Absolute and Relative Risks of Kidney Outcomes Associated With Lithium vs Valproate Use in Sweden.

Importance: Among patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy. Objective: To quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes. Design, Setting, and Participants: This cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a recurrent health care use cohort of all adult residents in Stockholm, Sweden. Exposures: New use of lithium vs new use of valproate and high (>1.0 mmol/L) vs low serum lithium levels. Main Outcomes and Measures: Progression of CKD (composite of >30% decrease relative to baseline estimated glomerular filtration rate [eGFR] and kidney failure), AKI (by diagnosis or transient creatinine elevations), new albuminuria, and annual eGFR decrease. Outcomes by attained lithium levels were also compared in lithium users. Results: The study included 10 946 people (median [IQR] age, 45 [32-59] years; 6227 female [56.9%]), of whom 5308 initiated lithium therapy and 5638 valproate therapy. During follow-up, 421 CKD progression events and 770 AKI events were identified. Compared with patients who received valproate, those who received lithium did not have increased risk of CKD (hazard ratio [HR], 1.11 [95% CI, 0.86-1.45]) or AKI (HR, 0.88 [95% CI, 0.70-1.10]). Absolute 10-year CKD risks were low and similar: 8.4% in the lithium group and 8.2% in the valproate group. No difference in the risk of developing albuminuria or the annual rate of eGFR decrease was found between groups. Among more than 35 000 routine lithium tests, only 3% of results were in the toxic range (>1.0 mmol/L). Lithium values greater than 1.0 mmol/L, compared with lithium values of 1.0 mmol/L or less, were associated with increased risk of CKD progression (HR, 2.86; 95% CI, 0.97-8.45) and AKI (HR, 3.51; 95% CI, 1.41-8.76). Conclusions and Relevance: In this cohort study, compared with new use of valproate, new use of lithium was meaningfully associated with adverse kidney outcomes, with low absolute risks that did not differ between therapies. However, elevated serum lithium levels were associated with future kidney risks, particularly AKI, emphasizing the need for close monitoring and lithium dose adjustment.

Quality of laboratory biomarker monitoring during treatment with lithium in patients with bipolar disorder.

BACKGROUND: Clinical guidelines recommend monitoring of creatinine and lithium throughout treatment with lithium. We here assessed the extent to which this occurs in healthcare in Sweden. METHODS: This is an observational study of all adults with bipolar disorder starting lithium therapy in Stockholm, Sweden, during 2007-2018. The main outcome was monitoring of blood lithium and creatinine at therapy initiation and/or once annually. The secondary outcome was monitoring of calcium and thyroid-stimulating hormone (TSH). Patients were followed up until therapy cessation, death, out-migration, or to the end of 2018. RESULTS: We identified 4428 adults with bipolar disorder who started lithium therapy and were followed up for up to 11 years. Their median age was 39 years, and 63% were women. The median duration on lithium therapy was 4.3 (IQR: 1.9-7.45) years, and the majority who discontinued therapy started another mood stabilizer soon after. Overall, 21% started lithium therapy without assessing the serum/plasma concentration of creatinine. The proportion of people who did not have both lithium and creatinine measured increased from 21% in the first year to 33% in the eleventh year. The proportion with annual testing for TSH or calcium was slightly lower. As few as 16% of patients had both lithium and creatinine tested once annually during their complete time on lithium. CONCLUSIONS: In a Swedish community sample, lithium and creatinine monitoring was inconsistent with guideline recommendations that call for measurement of annual biomarker levels.

Secular trends in hip fracture incidence and subsequent mortality in dialysis patients and the general population in Sweden.

BACKGROUND: Declining trends of hip fracture incidence in dialysis patients were reported from USA and Japan while studies from Europe are lacking. We investigated trends in hip fracture incidence and subsequent mortality in Swedish dialysis patients, comparing with the Swedish general population. METHODS: We used the population-based Swedish national database of fractures and the Swedish National Renal Registry to retrieve data on hip fractures incidence and subsequent mortality for years 2007-2016. Trends for age-standardized hip fracture incidence rate (ASRhip fracture) and age-standardized 30-day (ASMR30day) and 180-day (ASMR180day) post-hip fracture mortality rate in Swedish general population were evaluated by joinpoint regression analysis. Standardized incidence ratios of hip fracture (SIR) and standardized mortality ratios (SMR) were calculated for Swedish dialysis patients. RESULTS: In the general population, ASRhip fracture declined significantly: in women from 2007 and in men from 2009. In dialysis patients, SIR was 3-5 times higher compared to the general population and declined over time in women but not in men. In general population, mortality (ASMR30day and ASMR180day) declined significantly in women and men. In dialysis patients, post-fracture mortality (SMR, mainly for 180-day mortality) remained two-fold higher than in general population with no consistent trend towards improvement. CONCLUSIONS: Hip fracture incidence and subsequent mortality fell among women and men in the Swedish general population. In dialysis patients, hip fracture incidence declined in women but not in men while post-fracture mortality did not improve, and the incidence and subsequent mortality remained 3 to 5-fold and 2-fold higher than in the general population.

[Diethylene glycol poisoning - the first known Swedish case]. / Dietylenglykolförgiftning ­ första kända svenska fallet presenteras.

A woman in her sixties presented at the Emergency department with nausea, flank pain and profuse vomiting. She had an anion-gap metabolic acidosis, elevated liver enzymes and a pronounced renal failure with creatinine 1997 µmol/L (22,6 mg/dl). She was admitted and treated with haemodialysis. On hospital day 5 a bilateral facial palsy, blindness and a moderate generalized weakness rapidly developed. The patient now revealed that she had consumed about 2 dl of brake fluid with a high content of diethylene glycol about a week before hospital admission. Diethylene glycol poisoning typically causes irreversible kidney failure and demyelinating nerve damage in severe cases. The early and debilitating metabolic acidosis seen in ethylene glycol poisoning seems to be absent in diethylene glycol poisoning and patients often present late. This is the first known Swedish case of symptomatic diethylene glycol poisoning. Internationally, during the last century, several mass poisonings have been caused by diethylene glycol contaminated pharmaceutical products.

Fractures after kidney transplantation: Incidence, predictors, and association with mortality.

BACKGROUND: Major fractures (MF) are associated with increased mortality in the general population and represent an even higher risk in patients with chronic kidney disease. We investigated incidence, predictors and clinical outcomes associated with first MF (MFfirst) following kidney transplantation (KT). METHODS: We used the Swedish National Renal Registry of 3992 first KT recipients (2005-2016) (median age 53 years, 65% men) and identified all MFfirst in hip, spine, humerus and forearm following KT. We estimated incidence rates and predictors of MFfirst using flexible parametric hazard models and Fine-Gray analysis accounting for competing risk of death, and risk of all-cause mortality following MFfirst using Cox proportional hazards models with fracture as time-varying exposure. RESULTS: During median follow-up of 4.8 years (IQR 2.2-7.9 years), there were 279 fractures of which 139 were forearm fractures. The crude incidence rate of MFfirst (n = 279) was 13.5/1000 patient-years and that of hip fractures (n = 69) 3.4/1000 patient-years. The multivariate-adjusted fracture incidence rates were highest during the first 6 months following KT, and 86% higher in women than in men. High age, female sex, previous history of MF, diabetes nephropathy, pretransplant dialysis therapy and acute rejection were associated with increased risk for MFfirst, whereas pre-emptive KT was associated with lower risk of MFfirst. Spline curves showed markedly higher impact of higher age on risk of MFfirst in women than in men. MFfirst (n = 279) independently predicted increased all-cause mortality risk (hazard ratio, HR, 1.78(95%CI 1.35-2.36)). Among MFfirst, with humerus fracture as reference, hip fracture (HR, 4.68(95%CI 1.56-14.06)) and spine fracture (HR, 4.02(95%CI 1.19-13.54)), but not forearm fracture (HR, 1.17 (95%CI 0.38-3.53)), were associated with increased all-cause mortality risk. CONCLUSIONS: The initial 6 months following kidney transplantation is a high-risk period for MF. Among MF, hip fracture and spine fracture associate with substantially increased all-cause mortality risk.

Incidence of Fractures Before and After Dialysis Initiation.

Fractures are common in dialysis patients, but little is known about the trajectory of incidence rates of different types of fractures before and after dialysis initiation. To address this, we investigated the incidence of major fractures before and after dialysis initiation. We performed a retrospective statistical analysis using the Swedish Renal Registry of 9041 incident dialysis patients (median age 67 years, 67% men) starting dialysis 2005 through 2015 to identify major fractures (hip, spine, humerus, and forearm) occurring during the dialysis transition period from 1 year before until 1 year after dialysis initiation. Using flexible parametric hazard models and the Fine-Gray model, we estimated adjusted fracture incidence rates and predictors of major fractures. We identified 361 cases with primary diagnosis of major fracture, of which 196 (54%) were hip fractures. The crude incidence rate of major fractures before dialysis initiation was 17 per 1000 patient-years (n = 157) and after dialysis initiation it was 24 per 1000 patient-years (n = 204). The adjusted incidence rate of major fractures began to increase 6 months before dialysis initiation, and then stabilized at a higher rate after 1 year. The adjusted incidence rate of hip fractures started to increase sharply 3 months before dialysis initiation, peaked at initiation, and declined thereafter. In contrast, the adjusted incidence rate of non-hip fractures was stable during the transition period and gradually increased over time. Higher age, female sex, and history of previous major fractures were associated with increased fracture incidence both before and after dialysis initiation. We conclude that the incidence of major fractures, especially hip fractures, start to rise 6 months before initiation of dialysis therapy, indicating that heightened surveillance with implementation of preventive measures to avoid fractures is warranted during the transition period to dialysis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Association between reduced kidney function and incident hypoglycaemia in people with diabetes: The Stockholm Creatinine Measurements (SCREAM) project.

AIM: To evaluate possible associations between estimated glomerular filtration rate (eGFR) and hypoglycaemia in adults with diabetes. METHODS: We conducted an observational study in adults with diabetes from the Stockholm Creatinine Measurement (SCREAM) project, a Swedish healthcare utilization cohort during 2007 to 2011. We evaluated diagnoses and outpatient glucose tests for incidence rate ratios (IRRs) of hypoglycaemia (overall and by severity) in outpatient care by eGFR strata using zero-inflated negative binomial regression. We identified clinical predictors through ordinal logistic regression and assessed 7-day and 30-day mortality from hypoglycaemia in relation to eGFR with Cox proportional hazard models. RESULTS: We identified 29 434 people with diabetes (13% with type 1 diabetes). Their mean age was 66 years, 43% were women and the median eGFR was 80 mL/min/1.73 m2 . During 2 years of follow-up, 1812 patients (6.2%) had hypoglycaemia registered at least once. The risk of hypoglycaemia increased linearly with lower eGFR, with an IRR of 1.2 (95% confidence interval [CI] 1.0-1.4) for eGFR 60-89 mL/min/1.73 m2 and 5.8 (95% CI 3.8-9.0) for eGFR <15 mL/min/1.73 m2 compared to eGFR 90 to 104 mL/min/1.73 m2 . This trend was observed for both mild and severe hypoglycaemia. Both 7-day and 30-day post-hypoglycaemia mortality increased with lower eGFR, peaking in those with eGFR <15 mL/min/1.73 m2 (hazard ratio 21.2, 95% CI 5.1-87.9) as compared to those with eGFR 90 to 104 mL/min/1.73 m2 . Lower eGFR categories, type 1 diabetes, previous hypoglycaemia, liver disease, presence of diabetic complications and use of insulin and sulphonylureas increased the odds of hypoglycaemia. CONCLUSION: In this large, observational study, low eGFR was strongly associated with the occurrence, severity and fatality of hypoglycaemia in people with diabetes.

Major fractures after initiation of dialysis: Incidence, predictors and association with mortality.

BACKGROUND: Major fractures (MF) are common in dialysis patients. We investigated incidence, predictors and clinical outcomes associated with first MF occurring after initiation of dialysis (MFfirst). METHODS: In Swedish Renal Registry of 9714 incident (2005-2016) dialysis patients (age 68 years, 67% men), we identified all MFfirst in hip, spine, humerus and forearm. Using flexible parametric hazard models and Fine-Gray analysis, we estimated incidence, mortality rates and predictors of MFfirst, and, in time-dependent analysis, risk of all-cause and cardiovascular disease (CVD) mortality following MFfirst. RESULTS: During median follow-up of 2.2 years, the crude incidence rate of MFfirst (n = 835) was 23.7/1000 patient-years and that of hip fractures (n = 470) 13.3/1000 patient-years. The multivariate-adjusted fracture incidence rates increased gradually after dialysis initiation and were 47% higher among women. Female sex, higher age, comorbidity, and previous history of MF (MFprevious) were associated with increased risk for MFfirst, whereas peritoneal dialysis as compared to hemodialysis was associated with decreased risk. The adjusted fracture incidence rate of MFfirst during the first 90 days following dialysis initiation was higher in patients with MFprevious than in those without MFprevious. MFfirst independently predicted increased all-cause (sub-distribution hazard ratio, SHR, 1.67(95%CI 1.47-1.91)) and CVD (SHR 1.49 (95%CI 1.22-1.84)) mortality. Adjusted mortality rate following hip fractures was higher than for other types of MF. Spline curves showed that mortality following MFfirst was highest during the first 6 months of follow-up. CONCLUSIONS: MF are common and associated with increased mortality in incident dialysis patients.

Fractures and their sequelae in non-dialysis-dependent chronic kidney disease: the Stockholm CREAtinine Measurement project.

INTRODUCTION: People undergoing maintenance dialysis are at high risk for fractures, but less is known about fracture incidence and associated outcomes in earlier stages of chronic kidney disease (CKD). METHODS: We conducted an observational analysis from the Stockholm Creatinine Measurement project, a Swedish health care utilization cohort during 2006-11. We identified all adults with confirmed CKD Stages 3-5 and no documented history of fractures and extracted information on comorbid history, ongoing medication, cardiovascular events and death. We studied incidence rates of fractures (overall and by location), with the estimated glomerular filtration rate (eGFR) as time-dependent exposure. We then studied hazard ratios [HRs and 95% confidence intervals (CIs)] for the events of death and major adverse cardiac events (MACE) using Cox regression with fracture as time-varying exposure. RESULTS: We identified 68 764 individuals with confirmed CKD (mean age 79 years, 56% women). During a median follow-up of 2.7 years, 9219 fractures occurred, of which 3105 were hip fractures. A more severe CKD stage was associated with a higher risk of fractures, particularly hip fractures: compared with CKD Stage 3a, the adjusted HR was 1.10 (95% CI 1.02-1.19), 1.32 (1.17-1.49) and 2.47 (1.94-3.15) for CKD Stage 3b, 4 and 5, respectively. Spline curves suggested a linear association with fracture risk with an eGFR <30 mL/min/1.73 m2. Compared with non-fracture periods, incident fracture was associated with a 4-fold increased mortality within 90 days [HR 4.21 (95% CI 3.95-4.49)]. The risk remained elevated beyond 90 days [HR 1.47 (95% CI 1.40-1.54)] and was stronger after hip fractures. Post-fracture MACE risk was also highest in the first 90 days [HR 4.02 (95% CI 3.73-4.33)], particularly after hip fractures, and persisted beyond 90 days [HR 1.20 (95% CI 1.10-1.30)]. CONCLUSION: Our findings highlight the commonness of fractures and the increased risk for subsequent adverse outcomes in CKD patients. These results may inform clinical decisions regarding post-fracture clinical surveillance and fracture prevention strategies.

Causes of death across categories of estimated glomerular filtration rate: The Stockholm CREAtinine Measurements (SCREAM) project.

INTRODUCTION: Reduced kidney function increases the risk of death, but there is limited information on causes of death across stages of chronic kidney disease (CKD). We aimed to identify leading causes of death in community-dwelling individuals with differing kidney function. METHODS: Observational analysis from SCREAM, a healthcare utilization cohort of Stockholm, Sweden. We included all individuals who died during 2006-2012 and had one serum creatinine measured in the year prior to death. Using the CKD-EPI formula, we calculated eGFR and stratified individuals according to CKD stages. Causes of death were classified as cardiovascular (CVD), cancer, infection and other, using ICD-10 codes. We compared age- and sex-adjusted differences in the proportions of deaths from each cause. RESULTS: Out of 89,117 registered deaths, 70,547 (79%) had a recent eGFR estimation and were included in this study. Individuals had a median age of 82 (IRE 62-93) years and 52% were women. The proportions of deaths from CVD increased with lower eGFR, along with the proportion of deaths from infections. Deaths due to diabetes and genito-urinary diseases increased. Deaths due to cancer decreased, but other death causes did not vary. Within CVD causes of death, the proportion of arrhythmias and heart failure increased, but ischemic heart disease and cerebrovascular disease remained stable. CONCLUSION: In a region-representative Swedish healthcare extraction, we observe differences regarding specific causes of death across different CKD stages. Increasing patient and provider awareness of this differential pattern of risk may have benefits for patient management, prevention strategies, and health service planning.

Prevalence and recognition of chronic kidney disease in Stockholm healthcare.

BACKGROUND: Chronic kidney disease (CKD) is common, but the frequency of albuminuria testing and referral to nephrology care has been difficult to measure. We here characterize CKD prevalence and recognition in a complete healthcare utilization cohort of the Stockholm region, in Sweden. METHODS: We included all adult individuals (n = 1 128 058) with at least one outpatient measurement of IDMS-calibrated serum creatinine during 2006-11. Estimated glomerular filtration rate (eGFR) was calculated via the CKD-EPI equation and CKD was solely defined as eGFR <60 mL/min/1.73 m2. We also assessed the performance of diagnostic testing (albuminuria), nephrology consultations, and utilization of ICD-10 diagnoses. RESULTS: A total of 68 894 individuals had CKD, with a crude CKD prevalence of 6.11% [95% confidence interval (CI): 6.07-6.16%] and a prevalence standardized to the European population of 5.38% (5.33-5.42%). CKD was more prevalent among the elderly (28% prevalence >75 years old), women (6.85 versus 5.24% in men), and individuals with diabetes (17%), hypertension (17%) or cardiovascular disease (31%). The frequency of albuminuria monitoring was low, with 38% of diabetics and 27% of CKD individuals undergoing albuminuria testing over 2 years. Twenty-three per cent of the 16 383 individuals satisfying selected KDIGO criteria for nephrology referral visited a nephrologist. Twelve per cent of CKD patients carried an ICD-10 diagnostic code of CKD. CONCLUSIONS: An estimated 6% of the adult Stockholm population accessing healthcare has CKD, but the frequency of albuminuria testing, nephrology consultations and registration of CKD diagnoses was suboptimal despite universal care. Improving provider awareness and treatment of CKD could have a significant public health impact.

The Stockholm CREAtinine Measurements (SCREAM) project: protocol overview and regional representativeness.

BACKGROUND: We here describe the construction of the Stockholm CREAtinine Measurement (SCREAM) cohort and assess its coverage/representativeness of the Stockholm county in Sweden. SCREAM has the principal aims to estimate the burden and consequences of chronic kidney disease (CKD) and to identify inappropriate drug use (prescription of nephrotoxic, contraindicated or ill-dosed drugs). METHODS: SCREAM is a repository of laboratory data of individuals, residing or accessing healthcare in the region of Stockholm, who underwent creatinine assessments between 2006-11. Laboratory tests were linked to administrative databases with complete information on socioeconomic status, demographic data, healthcare utilization, diagnoses, vital status and dispensed prescription medicines. RESULTS: SCREAM identified 1 118 507 adult Stockholm citizens with available creatinine tests between 2006-11. This corresponded to 66% of the complete population in the region. Geographical coverage was uniform, ranging between 62 and 72% throughout its 26 municipalities. Population coverage was higher across older age strata (50% coverage for age range 18-44 years, >75% for 45-64 years and >90% coverage for ≥65 years). Of note, 97 and 98% of all individuals with a diagnosis of diabetes mellitus or cardiovascular disease, respectively, were captured by SCREAM. Further, 89% of all deaths registered in the period occurred in individuals with a creatinine test undertaken. CONCLUSION: SCREAM represents the largest cohort to estimate the burden and healthcare implications of CKD in Sweden. The coverage and representativeness of the region of Stockholm was high and in accordance to both the commonness of creatinine assessment, and the medical indications for creatinine testing. The inclusion of individuals who sought medical care and had a creatinine test undertaken resulted in a slight over-representation of elderly and comorbid patients.