Publications by authors named "Olafur S Indridason"

58 Publications

Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency.

Eur J Hum Genet 2021 Jul 11;29(7):1061-1070. Epub 2021 Mar 11.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1038/s41431-020-00805-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298615PMC
July 2021

Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study.

BMJ 2020 12 2;371:m4529. Epub 2020 Dec 2.

Landspitali-National University Hospital of Iceland, Hringbraut 101, 101 Reykjavík, Iceland

Objective: To characterise the symptoms of coronavirus disease 2019 (covid-19).

Design: Population based cohort study.

Setting: Iceland.

Participants: All individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription polymerase chain reaction (RT-PCR) between 17 March and 30 April 2020. Cases were identified by three testing strategies: targeted testing guided by clinical suspicion, open invitation population screening based on self referral, and random population screening. All identified cases were enrolled in a telehealth monitoring service, and symptoms were systematically monitored from diagnosis to recovery.

Main Outcome Measures: Occurrence of one or more of 19 predefined symptoms during follow-up.

Results: Among 1564 people positive for SARS-CoV-2, the most common presenting symptoms were myalgia (55%), headache (51%), and non-productive cough (49%). At the time of diagnosis, 83 (5.3%) individuals reported no symptoms, of whom 49 (59%) remained asymptomatic during follow-up. At diagnosis, 216 (14%) and 349 (22%) people did not meet the case definition of the Centers for Disease Control and Prevention and the World Health Organization, respectively. Most (67%) of the SARS-CoV-2-positive patients had mild symptoms throughout the course of their disease.

Conclusion: In the setting of broad access to RT-PCR testing, most SARS-CoV-2-positive people were found to have mild symptoms. Fever and dyspnoea were less common than previously reported. A substantial proportion of SARS-CoV-2-positive people did not meet recommended case definitions at the time of diagnosis.
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http://dx.doi.org/10.1136/bmj.m4529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708618PMC
December 2020

The prevalence of chronic kidney disease in Iceland according to KDIGO criteria and age-adapted estimated glomerular filtration rate thresholds.

Kidney Int 2020 11 3;98(5):1286-1295. Epub 2020 Jul 3.

Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Division of Nephrology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address:

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 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.
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http://dx.doi.org/10.1016/j.kint.2020.06.017DOI Listing
November 2020

GFR in Healthy Aging: an Individual Participant Data Meta-Analysis of Iohexol Clearance in European Population-Based Cohorts.

J Am Soc Nephrol 2020 07 4;31(7):1602-1615. Epub 2020 Jun 4.

Institute of Public Health, Charité - Berlin University of Medicine, Berlin, Germany.

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 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 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m 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.
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http://dx.doi.org/10.1681/ASN.2020020151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350990PMC
July 2020

Stone recurrence among childhood kidney stone formers: results of a nationwide study in Iceland.

Urolithiasis 2020 Oct 27;48(5):409-417. Epub 2020 Feb 27.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland.

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.
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http://dx.doi.org/10.1007/s00240-020-01179-6DOI Listing
October 2020

Kidney Transplant Outcomes in Patients With Adenine Phosphoribosyltransferase Deficiency.

Transplantation 2020 10;104(10):2120-2128

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1097/TP.0000000000003088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316615PMC
October 2020

Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.

J Am Coll Cardiol 2019 12 9;74(24):2982-2994. Epub 2019 Dec 9.

deCODE genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1016/j.jacc.2019.10.019DOI Listing
December 2019

CKD: A Call for an Age-Adapted Definition.

J Am Soc Nephrol 2019 10 10;30(10):1785-1805. Epub 2019 Sep 10.

Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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 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, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 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.
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http://dx.doi.org/10.1681/ASN.2019030238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779354PMC
October 2019

Urinary 2,8-dihydroxyadenine excretion in patients with adenine phosphoribosyltransferase deficiency, carriers and healthy control subjects.

Mol Genet Metab 2019 Sep - Oct;128(1-2):144-150. Epub 2019 May 28.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address:

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).

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 = 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.
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http://dx.doi.org/10.1016/j.ymgme.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864267PMC
April 2020

Association Between Preoperative Opioid and Benzodiazepine Prescription Patterns and Mortality After Noncardiac Surgery.

JAMA Surg 2019 08 21;154(8):e191652. Epub 2019 Aug 21.

Division of Anesthesia and Intensive Care Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1001/jamasurg.2019.1652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584895PMC
August 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

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.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Postoperative Acute Kidney Injury: Focus on Renal Recovery Definitions, Kidney Disease Progression and Survival.

Am J Nephrol 2019 30;49(3):175-185. Epub 2019 Jan 30.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland,

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.
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http://dx.doi.org/10.1159/000496611DOI Listing
May 2020

Computerized algorithms compared with a nephrologist's diagnosis of acute kidney injury in the emergency department.

Eur J Intern Med 2019 02 11;60:78-82. Epub 2018 Dec 11.

Division of Nephrology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejim.2018.11.013DOI Listing
February 2019

Genetics of common complex kidney stone disease: insights from genome-wide association studies.

Urolithiasis 2019 Feb 6;47(1):11-21. Epub 2018 Dec 6.

Department of Statistics, deCODE genetics, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1007/s00240-018-1094-2DOI Listing
February 2019

Sequence variants associating with urinary biomarkers.

Hum Mol Genet 2019 04;28(7):1199-1211

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1093/hmg/ddy409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423415PMC
April 2019

Long-term renal outcomes of APRT deficiency presenting in childhood.

Pediatr Nephrol 2019 03 15;34(3):435-442. Epub 2018 Nov 15.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

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 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.
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http://dx.doi.org/10.1007/s00467-018-4109-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349544PMC
March 2019

Acute kidney injury following coronary angiography: a nationwide study of incidence, risk factors and long-term outcomes.

J Nephrol 2018 Oct 5;31(5):721-730. Epub 2018 Sep 5.

Division of Anaesthesia and Intensive Care Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.

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, 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 (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. 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.
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http://dx.doi.org/10.1007/s40620-018-0534-yDOI Listing
October 2018

Incidence of kidney stone disease in Icelandic children and adolescents from 1985 to 2013: results of a nationwide study.

Pediatr Nephrol 2018 08 6;33(8):1375-1384. Epub 2018 Apr 6.

Division of Nephrology, Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1007/s00467-018-3947-xDOI Listing
August 2018

Comparison of glomerular filtration rate estimating equations derived from creatinine and cystatin C: validation in the Age, Gene/Environment Susceptibility-Reykjavik elderly cohort.

Nephrol Dial Transplant 2018 08;33(8):1380-1388

Department of Translational Medicine, Division of Medical Radiology, Lund University, Malmö, Sweden.

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.
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http://dx.doi.org/10.1093/ndt/gfx272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070032PMC
August 2018

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

J Thromb Thrombolysis 2017 May;43(4):550-561

Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.

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; 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 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.
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http://dx.doi.org/10.1007/s11239-017-1482-4DOI Listing
May 2017

Acute Kidney Injury After Abdominal Surgery: Incidence, Risk Factors, and Outcome.

Anesth Analg 2016 06;122(6):1912-20

From the *Internal Medicine, †Surgical, and ‡Perioperative Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; §Faculty of Medicine, University of Iceland, Reykjavik, Iceland; and ‖Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1213/ANE.0000000000001323DOI Listing
June 2016

Kidney Disease in Adenine Phosphoribosyltransferase Deficiency.

Am J Kidney Dis 2016 Mar 25;67(3):431-8. Epub 2015 Dec 25.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address:

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.
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http://dx.doi.org/10.1053/j.ajkd.2015.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819988PMC
March 2016

Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial.

Lancet Haematol 2015 Jun 25;2(6):e231-40. Epub 2015 May 25.

The National University Hospital of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1016/S2352-3026(15)00073-3DOI Listing
June 2015

Improved long-term survival and renal recovery after acute kidney injury in hospitalized patients: A 20 year experience.

Nephrology (Carlton) 2016 Dec;21(12):1027-1033

Internal Medicine Services, Iceland.

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.
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http://dx.doi.org/10.1111/nep.12698DOI Listing
December 2016

Impact of nephrolithiasis on kidney function.

BMC Nephrol 2015 Aug 28;16:149. Epub 2015 Aug 28.

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1186/s12882-015-0126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551564PMC
August 2015

Lifetime Risk of Stage 3-5 CKD in a Community-Based Sample in Iceland.

Clin J Am Soc Nephrol 2015 Sep 18;10(9):1575-84. Epub 2015 Aug 18.

Division of Nephrology and.

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.
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http://dx.doi.org/10.2215/CJN.00180115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559497PMC
September 2015

Common and rare variants associated with kidney stones and biochemical traits.

Nat Commun 2015 Aug 14;6:7975. Epub 2015 Aug 14.

1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.

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.
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http://dx.doi.org/10.1038/ncomms8975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557269PMC
August 2015

Gender comparison of factors associated with age-related differences in bone mineral density.

Arch Osteoporos 2015 4;10:214. Epub 2015 Aug 4.

School of Medicine, University of Iceland, Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1007/s11657-015-0214-7DOI Listing
July 2016

Midlife Blood Pressure and Late-Life GFR and Albuminuria: An Elderly General Population Cohort.

Am J Kidney Dis 2015 Aug 16;66(2):240-8. Epub 2015 May 16.

Tufts Medical Center, Boston, MA.

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.
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http://dx.doi.org/10.1053/j.ajkd.2015.03.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516633PMC
August 2015

Comparing GFR Estimating Equations Using Cystatin C and Creatinine in Elderly Individuals.

J Am Soc Nephrol 2015 Aug 19;26(8):1982-9. Epub 2014 Dec 19.

Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;

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.
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http://dx.doi.org/10.1681/ASN.2014060607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520174PMC
August 2015
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