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AIMS: Diabetic nephropathy is an uncommon cause of end-stage renal disease in Iceland in contrast to most industrialized countries. The aim of this study was to examine the incidence of diabetic nephropathy in Iceland. METHODS: All patients diagnosed with Type 1 diabetes in Iceland before 1992 were studied retrospectively. Patients diagnosed before age 30, who were insulin dependent from the onset, were defined as having Type 1 diabetes. Diabetic nephropathy was defined as persistent proteinuria measured with a dipstick test (Albustix) on three consecutive clinic visits at least 2 months apart. Patients were followed to the end of year 1998, to their last recorded outpatient visit, or until death. The cumulative incidence of diabetic nephropathy was calculated with the Kaplan-Meier method and presented according to the duration of diabetes divided into 5-year intervals. RESULTS: A total of 343 patients with Type 1 diabetes were identified. The mean follow-up period was 20.2 +/- 11.4 (mean +/- sd) years. Only 9.3% of patients were lost to follow-up. Sixty-five patients developed diabetic nephropathy. The cumulative incidence was 22.6% at 20 years and levelled off at 40.3% after approximately 35 years of diabetes duration. No significant changes in cumulative incidence were observed over time. Mean glycated haemoglobin was 8.4% in patients with proteinuria and 7.8% in a group of patients without proteinuria that was matched for age, gender and duration of diabetes (P = 0.04). CONCLUSIONS: The cumulative incidence of diabetic nephropathy in Iceland is comparable with previously reported cumulative incidence rates and has remained unchanged. Glycaemic control was significantly better in patients without proteinuria. [ABSTRACT FROM AUTHOR]

Background: The association between lithium use and chronic kidney disease, and the effect of comorbidities on this association are poorly understood. Our aim was to examine the risk of developing stage 3 or higher chronic kidney disease among people receiving lithium therapy., Methods: This was a retrospective, population-based cohort study of all adults (aged ≥18 years) in Iceland treated with lithium for a mood disorder who had two or more serum creatinine measurements available in the years 2008-17, irrespective of duration of lithium therapy, identified from the Prescription Medicines Register of the Directorate of Health, or through blood lithium measurements. The control group comprised all eligible outpatients with mood disorders (ICD-10 codes F30-F39) who had not been prescribed lithium and who had attended the national tertiary referral centre in 2014-16. Individuals with chronic kidney disease (identified by ICD codes or an estimated glomerular filtration rate [eGFR] <60 mL/min per 1·73 m 2 ) before Jan 1, 2008, or those with glomerular disease, genetic or congenital kidney disease, or small kidneys diagnosed before or after 2008 were excluded. Chronic kidney disease stages 3 and higher were defined according to the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, and the eGFR was calculated from serum creatinine; all ICD-10 and ICD-9 diagnosis codes, serum creatinine and blood lithium concentrations, and urine albumin-to-creatinine ratios were obtained from health-care institutions and laboratories. Risk of developing stage 3 or higher chronic kidney disease between Jan 1, 2008, and Dec 31, 2017, was assessed using time-to-event regression analysis, accounting for competing risk of death. People with lived experience were not involved in the design or conduct of this study., Findings: We identified 4310 individuals (2695 who had received lithium and 1615 control participants), of whom 3198 were included in the study. 2025 (75·1%) individuals in the lithium group (1165 [57·5%] female and 860 [42·5%] male) and 1173 (72·6%) in the control group (737 [62·8%] female and 436 [37·2%] male) were included in the study at end of follow-up. The mean age of the study sample at the end of follow-up was 46·6 years (SD 16·4; range 18·5-98·9). Ethnicity data were not available. In the lithium group, 211 (10·4%) of 2025 individuals developed stage 3 or higher chronic kidney disease, compared with 35 (3·0%) of 1173 individuals in the control group (hazard ratio [HR] 1·90, 95% CI 1·32-2·75 after adjusting for sex, age, and comorbid conditions). Compared with control participants, the risk of stage 3 or higher chronic kidney disease was significantly increased for subgroups with a mean blood lithium concentration of 0·60-0·79 mmol/L (HR 2·93, 95% CI 1·97-4·36) or 0·80-0·99 mmol/L (4·31, 2·66-6·99), but not for the subgroup with a mean blood lithium concentration of 0·30-0·59 mmol/L (1·22, 0·78-1·90). Analyses also showed that age, initial eGFR, diabetes, and history of acute kidney injury were significant risk factors for developing stage 3 or higher chronic kidney disease., Interpretation: Individuals with mood disorders receiving lithium treatment had an increased risk of developing stage 3 or higher chronic kidney disease in a blood concentration-dependent manner. We also found that other factors, including age, initial eGFR, and comorbidities were associated with increased risk of for developing stage 3 or higher chronic kidney disease. Overall, our findings suggest that in addition to considering other risk factors (eg, age or clinical comorbidities), careful monitoring of blood lithium concentrations and use of the lowest effective lithium dose for adequate mood stabilisation is recommended for helping to mitigate the risk of chronic kidney disease., Funding: Akureyri Hospital Research Fund and Landspitali University Hospital Science Fund., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Hypothesis: Causes and risk factors for community-acquired acute kidney injury (CA-AKI) have not been thoroughly studied. The aim of this study was to examine the risk factors for CA-AKI., Methods: In this prospective study, we examined serum creatinine from all individuals visiting a university hospital's emergency department (ED) over an 11-month period for the presence of AKI defined according to the KDIGO criteria. Patients with AKI were invited to participate. Randomly selected controls (1:2) were paired according to age, sex, and date of admission. Participants answered questions about their medical history and medication use, including over-the-counter (OTC) drugs. Conditional logistic regression was used to identify factors associated with AKI., Results: Of 602 AKI cases identified, 512 participated in the study. AKI cases were significantly more likely than controls to have used nonsteroidal anti-inflammatory drugs (NSAIDs) (26.0 % vs 18.0 %, p = 0,001) in the week preceding the ED visit, particularly OTC NSAIDs (23.3 % vs 15.9 %, p < 0.001). AKI was associated with a recent history of vomiting (OR 2.52 [95 %CI 1.87-3.39]), diarrhea (1.30 [1.00-1.70]) and urinary retention (1.92 [1.36-2.72]), use of non-selective NSAIDs (1.84, [1.37-2.48]), RAAS blockers (1.63 [1.21-2.19]), and diuretics (1.53 [1.13-2.08]), and a history of diabetes (1.42 [1.04-1.94]), CKD (1.36 [1.01-1.83]) and smoking (1.72 [1.24-2.37])., Conclusions: Events in the setting of acute illness and medication use, including OTC NSAIDs, may play a greater role in the development of CA-AKI than comorbid conditions. Frequent use of OTC NSAIDs is a concern and should be addressed in view of serious adverse effects., (Copyright © 2024. Published by Elsevier B.V.)

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: This paper compares the most recent data on the incidence and prevalence of kidney replacement therapy (KRT), kidney transplantation rates, and mortality on KRT from Europe to those from the United States (US), including comparisons of treatment modalities (haemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx))., Methods: Data were derived from the annual reports of the European Renal Association (ERA) Registry and the United States Renal Data System (USRDS). The European data include information from national and regional renal registries providing the ERA Registry with individual patient data. Additional analyses were performed to present results for all participating European countries together., Results: In 2021, the KRT incidence in the US (409.7 per million population (pmp)) was almost 3-fold higher than in Europe (144.4 pmp). Despite the substantial difference in KRT incidence, approximately the same proportion of patients initiated HD (Europe: 82%, US: 84%), PD (14%; 13%, respectively), or underwent pre-emptive KTx (4%; 3%, respectively). The KRT prevalence in the US (2436.1 pmp) was 2-fold higher than in Europe (1187.8 pmp). Within Europe, approximately half of all prevalent patients were living with a functioning graft (47%), while in the US, this was one third (32%). The number of kidney transplantations performed was almost twice as high in the US (77.0 pmp) compared to Europe (41.6 pmp). The mortality of patients receiving KRT was 1.6-fold higher in the US (157.3 per 1000 patient years) compared to Europe (98.7 per 1000 patient years)., Conclusions: The US had a much higher KRT incidence, prevalence, and mortality compared to Europe, and despite a higher kidney transplantation rate, a lower proportion of prevalent patients with a functioning graft., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias., Objective: To examine whether MGUS is associated with autoimmune diseases., Design: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS., Setting: Icelandic population of adults aged 40 years or older., Patients: 75 422 persons screened for MGUS., Measurements: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex., Results: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70])., Limitation: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results., Conclusion: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted., Primary Funding Source: The International Myeloma Foundation and the European Research Council., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2867.

Background: In Iceland, a small number of kidney transplants from living donors (LDs) are performed at Landspitali University Hospital (LUH) in Reykjavik, while deceased donor transplants have until recently invariably been carried out abroad. In this study, we evaluated the outcome of kidney transplantation in Icelandic patients., Methods: This was a retrospective study that included all Icelandic residents who underwent kidney transplantation between 1 January 2000 and 31 December 2019. Data were obtained from the Icelandic End-Stage Kidney Disease Registry, medical records at LUH, and the Scandiatransplant database. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate estimated glomerular filtration rate from serum creatinine for recipients and donors aged >18 years, and the modified Schwartz equation for those aged ≤18 years. Survival was estimated using the Kaplan-Meier method, and the log-rank test was employed for group comparisons., Results: A total of 229 kidney transplants in 221 patients were performed during the 20-year period, of which 135 (58.9%) were from LDs. Transplants carried out at LUH were 118 (51.5%), of which 116 were from LDs. During a median follow-up of 7.4 years (range 0.1-20), 27 (12.2%) patients died, 20 (74%) of whom had a functioning graft. One-year patient survival was 99.1% [95% confidence interval (CI), 97.9-100], 5-year survival was 95.7% (95% CI, 92.7-98.7), and 10-year survival was 87.7% (95% CI, 82.4-93.4). Death-censored graft survival was 98.3% (95% CI, 96.6-100), 96.8% (95% CI, 94.4-99.2), and 89.2% (95% CI, 84.1-94.7) at 1, 5, and 10 years, respectively., Conclusions: Patient and graft survival are comparable with those of large transplant centers, demonstrating the feasibility of running a quality kidney transplant program in a small nation in collaboration with a larger center abroad., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Palsson, Andresdottir, Jonsson, Jonsson, Hilmarsson, Indridason and Palsson.)

Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management., Objective: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model., Design: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597)., Setting: Icelandic population of adults aged 40 years or older., Patients: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample., Measurements: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater., Results: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds., Limitation: The prediction model will require external validation., Conclusion: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology., Primary Funding Source: International Myeloma Foundation and the European Research Council., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2540.

Objectives: Prior studies on the association of estimated glomerular filtration rate (eGFR) and mortality have failed to include methods to account for repeated eGFR determinations. The aim of this study was to estimate the association between eGFR and mortality in the general population in Iceland employing a joint model., Methods: We obtained all serum creatinine and urine protein measurements from all clinical laboratories in Iceland in the years 2008-16. Clinical data were obtained from nationwide electronic medical records. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and categorized as follows: 0-29, 30-44, 45-59, 60-74, 75-89, 90-104 and >104 mL/min/1.73 m2. A multiple imputation method was used to account for missing urine protein data. A joint model was used to assess risk of all-cause mortality., Results: We obtained 2 120 147 creatinine values for 218 437 individuals, of whom 84 364 (39%) had proteinuria measurements available. Median age was 46 (range 18-106) years and 47% were men. Proteinuria associated with increased risk of death for all eGFR categories in persons of all ages. In persons ≤65 years, the lowest risk was observed for eGFR of 75-89 mL/min/1.73 m2 without proteinuria. For persons aged >65 years, the lowest risk was observed for eGFR of 60-74 mL/min/1.73 m2 without proteinuria. eGFR of 45-59 mL/min/1.73 m2 without proteinuria did not associate with increased mortality risk in this age group. eGFR >104 mL/min/1.73 m2 associated with increased mortality., Conclusions: These results lend further support to the use of age-adapted eGFR thresholds for defining chronic kidney disease. Very high eGFR needs to be studied in more detail with regard to mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m 2 , not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m 2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented., (© 2022. The Author(s).)

Background: The severity of SARS-CoV-2 infection varies from asymptomatic state to severe respiratory failure and the clinical course is difficult to predict. The aim of the study was to develop a prognostic model to predict the severity of COVID-19 in unvaccinated adults at the time of diagnosis., Methods: All SARS-CoV-2-positive adults in Iceland were prospectively enrolled into a telehealth service at diagnosis. A multivariable proportional-odds logistic regression model was derived from information obtained during the enrollment interview of those diagnosed between February 27 and December 31, 2020 who met the inclusion criteria. Outcomes were defined on an ordinal scale: (1) no need for escalation of care during follow-up; (2) need for urgent care visit; (3) hospitalization; and (4) admission to intensive care unit (ICU) or death. Missing data were multiply imputed using chained equations and the model was internally validated using bootstrapping techniques. Decision curve analysis was performed., Results: The prognostic model was derived from 4756 SARS-CoV-2-positive persons. In total, 375 (7.9%) only required urgent care visits, 188 (4.0%) were hospitalized and 50 (1.1%) were either admitted to ICU or died due to complications of COVID-19. The model included age, sex, body mass index (BMI), current smoking, underlying conditions, and symptoms and clinical severity score at enrollment. On internal validation, the optimism-corrected Nagelkerke's R 2 was 23.4% (95%CI, 22.7-24.2), the C-statistic was 0.793 (95%CI, 0.789-0.797) and the calibration slope was 0.97 (95%CI, 0.96-0.98). Outcome-specific indices were for urgent care visit or worse (calibration intercept -0.04 [95%CI, -0.06 to -0.02], E max 0.014 [95%CI, 0.008-0.020]), hospitalization or worse (calibration intercept -0.06 [95%CI, -0.12 to -0.03], E max 0.018 [95%CI, 0.010-0.027]), and ICU admission or death (calibration intercept -0.10 [95%CI, -0.15 to -0.04] and E max 0.027 [95%CI, 0.013-0.041])., Conclusion: Our prognostic model can accurately predict the later need for urgent outpatient evaluation, hospitalization, and ICU admission and death among unvaccinated SARS-CoV-2-positive adults in the general population at the time of diagnosis, using information obtained by telephone interview., (© 2022. The Author(s).)

Background and Objectives: High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies., Design, Setting, Participants, & Measurements: All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010-2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation., Results: Tacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%-48%) compared with 28% (interquartile range, 20%-38%) for nondonor-specific antibody formers ( P <0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27)., Conclusions: High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation., (Copyright © 2022 by the American Society of Nephrology.)

Background: Information on the incidence of chronic kidney disease (CKD) in the general population is scarce. This study examined the incidence and risk factors of CKD stages 1-5 in Iceland, based on multiple markers of kidney damage., Methods: All serum creatinine (SCr) values, urine protein measurements and diagnosis codes for kidney diseases and comorbid conditions for people aged ≥18 years were obtained from electronic medical records of all healthcare institutions in Iceland in 2008-2016. CKD was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria as evidence for kidney damage and/or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 for >3 months. Alternatively, CKD was defined using age-adapted eGFR thresholds. Mean annual age-standardized incidence of CKD was calculated for persons without CKD at study entry. Risk factor assessment was based on International Classification of Diseases diagnosis codes. Incidence was reported per 100 000 population., Results: We retrieved 1 820 990 SCr values for 206 727 persons. Median age was 45 years (range, 18-106) and 47% were men. Mean annual age-standardized incidence of CKD per 100 000 was 649 in men and 694 in women, and 480 in men and 522 in women using age-adapted eGFR thresholds. The incidence reached over 3000 in men and women aged >75 years. Traditional CKD risk factors, such as acute kidney injury, diabetes, hypertension and cardiovascular disease, as well as less well characterized risk factors, including chronic lung disease, malignancy and major psychiatric illness were associated with increased risk of CKD, and the same was true for obesity and sleep apnoea in women., Conclusion: The annual incidence of CKD, with strict adherence to the KDIGO criteria, was <0.7% but markedly lower using age-adapted eGFR thresholds. Apart from acute kidney injury, the observed risk factors comprised chronic and potentially modifiable disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19., (© 2021. The Author(s).)

Adenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Most epidemiological studies on chronic kidney disease (CKD) are based solely on estimated glomerular filtration rate (eGFR). Few studies have included proteinuria, while the chronicity criterion is usually omitted. To explore this, we examined the prevalence of CKD stages 1-5 in Iceland based on multiple markers of kidney damage. All serum creatinine values, urine protein measurements and diagnostic codes for kidney diseases and comorbid conditions for people aged 18 years and older were obtained from electronic medical records of all healthcare institutions in Iceland in 2008-2016. CKD was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline using diagnoses indicative of a chronic kidney disease, proteinuria and/or an eGFR under 60 mL/min/1.73 m 2 for over three months. Mean annual age-standardized prevalence of CKD stages 1-5 was calculated based on the KDIGO criteria and age-adapted eGFR thresholds from 2,120,147 creatinine values for 218,437 individuals, 306,531 proteinuria measurements for 86,364 individuals and 6973 individuals carrying a kidney disease diagnosis. Median age was 63 years (range, 18-106) and 47% were male. The mean annual age standardized CKD prevalence was 5.13% for men and 6.75% for women using the KDIGO criteria but by age-adapted eGFR cut-offs, the prevalence was 3.27% for men and 4.01% for women. Thus, our nationwide study, defining CKD in Iceland with strict adherence to the KDIGO criteria, demonstrates a lower prevalence of CKD than anticipated from most previous studies., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the stone recurrence rate among childhood kidney stone formers in the Icelandic population., Materials and Methods: We retrospectively examined kidney stone recurrence in a recently reported population-based sample of 190 individuals who experienced their first stone before 18 years of age in the period 1985-2013. Of these 190 individuals, 112 (59%) were females and the median (range) age at the incident stone diagnosis was 15.0 (0.2-17.9) years. Stone recurrence was defined as an acute symptomatic episode with imaging confirmation or self-reported stone passage, new stone detected by imaging in asymptomatic patients, and suspected clinical stone episode without verification. The Kaplan-Meier method was used to assess stone-free survival and the Chi-square, Fisher's exact, Wilcoxon rank-sum and the log-rank tests to compare groups., Results: A total of 68 (35%) individuals experienced a second stone event, 1.7 (0.9-18.9) years after the initial diagnosis. The recurrence rate was 26%, 35%, 41% and 46% after 5, 10, 15 and 20 years of follow-up, respectively. The 5-year recurrence rate increased with time and was 9%, 24% and 37% in the periods 1985-1994, 1995-2004 and 2005-2013, respectively (P = 0.005). No difference in stone recurrence was observed between the sexes (P = 0.23)., Conclusions: In our population-based sample of childhood kidney stone formers, the stone recurrence rate is similar to that reported for adults. The observed rise in stone recurrence with time may be related to closer patient follow-up in recent years or increased stone risk in general.

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients., Methods: Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation., Results: Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0-39.0) mL/min/1.73 m (P = 0.009) when such treatment was not administered pretransplant., Conclusions: Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.

Background: Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals., Methods: We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status., Results: There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m 2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m 2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m 2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m 2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age., Conclusions: Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age., (Copyright © 2020 by the American Society of Nephrology.)

Background: Mild cases of acute kidney injury (AKI) are identified by a small rise in serum creatinine (SCr) according to the KDIGO AKI definition. The aim of this study was to examine the long-term outcomes of individuals with mild AKI.Methods. This was a retrospective cohort study of all adult patients who underwent abdominal, cardiothoracic, vascular or orthopaedic surgery at Landspitali-The National University Hospital of Iceland in 1998-2015. Incident chronic kidney disease (CKD), progression of pre-existing CKD and long-term survival were compared between patients with mild Stage 1 AKI (defined as a rise in SCr of ≥26.5 μmol/L within 48 h post-operatively without reaching 1.5× baseline SCr within 7 days), and a propensity score-matched control group without AKI stratified by the presence of CKD., Results: Pre- and post-operative SCr values were available for 47 333 (42%) surgeries. Of those, 1161 (2.4%) had mild Stage 1 AKI and 2355 (5%) more severe forms of AKI. Mild Stage 1 AKI was associated with both incident CKD and progression of pre-existing CKD (P < 0.001). After exclusion of post-operative deaths within 30 days, mild Stage 1 AKI was not associated with worse 1-year survival in patients with preserved kidney function (94% versus 94%, P = 0.660), and same was true for patients with pre-operative CKD (83% versus 82%, P = 0.870) compared with their matched individuals. Conclusions. Mild Stage 1 AKI is associated with development and progression of CKD, but not with inferior 1-year survival. These findings support the inclusion of a small absolute increase in SCr in the definition of AKI., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D)., Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal., Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D., Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D., Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable., (Copyright © 2019 by the American Society of Nephrology.)

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism that results in excessive urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. The purpose of this study was to assess urinary DHA excretion in patients with APRT deficiency, heterozygotes and healthy controls, using a recently developed ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay., Methods: Patients enrolled in the APRT Deficiency Registry and Biobank of the Rare Kidney Stone Consortium (http://www.rarekidneystones.org/) who had provided 24-h and first-morning void urine samples for DHA measurement were eligible for the study. Heterozygotes and healthy individuals served as controls. Wilcoxon-Mann-Whitney test was used to compare 24-h urinary DHA excretion between groups. Associations were examined using Spearman's correlation coefficient (r s )., Results: The median (range) 24-h urinary DHA excretion was 138 (64-292) mg/24 h and the DHA-to-creatinine (DHA/Cr) ratio in the first-morning void samples was 13 (4-37) mg/mmol in APRT deficiency patients who were not receiving xanthine oxidoreductase inhibitor therapy. The 24-h DHA excretion was highly correlated with the DHA/Cr ratio in first-morning void urine samples (r s  = 0.84, p < .001). DHA was detected in all urine samples from untreated patients but not in any specimens from heterozygotes and healthy controls., Conclusions: High urinary DHA excretion was observed in patients with APRT deficiency, while urine DHA was undetectable in heterozygotes and healthy controls. Our results suggest that the UPLC-MS/MS assay can be used for diagnosis of APRT deficiency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: The number of patients prescribed long-term opioids and benzodiazepines and complications from their long-term use have increased. Information regarding the perioperative outcomes of patients prescribed these medications before surgery is limited., Objective: To determine whether patients prescribed opioids and/or benzodiazepines within 6 months preoperatively would have greater short- and long-term mortality and increased opioid consumption postoperatively., Design, Setting, and Participants: This retrospective, single-center, population-based cohort study included all patients 18 years or older, undergoing noncardiac surgical procedures at a national hospital in Iceland from December 12, 2005, to December 31, 2015, with follow-up through May 20, 2016. A propensity score-matched control cohort was generated using individuals from the group that received prescriptions for neither medication class within 6 months preoperatively. Data analysis was performed from April 10, 2018, to March 9, 2019., Exposures: Patients who filled prescriptions for opioids only, benzodiazepines only, both opioids and benzodiazepines, or neither medication within 6 months preoperatively., Main Outcomes and Measures: Long-term survival compared with propensity score-matched controls. Secondary outcomes were 30-day survival and persistent postoperative opioid consumption, defined as a prescription filled more than 3 months postoperatively., Results: Among 41 170 noncardiac surgical cases in 27 787 individuals (16 004 women [57.6%]; mean [SD] age, 56.3 [18.8] years), a preoperative prescription for opioids only was filled for 7460 cases (17.7%), benzodiazepines only for 3121 (7.4%), and both for 2633 (6.2%). Patients who filled preoperative prescriptions for either medication class had a greater comorbidity burden compared with patients receiving neither medication class (Elixhauser comorbidity index >0 for 16% of patients filling prescriptions for opioids only, 22% for benzodiazepines only, and 21% for both medications compared with 14% for patients filling neither). There was no difference in 30-day (opioids only: 1.3% vs 1.0%; P = .23; benzodiazepines only: 1.9% vs 1.5%; P = .32) or long-term (opioids only: hazard ratio [HR], 1.12 [95% CI, 1.01-1.24]; P = .03; benzodiazepines only: HR, 1.11 [95% CI, 0.98-1.26]; P = .11) survival among the patients receiving opioids or benzodiazepines only compared with controls. However, patients prescribed both opioids and benzodiazepines had greater 30-day mortality (3.2% vs 1.8%; P = .004) and a greater hazard of long-term mortality (HR, 1.41; 95% CI, 1.22-1.64; P < .001). The rate of persistent postoperative opioid consumption was higher for patients filling prescriptions for opioids only (43%), benzodiazepines only (23%), or both (66%) compared with patients filling neither (12%) (P < .001 for all)., Conclusions and Relevance: The findings suggest that opioid and benzodiazepine prescription fills in the 6 months before surgery are associated with increased short-and long-term mortality and an increased rate of persistent postoperative opioid consumption. These patients should be considered for early referral to preoperative clinic and medication optimization to improve surgical outcomes.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context., (© The Author(s) 2018. Published by Oxford University Press.)

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD). The purpose of this study was to examine the course of APRT deficiency in patients who presented in childhood., Methods: The disease course of 21 (35%) patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, who presented with manifestations of APRT deficiency and/or were diagnosed with the disorder before the age of 18 years, was studied. The effect of pharmacotherapy on renal manifestations and outcomes was thoroughly assessed., Results: Fourteen children were placed on allopurinol, 100 (25-200) mg/day, at the age of 2.6 (0.6-16.5) years. Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment. During 18.9 (1.7-31.5) years of pharmacotherapy, stones occurred in two patients and AKI in three. Six adult patients started allopurinol treatment, 200 (100-300) mg/day, at age 29.8 (20.5-42.4) years. Five of these patients had experienced 28 stone episodes and AKI had occurred in two. Stone recurrence occurred in four patients and AKI in two during 11.2 (4.2-19.6) years of allopurinol therapy. Lack of adherence and insufficient dosing contributed to stone recurrence and AKI during pharmacotherapy. At latest follow-up, estimated glomerular filtration rate (eGFR) was 114 (70-163) and 62 (10-103) mL/min/1.73 m 2 in those who initiated treatment as children and adults, respectively. All three patients with CKD stages 3-5 at the last follow-up were adults when pharmacotherapy was initiated., Conclusion: Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function.

Background: The aim of this study was to examine acute kidney injury (AKI) diagnosis based on different computerized algorithms compared with a nephrologist's diagnosis in patients visiting an emergency department (ED) of a university hospital., Methods: In this retrospective study, we used electronic medical records at the University Hospital in Reykjavik to identify all patients aged ≥18 years, who presented to the ED in the year 2010 with an elevated serum creatinine (SCr) level. All SCr values were reviewed and a nephrologist determined whether AKI was present using the KDIGO SCr criteria and clinical data. Computerized algorithms based on the KDIGO SCr criteria, accounting for various time intervals for baseline SCr and changes in follow-up SCr, were constructed using the statiscal software R., Results: At 53,816 ED visits, SCr was measured in 15,588 patients for a total of 21,559 measurements. Elevated SCr was observed in 2878 (18.4%) patients. Strict adherence to the KDIGO SCr criteria yielded a 79% sensitivity, 94% specificity, 68% positive predictive value (PPV) and 96% negative predictive value (NPV) for the diagnosis of AKI. Allowing for a longer time frame (>365 days) for baseline SCr, resulted in 93% sensitivity, 96% specificity, 80% PPV and 99% NPV. The algorithms which included a decrease in SCr from the index ED value yielded a sensitivity of 97% but lower specificity, 74% and 80%., Conclusions: The algorithms that perform best yield excellent sensitivity and specificity and could be used to identify patients with AKI in the ED to enhance early diagnosis and treatment., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Kidney stone disease is a common disorder in Western countries that is associated with significant suffering, morbidity, and cost for the healthcare system. Numerous studies have demonstrated familial aggregation of nephrolithiasis and a twin study estimated the heritability to be 56%. Over the past decade, genome-wide association studies have uncovered several sequence variants that confer increased risk of common complex kidney stone disease. The first reported variants were observed at the CLDN14 locus in the Icelandic population. This finding has since been replicated in other populations. The CLDN14 gene is expressed in tight junctions of the thick ascending limb of the loop of Henle, where the protein is believed to play a role in regulation of calcium transport. More recent studies have uncovered variants at the ALPL, SLC34A1, CASR, and TRPV5 loci, the first two genes playing a role in renal handling of phosphate, while the latter two are involved in calcium homeostasis. Although genetic data have provided insights into the molecular basis of kidney stone disease, much remains to be learned about the contribution of genetic factors to stone formation. Nevertheless, the progress made in recent years indicates that exciting times lie ahead in genetic research on kidney stone disease.

Background: The aim of this study was to examine different definitions of renal recovery following postoperative acute kidney injury (AKI) and how these definitions associate with survival and the development and progression of chronic kidney disease (CKD)., Methods: This was a retrospective study of all patients who underwent abdominal, cardiothoracic, vascular, or orthopedic surgery at a single university hospital between 1998 and 2015. Recovery of renal function following postoperative AKI was assessed comparing 4 different definitions: serum creatinine (SCr) (i) < 1.1 × baseline, (ii) 1.1-1.25 × baseline, (iii) 1.25-1.5 × baseline, and (iv) > 1.5 × baseline. One-year survival and the development or progression of CKD within 5 years was compared with a propensity score-matched control groups., Results: In total, 2,520 AKI patients were evaluated for renal recovery. Risk of incident and progressive CKD within 5 years was significantly increased if patients did not achieve a reduction in SCr to < 1.5 × baseline (hazard ratio [HR] 1.50; 95% CI 1.29-1.75) and if renal recovery was limited to a fall in SCr to 1.25-1.5 × baseline (HR 1.32; 95% CI 1.12-1.57) within 30 days. The definition of renal recovery that best predicted survival was a reduction in SCr to < 1.5 × baseline within 30 days. One-year survival of patients whose SCr decreased to < 1.5 × baseline within 30 days was significantly better than that of a propensity score-matched control group that did not achieve renal recovery (85 vs. 71%, p < 0.001)., Conclusions: These findings should be considered when a consensus definition of renal recovery after AKI is established., (© 2019 S. Karger AG, Basel.)

Background: We studied the incidence and risk factors of acute kidney injury (AKI) following coronary angiography (CA) and examined short- and long-term outcomes of patients who developed AKI, including progression of chronic kidney disease (CKD)., Methods: This was a retrospective study of all patients undergoing CA in Iceland from 2008 to 2015, with or without percutaneous coronary intervention. All procedures were performed with iso-osmolar contrast. AKI was defined according to the SCr component of the KDIGO criteria. Patients without post-procedural SCr were assumed to be free of AKI. Incident CKD was defined as 90-day sustained estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 , and progression of CKD as worsening at least one stage sustained over 90 days., Results: AKI was detected in 231 of 13,561 cases (1.7%). There was an interaction between contrast dose and preexisting kidney function, where the risk for AKI was only significant at a dose > 150 mL in patients with baseline eGFR < 45 mL/min/1.73 m 2 (OR 5.3, 95% CI 2.1-14.2). The AKI patients had worse short-and long-term survival, as well as elevated hazard of both new-onset CKD (HR 3.7, 95% CI 2.7-5.0) and progression of preexisting CKD (HR 2.0, 95% CI 1.5-2.6) over a median follow-up of 3.3 years (range 0.1-8.4 years), compared to a propensity score-matched control group., Conclusions: For iso-osmolar contrast, the risk of AKI related to contrast dose was evident for higher amount of contrast in patients with baseline eGFR < 45 mL/min/1.73 m 2 . In addition to association with adverse short- and long-term survival AKI had a strong association with new-onset or progression of CKD when patients were followed longitudinally.

Background: Validation studies comparing glomerular filtration rate (GFR) equations based on standardized creatinine and cystatin C assays in the elderly are needed. The Icelandic Age, Gene/Environment Susceptibility-Kidney cohort was used to compare two pairs of recently developed GFR equations, the revised Lund-Malmö creatinine equation (LMRCr) and the arithmetic mean of the LMRCr and Caucasian, Asian, Paediatric and Adult cystatin C equations (MEANLMR+CAPA), as well as the Full Age Spectrum creatinine equation (FASCr) and its combination with cystatin C (FASCr+Cys), with the corresponding pair of Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPICr and CKD-EPICr+Cys)., Methods: A total of 805 individuals, 74-93 years of age, underwent measurement of GFR (mGFR) using plasma clearance of iohexol. Four metrics were used to compare the performance of the GFR equations: bias, precision, accuracy [including the percentage of participants with estimated GFR (eGFR) within 30% of mGFR (P30)] and the ability to detect mGFR <60 mL/min/1.73 m2., Results: All equations had a P30 >90%. LMRCr and FASCr yielded significantly higher precision and P30 than CKD-EPICr, while bias was significantly worse. LMRCr, FASCr and CKD-EPICr showed similar ability to detect mGFR <60 mL/min/1.73 m2 based on the area under the receiver operating characteristic curves. MEANLMR+CAPA, FASCr+Cys and CKD-EPICr+Cys all exhibited consistent improvements compared with the corresponding creatinine-based equations., Conclusion: None of the creatinine-based equations was clearly superior overall in this community-dwelling elderly cohort. The addition of cystatin C improved all of the creatinine-based equations.

Background: An increase in the incidence of kidney stone disease has been reported for all age groups worldwide. To examine this trend, we conducted a nationwide study of the epidemiology of kidney stones in Icelandic children and adolescents over a 30-year period., Methods: Computerized databases of all major hospitals and medical imaging centers in Iceland were searched for International Classification of Diseases and radiologic and surgical procedure codes indicative of kidney stones in patients aged < 18 years, followed by a thorough medical record review. Age-adjusted incidence was calculated for the time intervals 1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2013. Time trends in stone incidence were assessed by Poisson regression. The prevalence of stone disease for the years 1999-2013 was also determined., Results: Almost all the 190 patients (97%) that we identified had symptomatic stones, and acute flank or abdominal pain and hematuria were the most common presenting features. The total annual incidence of kidney stones increased from 3.7/100,000 in the first 5-year interval to 11.0/100,000 during the years 1995-2004 (p < 0.001) and decreased thereafter to 8.7/100,000 in 2010-2013 (p = 0.63). The incidence rise was highest in girls aged 13-17 years, in whom it rose from 9.8/100,000 in 1985-1989 to 39.2/100,000 in 2010-2013 (p < 0.001), resulting in an overall female predominance in this age group. The mean annual prevalence of stone disease in 1999-2013 was 48/100,000 for boys and 52/100,000 for girls., Conclusion: We found a significant increase in the incidence of childhood kidney stone disease, driven by a dramatic increase of stone frequency in teenage females which is poorly understood and warrants further study.

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B 1 ; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B 1 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.

Aim: Acute kidney injury (AKI) is a common complication of medical and surgical interventions in hospitalized patients and associates with high mortality. Our aim was to examine renal recovery and long-term survival and time trends in AKI survival., Methods: Changes in serum creatinine (SCr) were used to define AKI in patients at Landspitali University Hospital in Iceland from 1993 to 2013. Renal recovery was defined as SCr < 1.5× baseline., Results: Out of 25 274 individuals who had their highest measured SCr during hospitalization and an available baseline SCr, 10,419 (41%) had AKI during hospitalization (H-AKI), 19%, 11% and 12% with Stage 1, 2 and 3, respectively. The incidence of H-AKI increased from 18.6 (95% CI, 14.7-22.5) to 29.9 (95% CI, 26.7-33.1) per 1000 admissions/year over the study period. Survival after H-AKI was 61% at 90-days and 51% at one year. Comparing H-AKI patients to propensity score matched individuals the hazard ratio for death was 1.49 (1.36-1.62), 2.17 (1.95-2.41) and 2.95 (2.65-3.29) for Stage 1, 2 and 3, respectively. One-year survival of H-AKI patients improved from 47% in 1993-1997 to 57% in 2008-2013 and the adjusted hazard ratio for mortality improved, compared to the first 5-year period, 0.85 (0.81-0.89), 0.67 (0.64-0.71), and 0.57 (0.53-0.60) for each subsequent 5-year interval. Recovery of renal function was achieved in 88%, 58% and 44% of patients in Stages 1, 2 and 3, respectively, improving with time., Conclusions: Acute kidney injury is an independent predictor of long-term mortality in hospitalized patients but there has been a marked improvement in survival and renal recovery over the past two decades., (© 2015 Asian Pacific Society of Nephrology.)

Background: Acute kidney injury (AKI) is a serious complication after major surgical procedures. We examined the incidence, risk factors, and mortality of patients who sustained AKI after abdominal surgery in a large population-based cohort., Methods: All patients who underwent open and laparoscopic abdominal surgery (excluding genitourinary and abdominal vascular procedures), between 2007 and 2014 at the University Hospital in Reykjavik were identified and their perioperative serum creatinine (SCr) measurements used to identify AKI after surgery employing the Kidney Disease: Improving Global Outcome (KDIGO) criteria. Risk factors were evaluated using multivariate logistic regression analysis and 30-day mortality compared with a propensity score-matched control group., Results: During the 8-year period, a total of 11,552 abdominal surgeries were performed on 10,022 patients. Both pre- and postoperative SCr measurements were available for 3902 (33.8%) of the surgical cases. Of these, 264 (6.8%) were complicated by AKI; 172 (4.4%), 49 (1.3%), and 43 (1.1%) were classified as KDIGO stages 1, 2 and 3, respectively. The overall incidence of AKI for patients with available SCr values was 67.7 (99% confidence interval [CI], 57.7-78.6) per 1000 surgeries. In logistic regression analysis, independent risk factors for AKI were female sex (odds ratio [OR] = 0.68; 99% CI, 0.47-0.98), hypertension (OR = 1.75; 99% CI, 1.10-2.74), preoperative chronic kidney disease (OR= 1.68; 99% CI, 1.12-2.50), ASA physical status classification of IV (OR = 9.48; 99% CI, 3.66-29.2) or V (OR = 21.4; 99% CI, 5.28-93.6), and reoperation (OR = 4.30; 99% CI, 2.36-7.70). Patients with AKI had greater 30-day mortality (18.2% vs 5.3%; P < 0.001) compared with propensity score-matched controls., Conclusions: AKI is an important complication of abdominal surgery. In addition to sex, hypertension, and chronic kidney disease, ASA physical status classification is an independent predictor of AKI. Individuals who develop AKI have substantially worse short-term outcomes, including higher 30-day mortality, even after correcting for multiple patient- and procedure-related risk factors.

Background: Monitoring warfarin with Fiix-prothrombin time (Fiix-PT), which is only affected by coagulation factors II and X, stabilizes anticoagulation and reduces thromboembolism compared to PT/INR monitoring. We compared outcome in nonvalvular atrial fibrillation (NVAF) patients treated with Fiix-warfarin, direct oral anticoagulants (DOACs), or PT-warfarin., Methods: A systematic efficacy and safety assessment by retrieving data from the Fiix trial and the four major phase III DOAC trials in NVAF. Prespecified outcomes included stroke and systemic embolism (SSE), SSE and myocardial infarction (MI), major bleeding (MB), composite major vascular events (SSEMI and MB; CMVE), and deaths. We calculated relative risk, 95% CI, and 95% confidence limits (CL) for each outcome and performed meta-analysis using fixed- and random-effects modeling., Results: There were 613 and 628 observation years with Fiix-warfarin and PT-warfarin in the Fiix trial, and 70 628 and 57 962 with DOACs and PT-warfarin in DOAC trials. Populations were comparable although death rates were lower in the Fiix trial. Compared to pooled PT-warfarin, Fiix-warfarin reduced SSE (RR 0.54;95% CI 0.26-1.10/95% CL <1.00), SSEMI (0.51;0.26-0.99/<0.90), MB (RR 0.63;0.37-1.07/<0.99), and CMVE (RR 0.66;0.43-1.00/<0.94). Vascular death was lower (RR 0.13;0.04-0.47/<0.42). Compared to pooled DOACs, Fiix-warfarin consistently had lower point estimates for the RR for efficacy and safety, but only significant for lower death rates (vascular death RR 0.14;0.04-0.49/<0.43). Meta-analysis comparing Fiix-warfarin and DOACs with PT-warfarin consistently found Fiix-warfarin to have the lowest point estimates for efficacy., Conclusion: Monitoring warfarin with Fiix-PT reduces risk of vascular events in NVAF patients as much as DOACs. Warfarin monitored with Fiix-PT is an improved anticoagulant., (© 2016 John Wiley & Sons Ltd.)

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a purine metabolism disorder causing kidney stones and chronic kidney disease (CKD). The course of nephrolithiasis and CKD has not been well characterized. The objective of this study was to examine long-term kidney outcomes in patients with APRT deficiency., Study Design: An observational cohort study., Setting & Participants: All patients enrolled in the APRT Deficiency Registry of the Rare Kidney Stone Consortium., Outcomes: Kidney stones, acute kidney injury (AKI), stage of CKD, end-stage renal disease, estimated glomerular filtration rate (eGFR), and changes in eGFR., Measurements: Serum creatinine and eGFR calculated using creatinine-based equations., Results: Of 53 patients, 30 (57%) were females and median age at diagnosis was 37.0 (range, 0.6-67.9) years. Median duration of follow-up was 10.3 (range, 0.0-31.5) years. At diagnosis, kidney stones had developed in 29 (55%) patients and 20 (38%) had CKD stages 3 to 5, including 11 (21%) patients with stage 5. At latest follow-up, 33 (62%) patients had experienced kidney stones; 18 (34%), AKI; and 22 (42%), CKD stages 3 to 5. Of 14 (26%) patients with stage 5 CKD, 12 had initiated renal replacement therapy. Kidney stones recurred in 18 of 33 (55%) patients. The median eGFR slope was -0.38 (range, -21.99 to 1.42) mL/min/1.73m(2) per year in patients receiving treatment with an xanthine dehydrogenase inhibitor and -5.74 (range, -75.8 to -0.10) mL/min/1.73m(2) per year in those not treated prior to the development of stage 5 CKD (P=0.001)., Limitations: Use of observational registry data., Conclusions: Progressive CKD and AKI episodes are major features of APRT deficiency, whereas nephrolithiasis is the most common presentation. Advanced CKD without a history of kidney stones is more prevalent than previously reported. Our data suggest that timely therapy may retard CKD progression., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Low circulating levels of total 25-hydroxyvitamin D (25(OH)D) have been associated with an increased risk of adverse effects after cardiac surgery. The metabolites, 25(OH)D2 and 25(OH)D3, provide a good index of vitamin D status. In this study, we examined the association between preoperative plasma levels of total 25(OH)D, 25(OH)D2 and 25(OH)D3 and the risk of postoperative atrial fibrillation (POAF) following open heart surgery. The levels of plasma 25(OH)D2 and 25(OH)D3 in 118 patients, who underwent coronary artery bypass grafting and/or valvular surgery, were measured immediately prior to surgery and on postoperative day 3 by liquid chromatography-tandem mass spectrometry. Patients who developed POAF had higher median plasma levels of 25(OH)D2 than those who remained in sinus rhythm (SR) (P = 0·003), but no significant difference was noted in levels of 25(OH)D3 or total 25(OH)D between the two groups (P > 0·05). By univariate analysis, patients with total 25(OH)D and 25(OH)D2 levels above the median had higher frequency of POAF (P < 0·05) and the incidence of POAF increased significantly with each higher quartile of preoperative plasma levels of 25(OH)D2 (P = 0·001), an association that was independent of confounding factors. In both the SR and POAF groups, the median plasma levels of 25(OH)D2, 25(OH)D3 and total 25(OH)D were lower (P < 0·05) on the third postoperative day compared with preoperatively. Our findings demonstrate that higher plasma levels of 25(OH)D2 are associated with increased risk of POAF, while this is not the case for 25(OH)D3 or total 25(OH)D. The reason for these discrepant results is not clear but warrants further study.

Background and Objectives: Lifetime risk estimates of CKD can be used effectively in public education campaigns. This study sought to estimate lifetime risk of incident CKD stage 3 and higher in Iceland for people without CKD by the age of 45 years., Design, Setting, Participants, & Measurements: This was a prospective cohort study with longitudinal creatinine measurements of residents in Reykjavik, Iceland, from 1967 to 2005. CKD was ascertained by two consecutive eGFR measurements <60 ml/min per 1.73 m(2), development of treated kidney failure, one eGFR<60 ml/min per 1.73 m(2) if the participant died before the next evaluation, or one eGFR<45 ml/min per 1.73 m(2) if it was the last eGFR., Results: Mean follow-up was 25 (SD 10) years. Of the study participants, 727 (19%) developed the outcome and 942 (24%) died first. By age 85 years, the lifetime risks for 45-year-old women and men without prevalent CKD were 35.8% (95% confidence interval [95% CI], 32.7 to 38.9) and 21.3% (95% CI, 18.7 to 23.8), respectively. Risk was higher in individuals with a lower eGFR, hypertension, and a higher body mass index. Lifetime risk for higher stages of CKD 3b and 4 were less common than stage 3a; by age 85 years, the lifetime risks for CKD stages 3a, 3b, and 4 in women were 38.5% (95% CI, 25.8 to 51.1), 19.4% (95% CI, 8.9 to 29.9), and 3.6% (95% CI, 2.2 to 5.0), respectively., Conclusions: The lifetime risk of developing CKD stage 3 or higher is substantial, emphasizing the importance of strategies to prevent development of CKD throughout the course of life. Estimates are lower than reported using single estimates of GFR, emphasizing the importance of confirming estimates of reduced GFR in studies of CKD., (Copyright © 2015 by the American Society of Nephrology.)

Background: Kidney stone disease has been associated with reduced kidney function and chronic kidney disease (CKD). The objective of the study was to examine kidney function, body mass index (BMI) and the prevalence of cardiovascular disease, hypertension and diabetes in recurrent kidney stone formers., Methods: A cross-sectional, case-control study comparing measures of kidney function, BMI and comorbid conditions was conducted in 195 kidney stone patients aged 18 to 70 years with recurrent clinical stone events and 390 age- and gender-matched controls. Wilcoxon-Mann-Whitney, chi-square tests and analysis of covariance were used to compare serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) between the groups., Results: The median age of stone formers was 51 (range, 19-70) years and 108 (55 %) were males. Seventy patients (36 %) had experienced 2-4 clinical stone events, 41 (21 %) 5-10 episodes and 84 (43 %) more than 10. The median SCr was 75 (41-140) μmol/L in the stone formers and 64 (34-168) μmol/L in the control group (p < 0.001). The mean eGFR was 87 ± 20 and 104 ± 22 mL/min/1.73 m(2) in the stone formers and controls, respectively (p < 0.001). After adjustment for body size and comorbid conditions, the difference in SCr and eGFR between cases and controls remained highly significant (p < 0.001). The prevalence of CKD was 9.3 % among stone formers compared with 1.3 % in the control group (P < 0.001). Hypertension and diabetes were significantly more prevalent among the cases that also had higher BMI than controls., Conclusions: Recurrent kidney stone formers have a significantly lower level of kidney function and a markedly higher prevalence of CKD than age- and gender-matched control subjects. The observed deleterious effect of kidney stones on kidney function appears to be independent of comorbid conditions.

Kidney stone disease is a complex disorder with a strong genetic component. We conducted a genome-wide association study of 28.3 million sequence variants detected through whole-genome sequencing of 2,636 Icelanders that were imputed into 5,419 kidney stone cases, including 2,172 cases with a history of recurrent kidney stones, and 279,870 controls. We identify sequence variants associating with kidney stones at ALPL (rs1256328[T], odds ratio (OR)=1.21, P=5.8 × 10(-10)) and a suggestive association at CASR (rs7627468[A], OR=1.16, P=2.0 × 10(-8)). Focusing our analysis on coding sequence variants in 63 genes with preferential kidney expression we identify two rare missense variants SLC34A1 p.Tyr489Cys (OR=2.38, P=2.8 × 10(-5)) and TRPV5 p.Leu530Arg (OR=3.62, P=4.1 × 10(-5)) associating with recurrent kidney stones. We also observe associations of the identified kidney stone variants with biochemical traits in a large population set, indicating potential biological mechanism.

Background: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease., Study Design: Cross-sectional analysis of a substudy of a prospective cohort., Setting & Participants: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study., Predictor: Exposure to higher blood pressure in midlife., Outcomes & Measurements: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio., Results: GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment., Limitations: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit., Conclusions: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD., (Copyright © 2015 National Kidney Foundation, Inc. All rights reserved.)

Current guidelines recommend reporting eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFRcr-cys) as more accurate than either eGFRcr or eGFRcys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR (mGFR) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFRcr and eGFRcys with eGFRcr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR was 64 (52, 73) ml/min per 1.73 m(2), and the prevalence of decreased GFR was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr in four metrics, better than eGFRcys in two metrics, and similar to eGFRcys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr or eGFRcys., (Copyright © 2015 by the American Society of Nephrology.)

Background: Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well., Methods: The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239., Findings: Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1-1·9). During days 1-720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25-1·13; pnon-inferiority<0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45-1·61; pnon-inferiority=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring., Interpretation: Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR., Funding: Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: We found that age-related decline in bone mineral density (BMD) is more pronounced in women than in men, that lean mass was the most important determinant of BMD in all age groups in both sexes, and that different factors may be important for bone health of men and women and at different ages., Introduction: Multiple factors may affect bone mineral density (BMD). Our objective was to identify the correlates of age-related differences in BMD among men and women., Methods: We performed a cross-sectional study involving 490 men and 517 women between the age of 29 and 87 years that were free of medication and diseases known to affect bone metabolism. BMD was measured at various sites using dual-energy X-ray absorptiometry, and factors possibly associated with skeletal status were assessed by direct measurements and a detailed questionnaire., Results: BMD was lower with advancing age at all BMD measurement sites, the greatest difference being for the femoral neck where in women BMD was 37.5 % lower in the oldest compared to that in the youngest age group, but the difference was 22.9 % in men. Levels of free estradiol were sharply lower after age of 40 among women; free testosterone declined gradually with age among men but was not independently associated with BMD. Factors including lean mass, physical activity, ionized calcium, C-terminal telopeptide (CTX), serum sodium, free estradiol, and smoking explained a large fraction of difference in BMD in different age groups but to a varying degree in men and women. Lean mass was the strongest independent factor associated with BMD at all sites among men and women., Conclusions: Age-related decline in BMD is more pronounced in women than in men, but determinants of BMD are multiple and interrelated. Our study indicates that different factors may be important for bone health of men and women and at different ages.

Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/objectives: Randomised controlled trials (RCTs) evaluating the effect of fish oil supplementation on postoperative atrial fibrillation (POAF) following cardiac surgery have produced mixed results. In this study, we examined relationships between levels of red blood cell (RBC) n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and the incidence of POAF., Subjects/methods: We used combined data (n=355) from RCTs conducted in Australia and Iceland. The primary end point was defined as POAF lasting >10 min in the first 6 days following surgery. The odds ratios (ORs) for POAF were compared between quintiles of preoperative RBC n-3 LC-PUFA levels by multivariable logistic regression., Results: Subjects with RBC docosahexaenoic acid (DHA) in the fourth quintile, comprising a RBC DHA range of 7.0-7.9%, had the lowest incidence of POAF. Subjects in the lowest and highest quintiles had significantly higher risk of developing POAF compared with those in the fourth quintile (OR=2.36: 95% CI; 1.07-5.24 and OR=2.45: 95% CI; 1.16-5.17, respectively). There was no association between RBC eicosapentaenoic acid levels and POAF incidence., Conclusions: The results suggest a 'U-shaped' relationship between RBC DHA levels and POAF incidence. The possibility of increased risk of POAF at high levels of DHA suggests an upper limit for n-3 LC-PUFAs in certain conditions.