Predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease: multinational, longitudinal, population based, cohort study.

OBJECTIVE: To train and test a super learner strategy for risk prediction of kidney failure and mortality in people with incident moderate to severe chronic kidney disease (stage G3b to G4). DESIGN: Multinational, longitudinal, population based, cohort study. SETTINGS: Linked population health data from Canada (training and temporal testing), and Denmark and Scotland (geographical testing). PARTICIPANTS: People with newly recorded chronic kidney disease at stage G3b-G4, estimated glomerular filtration rate (eGFR) 15-44 mL/min/1.73 m2. MODELLING: The super learner algorithm selected the best performing regression models or machine learning algorithms (learners) based on their ability to predict kidney failure and mortality with minimised cross-validated prediction error (Brier score, the lower the better). Prespecified learners included age, sex, eGFR, albuminuria, with or without diabetes, and cardiovascular disease. The index of prediction accuracy, a measure of calibration and discrimination calculated from the Brier score (the higher the better) was used to compare KDpredict with the benchmark, kidney failure risk equation, which does not account for the competing risk of death, and to evaluate the performance of KDpredict mortality models. RESULTS: 67 942 Canadians, 17 528 Danish, and 7740 Scottish residents with chronic kidney disease at stage G3b to G4 were included (median age 77-80 years; median eGFR 39 mL/min/1.73 m2). Median follow-up times were five to six years in all cohorts. Rates were 0.8-1.1 per 100 person years for kidney failure and 10-12 per 100 person years for death. KDpredict was more accurate than kidney failure risk equation in prediction of kidney failure risk: five year index of prediction accuracy 27.8% (95% confidence interval 25.2% to 30.6%) versus 18.1% (15.7% to 20.4%) in Denmark and 30.5% (27.8% to 33.5%) versus 14.2% (12.0% to 16.5%) in Scotland. Predictions from kidney failure risk equation and KDpredict differed substantially, potentially leading to diverging treatment decisions. An 80-year-old man with an eGFR of 30 mL/min/1.73 m2 and an albumin-to-creatinine ratio of 100 mg/g (11 mg/mmol) would receive a five year kidney failure risk prediction of 10% from kidney failure risk equation (above the current nephrology referral threshold of 5%). The same man would receive five year risk predictions of 2% for kidney failure and 57% for mortality from KDpredict. Individual risk predictions from KDpredict with four or six variables were accurate for both outcomes. The KDpredict models retrained using older data provided accurate predictions when tested in temporally distinct, more recent data. CONCLUSIONS: KDpredict could be incorporated into electronic medical records or accessed online to accurately predict the risks of kidney failure and death in people with moderate to severe CKD. The KDpredict learning strategy is designed to be adapted to local needs and regularly revised over time to account for changes in the underlying health system and care processes.

Oral anticoagulant treatment and risk of kidney disease-a nationwide, population-based cohort study.

Background: Direct oral anticoagulants (DOACs) are recommended as first-line treatment of atrial fibrillation. Whether DOAC use is associated with lower risks of kidney complications compared with vitamin K antagonists (VKAs) remains unclear. We examined this association in a nationwide, population-based cohort study. Methods: We conducted a cohort study including patients initiating oral anticoagulant treatment within 3 months after an atrial fibrillation diagnosis in Denmark during 2012-18. Using routinely collected creatinine measurements from laboratory databases, we followed patients in an intention-to-treat approach for acute kidney injury (AKI) and chronic kidney disease (CKD) progression. We used propensity-score weighting to balance baseline confounders, computed weighted risks and weighted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing DOACs with VKAs. We performed several subgroup analyses and a per-protocol analysis. Results: We included 32 781 persons with atrial fibrillation initiating oral anticoagulation (77% initiating DOACs). The median age was 75 years, 25% had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2, and median follow-up was 2.3 (interquartile range 1.1-3.9) years. The weighted 1-year risks of AKI were 13.6% in DOAC users and 15.0% in VKA users (HR 0.86, 95% CI 0.82; 0.91). The weighted 5-year risks of CKD progression were 13.9% in DOAC users and 15.4% in VKA users (HR 0.85, 95% CI 0.79; 0.92). Results were similar across subgroups and in the per-protocol analysis. Conclusions: Initiation of DOACs was associated with a decreased risk of AKI and CKD progression compared with VKAs. Despite the potential limitations of observational studies, our findings support the need for increased clinical awareness to prevent kidney complications among patients who initiate oral anticoagulants.

Proton pump inhibitors and the risk of acute kidney injury in cancer patients receiving immune checkpoint inhibitors: A Danish population-based cohort study.

Previous studies have suggested that the use of proton pump inhibitors (PPIs) more than doubles the risk of acute kidney injury (AKI) in cancer patients receiving immune checkpoint inhibitors (ICIs). However, this association may be confounded. Therefore, we conducted a register-based cohort study to examine the risk of AKI in users and nonusers of PPIs among cancer patients treated with ICIs in Denmark from 2011 through 2021 while accounting for a comprehensive range of potential confounders. PPI use was determined based on redeemed prescriptions of PPIs before ICI initiation. We identified laboratory-recorded AKI events within the first year after ICI initiation. We estimated the risks and hazard ratios (HRs) of AKI while accounting for a comprehensive range of confounders (including comorbidities and comedication) by propensity score weighting. Furthermore, we performed an additional per-protocol analysis while accounting for informative censoring by weighting. We identified 10 200 cancer patients including 2749 (27%) users, 6214 (61%) nonusers, and 1237 (12%) former users of PPIs. PPI users had an increased risk of AKI compared to nonusers (1-year risk, 24.7% vs 19.9%; HR, 1.42 [95% confidence interval (CI), 1.29-1.56]); however, this association attenuated when accounting for confounders (weighted 1-year risk, 24.2% vs 23.8%; weighted HR, 1.06 [95% CI, 0.93-1.21]). In the per-protocol analysis, the crude HR was 1.86 (95% CI, 1.63-2.12), while the weighted HR was 1.24 (95% CI, 1.03-1.49). Thus, the association between PPI use and AKI could largely be explained by confounding, suggesting that previous studies may have overestimated the association.

Fifteen-year temporal changes in rates of acute kidney injury among children in Denmark.

BACKGROUND: We aimed to examine temporal changes in the annual rate of acute kidney injury (AKI) in Danish children and associated changes in patient characteristics including potential underlying risk factors. METHODS: In this population-based cohort study, we used plasma creatinine measurements from Danish laboratory databases to identify AKI episodes in children aged 0-17 years from 2007 to 2021. For each child, the first AKI episode per calendar year was included. We estimated the annual crude and sex- and age-standardized AKI rate as the number of children with an AKI episode divided by the total number of children as reported by census numbers. Using Danish medical databases, we assessed patient characteristics including potential risk factors for AKI, such as use of nephrotoxic medication, surgery, sepsis, and perinatal factors. RESULTS: In total, 14,200 children contributed with 16,345 AKI episodes over 15 years. The mean annual AKI rate was 148 (95% CI: 141-155) per 100,000 children. From 2007 to 2021, the annual AKI rate demonstrated minor year-to-year variability without any discernible overall trend. The highest AKI rate was recorded in 2007 at 174 (95% CI: 161-187) per 100,000 children, while the lowest rate occurred in 2012 at 129 (95% CI: 118-140) per 100,000 children. In 2021, the AKI rate was 148 (95% CI: 141-155) per 100,000 children. Characteristics of children with AKI were similar throughout the study period. CONCLUSION: The rate of AKI among Danish children was stable from 2007 to 2021 with little variation in patient characteristics over time.

Regional variation in incidence and prognosis of acute kidney injury.

BACKGROUND: Examining regional variation in acute kidney injury (AKI) and associated outcomes may reveal inequalities and possibilities for optimization of the quality of care. Using the Danish medical databases, we examined regional variation in the incidence, follow-up and prognosis of AKI in Denmark. METHODS: Patients with one or more AKI episodes in 2017 were identified using population-based creatinine measurements covering all Danish residents. Crude and sex-and-age-standardized incidence rates of AKI were estimated using census statistics for each municipality. Adjusted hazard ratios (aHR) of chronic kidney disease (CKD), all-cause death, biochemical follow-up and outpatient contact with a nephrology department after AKI were estimated across geographical regions and categories of municipalities, accounting for differences in demographics, comorbidities, medication use, lifestyle and social factors, and baseline kidney function. RESULTS: We identified 63 382 AKI episodes in 58 356 adults in 2017. The regional standardized AKI incidence rates ranged from 12.9 to 14.9 per 1000 person-years. Compared with the Capital Region of Denmark, the aHRs across regions ranged from 1.04 to 1.25 for CKD, from 0.97 to 1.04 for all-cause death, from 1.09 to 1.15 for biochemical follow-up and from 1.08 to 1.49 for outpatient contact with a nephrology department after AKI. Similar variations were found across municipality categories. CONCLUSIONS: Within the uniform Danish healthcare system, we found modest regional variation in AKI incidence. The mortality after AKI was similar; however, CKD, biochemical follow-up and nephrology follow-up after AKI varied across regions and municipality categories.

Performance of the race-free CKD-EPI creatinine-based eGFR equation in a Danish cohort with measured GFR.

Background: In 2021, an updated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) without a coefficient for race (CKD-EPI21) was developed. The performance of this new equation has yet to be examined among specific patient groups. Methods: We compared the performances of the new CKD-EPI21 equation and the 2009 equation assuming non-Black race (CKD-EPI09-NB) in patients with GFR measured by chromium-51-EDTA plasma clearance at Aarhus University Hospital in Denmark during 2010-18. We examined bias, accuracy, precision and correct classification of chronic kidney disease (CKD) stage using chromium-51-EDTA clearance as the reference standard. We assessed the performance in the total cohort, cancer patients and potential living kidney donors. We also assessed the performance stratified by CKD stage in the total cohort. Results: In this predominantly white population, the CKD-EPI21 equation performed slightly better than the CKD-EPI09-NB equation in both the total cohort (N = 4668), and in cancer patients (N = 3313) and potential living kidney donors (N = 239). In the total cohort, the CKD-EPI21 equation demonstrated a slightly lower median absolute bias (-0.2 versus -4.4 mL/min/1.73 m2), and a similar accuracy, precision and correct classification of CKD stage compared with the CKD-EPI09-NB equation. When stratified by CKD stage, the CKD-EPI09-NB equation performed slightly better than the CKD-EPI21 equation among patients with a measured GFR (mGFR) <60 mL/min/1.73 m2. Conclusions: In a selected cohort of Danish patients with mGFR, the CKD-EPI21 equation performed slightly better than the CKD-EPI09-NB equation except for patients with a mGFR <60 mL/min/1.73 m2, where CKD-EPI09-NB performed slightly better although the differences were considered clinically insignificant.

Sampling from upper and/or lower respiratory tract when diagnosing coronavirus disease 2019 (COVID-19) - results from a Danish cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can replicate in the upper and lower respiratory tract. We aimed to evaluate whether symptom characteristics and symptom duration prior to sampling are associated with test positivity in upper or lower respiratory tract samples. METHODS: We conducted a retrospective cohort study in the Central Denmark Region from 14 April 2020 to 2 November 2020 including hospitalised patients with SARS-CoV-2 reverse transcriptase-polymerase chain reaction samples from both the upper and lower respiratory tract within 48 h and at least one positive test result. RESULTS: Of 122 patients, 101 were positive in both samples (83%), 7 (5%) were positive only in the upper respiratory tract sample, and 14 (11%) were only positive in the lower respiratory tract sample. The median number of symptoms was 4 (IQR 3, 5.75) and 5 (IQR 3, 7), respectively, in patients with only a positive upper respiratory tract sample and in concordant positive patients; while 1 (IQR 1, 3) in patients with only a positive upper respiratory tract sample. 98% (120/122) of patients would have been diagnosed with coronavirus disease 2019 if supplemental sampling from the lower respiratory tract was guided by lower respiratory tract symptoms. No substantial difference in the duration of symptoms was observed across the three patient groups. CONCLUSIONS: The presence of lower respiratory tract symptoms could have been used to determine whether supplemental sampling from the lower respiratory tract was necessary. Symptom duration was not associated with test positivity in the upper or lower respiratory tract.

Kidney function before and after acute kidney injury: a nationwide population-based cohort study.

Background: Acute kidney injury (AKI) is a common and serious condition defined by a rapid decline in kidney function. Data on changes in long-term kidney function following AKI are sparse and conflicting. Therefore, we examined the changes in estimated glomerular filtration rate (eGFR) from before to after AKI in a nationwide population-based setting. Methods: Using Danish laboratory databases, we identified individuals with first-time AKI defined by an acute increase in plasma creatinine (pCr) during 2010 to 2017. Individuals with three or more outpatient pCr measurements before and after AKI were included and cohorts were stratified by baseline eGFR (≥/<60 mL/min/1.73 m2). Linear regression models were used to estimate and compare individual eGFR slopes and eGFR levels before and after AKI. Results: Among individuals with a baseline eGFR ≥60 mL/min/1.73 m2 (n = 64 805), first-time AKI was associated with a median difference in eGFR level of -5.6 mL/min/1.73 m2 [interquartile range (IQR) -16.1 to 1.8] and a median difference in eGFR slope of -0.4 mL/min/1.73 m2/year (IQR -5.5 to 4.4). Correspondingly, among individuals with a baseline eGFR <60 mL/min/1.73 m2 (n = 33 267), first-time AKI was associated with a median difference in eGFR level of -2.2 mL/min/1.73 m2 (IQR -9.2 to 4.3) and a median difference in eGFR slope of 1.5 mL/min/1.73 m2/year (IQR -2.9 to 6.5). Conclusion: Among individuals with first-time AKI surviving to have repeated outpatient pCr measurements, AKI was associated with changes in eGFR level and eGFR slope for which the magnitude and direction depended on baseline eGFR.

Twenty-Three-Year Trends in the Use of Potentially Nephrotoxic Drugs in Denmark.

Background: The occurrence of acute and chronic kidney diseases has been rising in the last decades. Although drug use is a common risk factor for impaired kidney function, changes in utilization of potential nephrotoxic drugs have received little attention. Purpose: To describe temporal trends in the utilization of potentially nephrotoxic drugs in Denmark between 1999 and 2021. Methods: Specific drugs known or suspected to be nephrotoxic were identified in the literature. Data on the sold defined daily doses (DDDs) of potentially nephrotoxic drugs between 1999 and 2021 were retrieved using the Danish Register of Medical Product Statistics. Trends in sales of DDDs per 1000 inhabitants per day were tabulated and illustrated graphically. Results: From 1999 to 2021, the total sale of all selected drugs increased from 286 to 457 DDDs per 1000 inhabitants per day. The overall sale reached a preliminary peak in 2012 with 449 DDDs per 1000 inhabitants per day and remained relatively stable thereafter until reaching an all-time high in 2021 with 457 DDDs per 1000 inhabitants per day. Contributing with the majority in volume, sales of drugs inhibiting the renin-angiotensin-aldosterone system (RAAS) increased dramatically throughout the period. The same was observed for acetaminophen, methotrexate, tacrolimus, and iodinated contrast dye. In contrast, the sales of diuretics, acetylsalicylic acid, and ciclosporin decreased during the last decade of the study period. Conclusion: From 1999-2021 considerable changes in sales of potentially nephrotoxic drugs were observed. In general, the sales increased, in volume predominated by RAAS inhibiting drugs. This increase in sales of potential nephrotoxins could contribute to an increasing occurrence of kidney diseases.

Twenty-four-Year Trends in Incidence and Mortality of Nephrotic Syndrome: A Population-Based Cohort Study.

BACKGROUND: With the increasing prevalence of risk factors for nephrotic syndrome, updated epidemiologic data on the syndrome are needed. We examined its age- and sex-specific incidence, histopathology, and mortality over 24 years. METHODS: This nationwide cohort study included all adults with first-time-recorded nephrotic syndrome in Denmark during 1995-2018 using the Danish National Patient Registry. We obtained data on age, sex, hospital-diagnosed comorbidities, and histopathologic findings. We computed overall, and age- and sex-specific, incidence rates of nephrotic syndrome, 1- and 5-year mortality by calendar period, and 1-year hazard ratios (HRs) of death using Cox models. RESULTS: We identified 3,970 adults with first-time nephrotic syndrome diagnosis. Incidence was highest in men and increased with age to 11.77 per 100,000 person-years (95% confidence interval [CI]: 10.21-13.32) in men aged 80+ years, and 6.56 per 100,000 person-years (95% CI: 5.71-7.41) in women aged 80+ years. Incidence of nephrotic syndrome increased from 3.35 per 100,000 person-years (95% CI: 3.12-3.58) in 1995-2000 to 4.30 per 100,000 person-years (95% CI: 4.05-4.54) in 2013-2018. Over time, 1-year mortality of nephrotic syndrome was stable at 13%-16%, but HR of death was 0.54 (95% CI: 0.42-0.69), adjusted for age, sex, and comorbidities, in 2013-2018 compared with 1995-2000. Subdistribution of glomerulopathies was stable over time with membranous nephropathy and minimal change disease being the most common. CONCLUSION: During 1995-2018, the incidence of recorded adult nephrotic syndrome increased slightly, and the adjusted mortality of nephrotic syndrome decreased markedly. Whether these findings reflect changes in epidemiology or awareness and coding of nephrotic syndrome, remains to be clarified.

Defining measures of kidney function in observational studies using routine health care data: methodological and reporting considerations.

The availability of electronic health records and access to a large number of routine measurements of serum creatinine and urinary albumin enhance the possibilities for epidemiologic research in kidney disease. However, the frequency of health care use and laboratory testing is determined by health status and indication, imposing certain challenges when identifying patients with kidney injury or disease, when using markers of kidney function as covariates, or when evaluating kidney outcomes. Depending on the specific research question, this may influence the interpretation, generalizability, and/or validity of study results. This review illustrates the heterogeneity of working definitions of kidney disease in the scientific literature and discusses advantages and limitations of the most commonly used approaches using 3 examples. We summarize ways to identify and overcome possible biases and conclude by proposing a framework for reporting definitions of exposures and outcomes in studies of kidney disease using routinely collected health care data.

Routine Clinical Care Creatinine Data in Denmark - An Epidemiological Resource for Nationwide Population-Based Studies of Kidney Disease.

Purpose: Creatinine data are key in identifying acute and chronic kidney disease. In Denmark, routine clinical care creatinine data have been collected regionally in the Clinical Laboratory Information System Research Database (LABKA) since the 1990s and nationwide in the Register of Laboratory Results for Research (RLRR) since 2013. Here we describe the geographical coverage of the databases and characteristics of Danish individuals with creatinine tests. This information is pivotal for the design and interpretation of studies using these data to examine kidney disease epidemiology. Patients and Methods: We included all creatinine tests in LABKA and RLRR from 1990 through 2018. The daily number of creatinine tests by municipality and region of residence were plotted and geographical coverage was ascertained. In addition, we characterized a contemporary cohort of creatinine-tested individuals in 2016-2018. Results: During 1990-2018, 61,011,941 creatinine tests were available for 4,647,966 unique Danish residents. The North Denmark Region was the first region to achieve complete reporting in November 2004, and nationwide reporting was complete starting in October 2015. In each year from 2016 to 2018, more than a third of Danish residents had a recorded creatinine measurement, with the highest proportion of tested individuals aged 77-87 years and the lowest proportion aged 3-5 years. During 2016-2018, the creatinine-tested cohort had a median age of 53 years (IQR, 35-67 years) and included 54.3% women. The most common comorbidity was a hospital-based diagnosis of hypertension (12.0%), and the most common prescription drug was angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (15.8%). Conclusion: In combination, the population-based LABKA and RLRR databases provide regional creatinine data with long follow-up and nationwide data for the Danish population. There was considerable variation in the time of complete geographical coverage by region, which needs to be considered when using these data for studies on kidney disease epidemiology.

Harmonization of epidemiology of acute kidney injury and acute kidney disease produces comparable findings across four geographic populations.

There is substantial variability in the reported incidence and outcomes of acute kidney injury (AKI). The extent to which this is attributable to differences in source populations versus methodological differences between studies is uncertain. We used 4 population-based datasets from Canada, Denmark, and the United Kingdom to measure the annual incidence and prognosis of AKI and acute kidney disease (AKD), using a homogenous analytical approach that incorporated KDIGO creatinine-based definitions and subsets of the AKI/AKD criteria. The cohorts included 7 million adults ≥18 years of age between 2011 and 2014; median age 59-68 years, 51.9-54.4% female sex. Age- and sex-standardised incidence rates for AKI or AKD were similar between regions and years; range 134.3-162.4 events/10,000 person years. Among patients who met either KDIGO 48-hour or 7-day AKI creatinine criteria, the standardised 1-year mortality was similar (30.4%-38.5%) across the cohorts, which was comparable to standardised 1-year mortality among patients who met AKI/AKD criteria using a baseline creatinine within 8-90 days prior (32.0%-37.4%). Standardised 1-year mortality was lower (21.0%-25.5% across cohorts) among patients with AKI/AKD ascertained using a baseline creatinine >90 days prior. These findings illustrate that the incidence and prognosis of AKI and AKD based on KDIGO criteria are consistent across 3 high-income countries when capture of laboratory tests is complete, creatinine-based definitions are implemented consistently within but not beyond a 90-day period, and adjustment is made for population age and sex. These approaches should be consistently applied to improve the generalizability and comparability of AKI research and clinical reporting.

NKT cell activation by local α-galactosylceramide administration decreases susceptibility to HSV-2 infection.

NKT cells are a subgroup of T cells, which express a restricted TCR repertoire and are critical for the innate immune responses to viral infections. Activation of NKT cells depends on the major histocompatibility complex-related molecule CD1d, which presents bioactive lipids to NKT cells. The marine sponge derived lipid αGalCer has recently been demonstrated as a specific agonist for activation of human and murine NKT cells. In the present study we investigated the applicability of αGalCer pre-treatment for immune protection against intra-vaginal HSV-2 infection. We found that C57BL/6 WT mice that received local pre-treatment with αGalCer prior to intra-vaginal HSV-2 infection had a lower mean disease score, mortality and viral load in the vagina following infection, compared to mice that did not receive αGalCer pre-treatment. Further, we found increased numbers of CD45 and NK1.1 positive cells in vaginal tissue and elevated levels of IFN-γ in the vaginal tissue and in vaginal fluids 24h after αGalCer pre-treatment. Collectively our data demonstrate a protective effect of αGalCer induced activation of NKT cells in the innate immune protection against viral infection.