When impact trials are not feasible: alternatives to study the impact of prediction models on clinical practice.

Patients with kidney disease have an uncertain future with prognosis varying greatly per patient. To get a better idea of what the future holds and tailor interventions to the individual patient, prediction models can be of great value. Before a prediction model can be applied in practice, its performance should be measured in target populations of interest (i.e., external validation) and whether it helps improve clinical practice (i.e., whether it impacts clinical practice) should be determined. The impact would ideally be determined using an impact trial, but such a trial is often not feasible, and the impact of prediction models is therefore rarely assessed. As a result, prediction models that may not be so impactful may end up in clinical practice and impactful models may not be implemented due to a lack of impact studies. Ultimately, many prediction models end up never being implemented, resulting in much research waste. To allow researchers to get an indication of a prediction model's impact on clinical practice, alternative methods to assess a prediction model's impact are important. In this paper, we discuss several alternatives, including interviews, case-based surveys, decision comparisons, outcome modelling, before-after analyses, and decision curve analyses. We discuss the general idea behind these approaches, including what information can be gathered from such studies and important pitfalls. Lastly, we provide examples of the different alternatives.

The impact of population ageing on the burden of chronic kidney disease.

The burden of chronic kidney disease (CKD) and its risk factors are projected to rise in parallel with the rapidly ageing global population. By 2050, the prevalence of CKD category G3-G5 may exceed 10% in some regions, resulting in substantial health and economic burdens that will disproportionately affect lower-income countries. The extent to which the CKD epidemic can be mitigated depends largely on the uptake of prevention efforts to address modifiable risk factors, the implementation of cost-effective screening programmes for early detection of CKD in high-risk individuals and widespread access and affordability of new-generation kidney-protective drugs to prevent the development and delay the progression of CKD. Older patients require a multidisciplinary integrated approach to manage their multimorbidity, polypharmacy, high rates of adverse outcomes, mental health, fatigue and other age-related symptoms. In those who progress to kidney failure, comprehensive conservative management should be offered as a viable option during the shared decision-making process to collaboratively determine a treatment approach that respects the values and wishes of the patient. Interventions that maintain or improve quality of life, including pain management and palliative care services when appropriate, should also be made available.

Biomarkers in clinical epidemiology studies.

This paper discusses the use of biomarkers in clinical practice and biomedical research. Biomarkers are measurable characteristics that can be used to indicate the presence or absence of a disease or to track the progression of a disease. They can also be used to predict how a patient will respond to a particular treatment. Biomarkers have enriched clinical practice and disease prognosis by providing measurable characteristics that indicate biological processes. They offer valuable insights into disease susceptibility, progression, and treatment response, aiding drug development and personalized medicine. However, developing and implementing biomarkers come with challenges that must be addressed. Rigorous testing, standardization of assays, and consideration of ethical factors are crucial in ensuring the reliability and validity of biomarkers. Reliability is vital in biomarker research. It ensures accurate measurements by preventing biases and facilitating robust correlations with outcomes. Conversely, validation examines which and how many biomarkers correspond to theoretical constructs and external criteria, establishing their predictive value. Multiple biomarkers are sometimes necessary to represent the complex relationship between exposure and disease outcomes accurately. Susceptibility factors are pivotal in disease states' complex interaction among genetic and environmental factors. Gaining a comprehensive understanding of these factors is essential for effectively interpreting biomarker data and maximizing their clinical usefulness. Using well-validated biomarkers can improve diagnoses, more effective treatment evaluations, and enhanced disease prediction. This, in turn, will contribute to better patient outcomes and drive progress in medicine.

Changes in the epidemiology of kidney replacement therapy across Europe in 2020 - the first year of the COVID-19 pandemic: an ERA Registry study.

BACKGROUND: In 2020, the COVID-19 pandemic caused disruptions in kidney replacement therapy (KRT) services worldwide. The aim of this study was to assess the effect of the COVID-19 pandemic in 2020 on the incidence of KRT, kidney transplantation activity, mortality and prevalence of KRT across Europe. METHODS: Patients receiving KRT were included from 17 countries providing data to the European Renal Association Registry. The epidemiology of KRT in 2020 was compared with average data from the period 2017-2019. Also changes occurring during the first and second wave of the pandemic were explored. RESULTS: The incidence of KRT was 6.2% lower in 2020 compared with 2017-2019, with the lowest point (-22.7%) during the first wave in April. The decrease varied across countries, was smaller in males (-5.2%) than in females (-8.2%), and was moderate for peritoneal dialysis (-3.7%) and haemodialysis (-5.4%), but substantial for pre-emptive kidney transplantation (-23.6%). The kidney transplantation rate decreased by 22.5%, reaching a nadir of -80.1% during the first wave, and most for living donor kidney transplants (-30.5%). While in most countries the kidney transplantation rate decreased, in the Nordic/Baltic countries and Greece there was no clear decline. In dialysis patients, mortality increased by 11.4%, and was highest in those aged 65-74 years (16.1%), in those with diabetes as primary renal disease (15.1%), and in those on haemodialysis (12.4%). In transplant recipients, the mortality was 25.8% higher, but there were no subgroups that stood out. In contrast to the rising prevalence of KRT observed over the past decades across Europe, the prevalence at the end of 2020 (N=317787) resembled that of 2019 (N=317077). CONCLUSION: The COVID-19 pandemic has had a substantial impact on the incidence of KRT, kidney transplant activity, mortality of KRT, and prevalence of KRT in Europe with variations across countries.

Time trends in preemptive kidney transplantation in Europe: an era registry study.

BACKGROUND: Preemptive kidney transplantation has better outcomes when compared to transplantation after dialysis. We aimed to examine trends in preemptive kidney transplantation between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives. METHODS: Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around preemptive kidney transplantation. RESULTS: Between 2000 and 2019, 20 251 adults underwent preemptive kidney transplantation (11 169 from living donors, 8937 from deceased donors). The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for living donor kidney recipients (from 21% to 43%) and deceased donor kidney recipients (from 4% to 11%). Large international differences were found. The increase in preemptive kidney transplantation was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor or recipient work-up. Suggested initiatives included raising awareness on the possibility of preemptive kidney transplantation, earlier start and shorter work-up time for recipient and living donor. CONCLUSIONS: Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and deceased donor kidney recipients.

The ERA Registry Annual Report 2021: a summary.

Background: The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities. Methods: Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated. Result: In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012-2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft.

A comparison of the epidemiology of kidney replacement therapy between Europe and the United States: 2021 data of the ERA Registry and the USRDS.

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

The safety of a low protein diet in older adults with advanced chronic kidney disease.

BACKGROUND: A low protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD. METHODS: The EQUAL study is a prospective, observational study, including patients ≥65 years, incident estimated glomerular filtration rate <20 ml/min/1.73m², in six European countries with follow-up up till six years. Nutritional status was assessed by 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (gram protein/kilogram/bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease by ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights. RESULTS: Out of 1738 adults (631 prescribed LPD at any point during follow-up) there were 1319 with repeated SGA measurements of which 267 (20%) declined in SGA ≥ 2 points and 565 (32.5%) died. There was no difference in survival or decline in nutritional status for patients prescribed LPD ≤0.8 g/kg ideal bodyweight (Odds Ratio (OR) for mortality 1.15 (95% Confidence interval (CI) 0.86-1.55) and OR for decline in SGA 1.11 (95% CI 0.74-1.66) in the adjusted models. In patients prescribed LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and higher age >75 years, lower SGA, and higher comorbidity burden for both mortality and nutritional status decline. CONCLUSIONS: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe.

Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry.

BACKGROUND AND HYPOTHESIS: Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death. METHODS: We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence, and survival. RESULTS: The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidence of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium, and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had five-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death (adjusted hazard ratio: 1.8 [95% confidence interval: 1.6-1.9]) compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%). CONCLUSION: The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.

Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study.

Rationale & Objective: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs). Study Design: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2. Setting & Participants: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292). Exposure: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually. Outcome: MACE. Analytical Approach: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE. Results: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE. Limitations: Single protein concentration measurements and limited follow-up time. Conclusions: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies. Plain-Language Summary: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

The epidemiology of renal replacement therapy in two different parts of the world: the Latin American Dialysis and Transplant Registry versus the European Renal Association-European Dialysis and Transplant Association Registry / Datos epidemiológicos del tratamiento sustitutivo de la función renal en dos partes del mundo: el Registro Latinoamericano de Diálisis y Trasplante Renal frente al Registro de la Asociación Europea de Nefrología y Asociación Europea de Diálisis y trasplante / Epidemiologia da terapia renal substitutiva em dois pontos distintos do planeta: Registro Latino-Americano de Diálise e Transplante Renal e Registro da Associação Europeia de Nefrologia e Associação Europeia de Diálise e Transplante

ABSTRACT Objective To compare the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in Latin America and Europe, as well as to study differences in macroeconomic indicators, demographic and clinical patient characteristics, mortality rates, and causes of death between these two populations. Methods We used data from 20 Latin American and 49 European national and subnational renal registries that had provided data to the Latin American Dialysis and Renal Transplant Registry (RLADTR) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry, respectively. The incidence and prevalence of RRT in 2013 were calculated per million population (pmp), overall and by subcategories of age, sex, primary renal disease, and treatment modality. The correlation between gross domestic product and the prevalence of RRT was analyzed using linear regression. Trends in the prevalence of RRT between 2004 and 2013 were assessed using Joinpoint regression analysis. Results In 2013, the overall incidence at day 91 after the onset of RRT was 181 pmp for Latin American countries and 130 pmp for European countries. The overall prevalence was 660 pmp for Latin America and 782 pmp for Europe. In the Latin American countries, the annual increase in the prevalence averaged 4.0% (95% confidence interval (CI): 2.5%-5.6%) from 2004 to 2013, while the European countries showed an average annual increase of 2.2% (95% CI: 2.0%-2.4%) for the same time period. The crude mortality rate was higher in Latin America than in Europe (112 versus 100 deaths per 1 000 patient-years), and cardiovascular disease was the main cause of death in both of those regions. Conclusions There are considerable differences between Latin America and Europe in the epidemiology of RRT for ESRD. Further research is needed to explore the reasons for these differences.

RESUMEN Objetivo Comparar los datos epidemiológicos del tratamiento sustitutivo de la función renal (TSFR) para la nefropatía terminal en América Latina y Europa, así como estudiar las diferencias en cuanto a indicadores macroeconómicos, características demográficas y clínicas de los pacientes, tasas de mortalidad y causas de defunción entre estas dos poblaciones. Métodos Utilizamos los datos de 20 registros renales latinoamericanos y 49 europeos, a nivel nacional y subnacional, que le habían proporcionado datos al Registro Latinoamericano de Diálisis y Trasplante Renal (RLADTR) y al Registro de la Asociación Europea Renal-Asociación Europea de Diálisis y Trasplantes (ERA-EDTA, por su sigla en inglés), respectivamente. Se calculó la incidencia y la prevalencia del TSFR en el 2013 por millón de habitantes, en total y por subcategoría (edad, sexo, nefropatía primaria y modalidad de tratamiento). Se analizó la correlación entre el producto interno bruto y la prevalencia de TSFR mediante regresión lineal. Se evaluaron las tendencias en la prevalencia de TSFR entre el 2004 y el 2013 mediante un análisis de regresiones lineales segmentadas. Resultados En el 2013, la incidencia general al día 91 después de iniciar el tratamiento sustitutivo de la función renal era de 181 por millón de habitantes en los países latinoamericanos y de 130 en los países europeos. La prevalencia general era de 660 por millón de habitantes para América Latina y de 782 para Europa. En los países latinoamericanos, el aumento anual promedio de la prevalencia fue de 4,0% (intervalo de confianza de 95% [IC]: 2,5%-5,6%) entre el 2004 y el 2013, mientras que los países europeos registraron un aumento anual promedio de 2,2% (IC de 95%: 2,0%-2,4%) durante el mismo período. La tasa bruta de mortalidad fue mayor en América Latina que en Europa (112 defunciones por 1 000 años-paciente, en comparación con 100 defunciones), y las enfermedades cardiovasculares fueron la principal causa de muerte en ambas regiones. Conclusiones Hay considerables diferencias entre América Latina y Europa en cuanto a los datos epidemiológicos del tratamiento sustitutivo de la función renal para la nefropatía terminal. Es necesario hacer más investigaciones para explorar las razones de tales diferencias.

RESUMO Objetivo Comparar o perfil epidemiológico de pacientes com doença renal em estágio final (DREF) em terapia renal substitutiva (TRS) na América Latina e na Europa e examinar as diferenças nos indicadores macroeconômicos, características demográficas e clínicas, taxas de mortalidade e causas de morte entre as duas populações de pacientes. Métodos O estudo foi baseado em informação de 20 registros latino-americanos e 49 registros nacionais e subnacionais europeus que haviam fornecido dados ao Registro Latino-Americano de Diálise e Transplante Renal (RLADTR) e Registro da Associação Europeia de Nefrologia e Associação Europeia de Diálise e Transplante (ERA-EDTA), respectivamente. A incidência e a prevalência de TRS em 2013 foram calculadas por milhão de habitantes (pmh), geral e por subcategorias de idade, sexo, doença renal primária e modalidade de tratamento. A correlação entre o produto interno bruto (PIB) e a prevalência de TRS foi analisada com o uso de regressão linear. Tendências na prevalência de TRS entre 2004 e 2013 foram analisadas com o uso de regressão linear segmentada. Resultados Em 2013, a incidência geral ao dia 91 do início de TRS foi 181 pmh nos países latino-americanos e 130 pmh nos países europeus. Observou-se uma prevalência geral de TRS de 660 pmh na América Latina e 782 pmh na Europa. No período 2004-2013, o aumento médio anual da prevalência foi de 4,0% (intervalo de confiança de 95% [IC 95%] 2,5%-5,6%) nos países latino-americanos, enquanto que houve um aumento médio anual de 2,2% (IC 95% 2,0%-2,4%) nos países europeus. A taxa de mortalidade bruta foi maior na América Latina que na Europa (112 versus 100 óbitos por 1.000 pacientes-anos) e doença cardiovascular foi a principal causa de morte em ambas as regiões. Conclusões Existem diferenças consideráveis entre a América Latina e a Europa no perfil epidemiológico dos pacientes com DREF em TRS. Outras pesquisas devem ser realizadas para investigar mais a fundo estas diferenças.