.) dalteparin with the direct thrombin inhibitor (DTI) melagatran administered via dialysis fluid in patients undergoing haemodialysis, and also examined the pharmacokinetics of melagatran with and without dialysis. METHODS: During two 4 h haemodialysis sessions, 10 adult patients were administered i.v. dalteparin. During two subsequent sessions, melagatran was administered as an i.v. bolus before dialysis, and in the dialysis fluid. The pharmacokinetics of melagatran administered as a bolus before dialysis, and of i.v. melagatran during a dialysis-free day, were studied. Dialysis performances were evaluated from clinical criteria including clot formation in the dialyzer and bloodlines, pre-post dialyzer pressures and iohexol clearance. Anticoagulant efficacy was evaluated from dialysis success. RESULTS: All dialysis sessions were successful, with no apparent difference in clot formation between the two treatments. Median iohexol clearance was similar with dalteparin (99-103 ml/min) and melagatran in the dialysis fluid (98-100 ml/min). There was no difference in pre- and post-dialyzer bloodline pressures between the two treatments. During dialysis sessions with melagatran in dialysis fluid, melagatran concentrations in plasma rapidly equilibrated to approximately 70% of those in dialysis fluid. While the clearance of melagatran was low in patients with renal failure (mean+/-SD, 0.93+/-0.36 l/h), haemodialysis provided efficient clearance of melagatran (7.20+/-0.76 l/h). Melagatran clearance by dialysis (104+/-10 ml/min) was comparable to iohexol clearance. CONCLUSIONS: The DTI melagatran administered via dialysis fluid may provide sufficient anticoagulation for haemodialysis. Melagatran is rapidly cleared from plasma by haemodialysis, suggesting that this method may be used to decrease drug levels in patients with renal impairment.

Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.

BACKGROUND: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. OBJECTIVE: To investigate the effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran. STUDY DESIGN: This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1-3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5-24) and 86 (70-105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration. RESULTS: For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29-4.93) after subcutaneous melagatran and 5.33 (3.76-7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CL(R)) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CL(R) of melagatran was 12.5 and 81.3 mL/min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups. CONCLUSIONS: After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CL(R) of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.