Association of eGFR and mortality with use of a joint model: results of a nationwide study in Iceland.

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.

Incidence of and risk factors of chronic kidney disease: results of a nationwide study in Iceland.

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 m2 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.

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

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

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 m2 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.