Organization and Structures for Detection and Monitoring of CKD Across World Countries and Regions: Observational Data From a Global Survey.

RATIONALE & OBJECTIVE: Established therapeutic interventions effectively mitigate the risk and progression of chronic kidney disease (CKD). Countries and regions have a compelling need for organizational structures that enable early identification of people with CKD who can benefit from these proven interventions. We aimed to report the current global status of CKD detection programs. STUDY DESIGN: A multinational cross-sectional survey. SETTING & PARTICIPANTS: Stakeholders, including nephrologist leaders, policymakers, and patient advocates from 167 countries, participating in the International Society of Nephrology (ISN) survey from June to September 2022. OUTCOMES: Structures for the detection and monitoring of CKD, including CKD surveillance systems in the form of registries, community-based detection programs, case-finding practices, and availability of measurement tools for risk identification. ANALYTICAL APPROACH: Descriptive statistics. RESULTS: Of all participating countries, 19% (n=31) reported CKD registries and 25% (n=40) reported implementing CKD detection programs as part of their national policies. There were variations in CKD detection program, with 50% (n=20) using a reactive approach (managing cases as identified) and 50% (n=20) actively pursuing case-finding in at-risk populations. Routine case-finding for CKD in high-risk populations was widespread, particularly for diabetes (n=152; 91%) and hypertension (n=148; 89%). Access to diagnostic tools, estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), was limited, especially in low-income (LICs) and lower-middle-income (LMICs) countries, at primary (eGFR: LICs 22%, LMICs 39%, UACR: LICs 28%, LMICs 39%) and secondary/tertiary healthcare levels (eGFR: LICs 39%, LMICs 73%, UACR: LICs 44%, LMICs 70%), potentially hindering CKD detection. LIMITATIONS: A lack of detailed data prevented an in-depth analysis. CONCLUSION: This comprehensive survey highlights a global heterogeneity in the organization and structures (surveillance systems, detection programs and tools) for early identification of CKD. Ongoing efforts should be geared toward bridging such disparities to optimally prevent the onset and progression of CKD and its complications.

Peritoneal Dialysis-Related Infections.

Peritoneal dialysis (PD) represents an important treatment choice for patients with kidney failure. It allows them to dialyze outside the hospital setting, facilitating enhanced opportunities to participate in life-related activities, flexibility in schedules, time and cost savings from reduced travel to dialysis centers, and improved quality of life. Despite its numerous advantages, PD utilization has been static or diminishing in parts of the world. PD-related infection, such as peritonitis, exit-site infection, or tunnel infection, is a major concern for patients, caregivers, and health professionals-which may result in hesitation to consider this as treatment or to cease therapy when these complications take place. In this review, the definition, epidemiology, risk factors, prevention, and treatment of PD-related infection on the basis of the contemporary evidence will be described.

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD.

SIGNIFICANCE STATEMENT: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. BACKGROUND: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. RESULTS: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. CONCLUSIONS: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Living Well With Kidney Disease by Patient and Care Partner Empowerment: Kidney Health for Everyone Everywhere.

Living with chronic kidney disease is associated with hardships for patients and their care partners. Empowering patients and their care partners, including family members and friends involved in their care, may help minimize the burden and consequences of chronic kidney disease-related symptoms to enable increased life participation. There is a need to broaden the focus on living well with kidney disease and reengagement in life, including emphasis on the patient being in control. The World Kidney Day Joint Steering Committee has declared 2021 the year of "Living Well with Kidney Disease" in an effort to increase education about and awareness of the important goal of patient empowerment and life participation. This calls for the development and implementation of validated patient-reported outcome measures to assess and address areas of life participation in routine care. It could be supported by regulatory agencies as a metric for quality care or to support labeling claims for medicines and devices. Funding agencies could establish targeted calls for research that address the priorities of patients. Patients with kidney disease and their care partners should feel supported to live well through concerted efforts by kidney care communities, including during pandemics. In the overall wellness program for patients with kidney disease, the need for prevention should be reiterated. Early detection with prolonged course of wellness despite kidney disease, after effective secondary and tertiary prevention programs, should be promoted. World Kidney Day 2021 continues to call for increased awareness of the importance of preventive measures across populations, professionals, and policy makers, applicable to both developed and developing countries.

[Living well with kidney disease by patient and care-partner empowerment: kidney health for everyone everywhere].

Living with chronic kidney disease (CKD) is associated with hardships for patients and their care-partners. Empowering patients and their care-partners, including family members or friends involved in their care, may help minimize the burden and consequences of CKD related symptoms to enable life participation. There is a need to broaden the focus on living well with kidney disease and re-engagement in life, including an emphasis on patients being in control. The World Kidney Day (WKD) Joint Steering Committee has declared 2021 the year of "Living Well with Kidney Disease" in an effort to increase education and awareness on the important goal of patient empowerment and life participation. This calls for the development and implementation of validated patient-reported outcome measures to assess and address areas of life participation in routine care. It could be supported by regulatory agencies as a metric for quality care or to support labelling claims for medicines and devices. Funding agencies could establish targeted calls for research that address the priorities of patients. Patients with kidney disease and their care-partners should feel supported to live well through concerted efforts by kidney care communities including during pandemics. In the overall wellness program for kidney disease patients, the need for prevention should be reiterated. Early detection with a prolonged course of wellness despite kidney disease, after effective secondary and tertiary prevention programs, should be promoted. WKD 2021 continues to call for increased awareness of the importance of preventive measures throughout populations, professionals, and policy makers, applicable to both developed and developing countries.

Vivir con enfermedad renal crónica se asocia con penurias para el paciente y sus cuidadores. Su empoderamiento, que incluye a los familiares o los amigos comprometidos en los cuidados, puede ayudar a minimizar la carga y las consecuencias de los síntomas asociados a la enfermedad renal crónica y permitir las actividades cotidianas. Es necesario ampliar el foco sobre vivir bien con la enfermedad renal y reinsertarse en la vida, con énfasis en que los pacientes tengan sus controles. El World Kidney Day (WKD) Joint Steering Committee (Comité Directivo Conjunto del Día Mundial del Riñón) ha declarado al 2021 como el año de "Vivir bien con enfermedad renal" en un esfuerzo por aumentar la educación y la conciencia sobre el objetivo importante del empoderamiento del paciente y su participación en la vida. Esto reclama el desarrollo e implementación de evaluaciones validadas de la evolución referida por los pacientes para medir e incluir las áreas de participación en la vida en los cuidados de rutina. Esto podría ser respaldado por las agencias reguladoras como una métrica de la calidad de la atención o para respaldar las declaraciones de etiquetado de medicamentos y dispositivos. Las agencias financiadoras podrían establecer llamados dirigidos a investigar las prioridades de los pacientes. Los pacientes con enfermedad renal y sus cuidadores deberían sentirse respaldados para vivir bien mediante esfuerzos concertados de los servicios de atención renal, incluso durante las pandemias. En el programa de bienestar general para pacientes con enfermedad renal, se debe reiterar la necesidad de prevención. Se debe promover la detección precoz acompañada de un curso prolongado de bienestar a pesar de la enfermedad renal, después de programas de prevención efectiva secundaria y terciaria. El WKD 2021 continua su reclamo de aumentar la conciencia de la importancia de las medidas preventivas entre las comunidades, los profesionales y los responsables de las políticas, aplicable tanto a los países desarrollados como a aquellos en vías de desarrollo.

Living well with kidney disease by patient and care-partner empowerment: kidney health for everyone everywhere.

Living with chronic kidney disease (CKD) is associated with hardships for patients and their care partners. Empowering patients and their care partners, including family members and friends involved in their care, may help minimize the burden and consequences of CKD-related symptoms to enable increased life participation. There is a need to broaden the focus on living well with kidney disease and reengagement in life, including emphasis on the patient being in control. The World Kidney Day (WKD) Joint Steering Committee has declared 2021 the year of "Living Well with Kidney Disease" in an effort to increase education about and awareness of the important goal of patient empowerment and life participation. This calls for the development and implementation of validated patient-reported outcome measures to assess and address areas of life participation in routine care. It could be supported by regulatory agencies as a metric for quality care or to support labeling claims for medicines and devices. Funding agencies could establish targeted calls for research that address the priorities of patients. Patients with kidney disease and their care partners should feel supported to live well through concerted efforts by kidney care communities, including during pandemics. In the overall wellness program for patients with kidney disease, the need for prevention should be reiterated. Early detection with prolonged course of wellness despite kidney disease, after effective secondary and tertiary prevention programs, should be promoted. WKD 2021 continues to call for increased awareness of the importance of preventive measures across populations, professionals, and policy makers, applicable to both developed and developing countries.

Kidney Health for Everyone Everywhere, from Prevention to Detection and Equitable Access to Care.

The global burden of chronic kidney disease (CKD) is rapidly increasing with a projection of becoming the 5th most common cause of years of life lost globally by 2040. Aggravatingly, CKD is a major cause of catastrophic health expenditure. The costs of dialysis and transplantation consume up to 3% of the annual healthcare budget in high-income countries. Crucially, however, the onset and progression of CKD is often preventable. In 2020, the World Kidney Day campaign highlights the importance of preventive interventions - be it primary, secondary, or tertiary. This complementing article focuses on outlining and analyzing measures that can be implemented in every country to promote and advance CKD prevention. Primary prevention of kidney disease should focus on the modification of risk factors and addressing structural abnormalities of the kidney and urinary tracts, as well as exposure to environmental risk factors and nephrotoxins. In persons with pre-existing kidney disease, secondary prevention; including blood pressure optimization and glycemic control, should be the main goal of education and clinical interventions. In patients with advanced CKD, management of co-morbidities such as uremia and cardiovascular disease is a highly recommended preventative intervention to avoid or delay dialysis or kidney transplantation. Political efforts are needed to proliferate the preventive approach. While national policies and strategies for non-communicable diseases might be present in a country, specific policies directed toward education and awareness about CKD screening, management and treatment are often lacking. Hence, there is an urgent need to increase the awareness of the importance of preventive measures throughout populations, professionals and policy makers.

Kidney health for everyone everywhere - from prevention to detection and equitable access to care. / Salud renal para todos en todos lados - de la prevención a la detección y acceso equitativo a la atención.

Chronic kidney disease (CKD) is rapidly becoming the 5th most common cause of years of life lost globally by 2040. Crucially, the onset and progression of CKD is often preventable. The World Kidney Day 2020 campaign highlights the importance of preventive interventions on CKD. Primary prevention should focus on risks modification as well as reduced exposure to environmental risk factors and nephrotoxins. Blood pressure optimization and glycemic control should be one of the main interventions in persons with pre-existing kidney disease. Management of co-morbidities such as uremia and cardiovascular disease is highly recommended to avoid or delay dialysis or kidney transplantation. Globally, specific policies directed toward education and awareness about CKD screening, management and treatment are often lacking. Hence, there is an urgent need to increase the awareness of the importance of preventive measures throughout populations, professionals and policy makers around the world.

La enfermedad renal crónica (ERC) será la 5.ta causa más común de años de vida perdidos para 2040. Su comienzo y progresión son, con frecuencia, prevenibles. La campaña del Día Mundial del Riñón 2020 resalta la importancia de las intervenciones preventivas. La prevención primaria debe focalizarse en modificar los riesgos y reducir la exposición a factores ambientales y nefrotoxinas. El control de la tensión arterial y de la glucemia deberían ser una de las principales intervenciones en personas con enfermedad renal pre-existente. El manejo de las comorbilidades (uremia, enfermedad cardiovascular) es altamente recomendado para evitar o postergar el uso de diálisis o trasplante renal. Con frecuencia faltan políticas específicas dirigidas a la educación, la pesquisa, el manejo y el tratamiento de la ERC. Es urgente aumentar la concientización sobre la importancia de medidas preventivas en la población, los profesionales y los responsables de políticas de salud a nivel mundial.

Depression in dialysis patients.

Depression is the most common psychiatric illness in patients with end-stage renal disease (ESRD). The reported prevalence of depression in dialysis population varied from 22.8% (interview-based diagnosis) to 39.3% (self- or clinician-administered rating scales). Such differences were attributed to the overlapping symptoms of uraemia and depression. Systemic review and meta-analysis of observational studies showed that depression was a significant predictor of mortality in dialysis population. The optimal screening tool for depression in dialysis patients remains uncertain. The Beck Depression Inventory (BDI), Patient Health Questionnaire (PHQ) and Center for Epidemiologic Studies Depression Scale (CESD) have been validated for screening purposes. Patients who scored ≥14 using BDI should be referred to a psychiatrist for early evaluation. Structured Clinical Interview for DSM disorders (SCID) remains the gold standard for diagnosis. Non-pharmacological treatment options include cognitive behavioural therapy and exercise training programs. Although frequent haemodialysis may have beneficial effects on patients' physical and mental well-being, it cannot and should not be viewed as a treatment of depression. Selective serotonin reuptake inhibitors (SSRIs) are generally effective and safe in ESRD patients, but most studies were small, non-randomized and uncontrolled. The European Renal Best Practice (ERBP) guideline suggests a trial of SSRI for 8 to 12 weeks in dialysis patients who have moderate-major depression. The treatment effect should be re-evaluated after 12 weeks to avoid prolonging ineffective medication. This review will discuss the current understanding in the diagnosis and management of depression in dialysis patients.

Acute kidney injury: Global health alert.

Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI.

Micro-RNA expression in the urinary sediment of patients with chronic kidney diseases.

BACKGROUND: Evidence indicates that microRNAs (miRNA) play a role in the pathogenesis of chronic kidney diseases (CKD). We explored the possibility of using urinary miRNA as non-invasive biomarkers for CKD. METHODS: We quantified miRNA expression in urinary sediment of 56 CKD patients who underwent kidney biopsy. Patients were followed for 16.2 ± 15.5 months. RESULTS: Patients with diabetic glomerulosclerosis had lower urinary miR-15 expression, while those with IgA nephropathy had higher urinary miR-17 expression, than other diagnosis groups. Baseline proteinuria had significant inverse correlation with urinary expression of miR-15, miR-192, and miR-216a; baseline renal function correlated with urinary expression of miR-15, miR-17, miR-192, and miR-217. The rate of renal function decline correlated with urinary expression of miR-21 (r=0.301, p=0.026) and miR-216a (r=0.515, p < 0.0001). Patients with a high urinary expression of miR-21 and miR-216a had better dialysis-free survival than those with low expression (log rank test, p=0.005 and p=0.003, respectively). CONCLUSIONS: Urinary miR-21 and miR-216a expression correlated with the rate of renal function decline and risk of progression to dialysis-dependent renal failure. Our results suggest that urinary miRNA profiling has the potential of further development as biomarkers of CKD.

Peritoneal dialysis as the first-line renal replacement therapy in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of kidney failure. Peritoneal dialysis (PD) often is avoided because of concerns about hernias and peritonitis. STUDY DESIGN: Retrospective matched-cohort study. SETTING & PARTICIPANTS: 42 consecutive patients with ADPKD and 84 nondiabetic patients matched by time of PD therapy initiation. PREDICTORS: ADPKD and comorbid conditions. OUTCOMES: Patient survival, technique survival, peritonitis-free survival; peritonitis rate; abdominal hernias. MEASUREMENTS: Dialysis adequacy and nutritional indexes; rate of decrease in residual renal function; bacteriologic cause of peritonitis. RESULTS: 5-year actuarial survival of the ADPKD and control groups was 71.0% and 69.7% (P = 0.4), whereas technique survival was 51.6% and 37.3%, respectively (P = 0.2). There was no difference in overall rates of peritonitis between the ADPKD and control groups (0.51 vs 0.53 episodes/patient-year; P = 0.3), and the incidence of Gram-negative peritonitis also was similar (0.16 vs 0.14 episodes/patient year; P = 0.5). Abdominal wall hernia was significantly more common in the ADPKD than control group (14 vs 6 cases; P < 0.001), but all patients were able to resume PD therapy after surgical repair. LIMITATIONS: Retrospective study with limited sample size. CONCLUSION: PD is a feasible treatment option for most patients with ADPKD with end-stage renal disease. Although patients with ADPKD have a higher risk of abdominal wall hernia, their overall survival rate and risk of peritonitis are similar to those of other nondiabetic PD patients.

Expression of microRNAs in the urinary sediment of patients with IgA nephropathy.

BACKGROUND: Micro-RNAs (miRNAs) regulate one-third of all protein-coding genes and are fundamental in the pathophysiology of a wide range of diseases. We studied the expression of several miRNA species (miR-200 family, miR-205 and miR-192) in the urinary sediment of patients with IgA nephropathy (IgAN). METHODS: We studied 43 patients with biopsy-proven IgAN. Urinary expression of miRNAs was determined and compared to that from 13 healthy controls. RESULTS: The levels of urinary miR-200a, miR-200b and miR-429, but not miR-200c, miR-141, miR-205, or miR-192, were down-regulated in patients with IgAN. Proteinuria significantly correlated with urinary expression of miR-200a (r= -0.483, P < 0.001), miR-200b (r= -0.448, P=0.001) and miR-429 (r=-0.466, P=0.001). Baseline renal function significantly correlated with urinary expression of miR-200b (r= 0.512, P < 0.001) and miR-429 (r=0.425, P=0.005). Urinary gene expression of ZEB2 inversely correlated with miR-200b (r=-0.321, P=0.017); and vimentin expression inversely correlated with that of miR-200a (r=-0.360, P=0.007), miR-200b (r=-0.416, $P =$ 0.002) and miR-429 (r=-0.375, P=0.005). After 33.4 +/- 12.6 months, the rate of renal function decline significantly correlated with urinary expression of miR-200b (r=0.316, P=0.034). CONCLUSIONS: Urinary expression of miR-200a, miR-200b and miR-429 were down-regulated in patients with IgAN, and the degree of reduction correlated with disease severity and rate of progression. The results suggested that these miRNA species might play important roles in the pathophysiology of IgAN. Further studies are needed to clarify the role of urinary miRNA repression as a non-invasive marker of IgAN.

Influence of peritoneal dialysis training nurses' experience on peritonitis rates.

BACKGROUND: This study examined the clinical impact of peritoneal dialysis (PD) training nurses regarding Gram-positive peritonitis among incident dialysis patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study included 200 consecutive inception PD patients in a single center from September 1999 through April 2003. Effects of PD nurse trainers on the clinical outcomes of Gram-positive peritonitis were evaluated. RESULTS: A total of 81 patients of 200 incident PD patients (mean age 56.9 yr) developed Gram-positive peritonitis. Mean Gram-positive peritonitis-free time for patients who were trained by nurses with years of experience in the lowest tertile was 58.8 mo, as compared with 47.0 mo in those who were trained by nurses within the intermediate tertile of experience (log-rank test, P = 0.044). After adjustment for diabetes and relevant coexisting medical factors, PD trainers' having > or =3 yr of experience, body mass index, and baseline serum albumin were the only independent risk factors for the time to a first Gram-positive peritonitis. Training nurses with > or =3 yr of experience was associated with more than two-fold increased likelihood of subsequent Gram-positive peritonitis, with an adjusted hazard ratio of 2.24 (95% confidence interval [CI] 1.14 to 4.41; P = 0.020). When the lowest tertile group of trainers was used as the reference group in the Cox proportional hazards regression model, the hazard ratio was 1.94 (95% CI 1.04 to 3.61) for the intermediate tertile and 2.13 (95% CI 1.12 to 4.06) for the highest tertile. Experience of the PD trainers was not predictive of Gram-negative peritonitis. CONCLUSIONS: The finding of negative association between the trainers' length of time in practice and peritonitis incidence reminds us that active continued learning and applying principles of adult learning might be the answers for the nurses to teach the patients.

Carotid intima media thickness predicts cardiovascular diseases in Chinese predialysis patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have a high risk for cardiovascular disease. Ultrasound measurements of the intima media thickness (IMT) in the carotid arteries is a strong predictor for cardiovascular events in the general population and dialysis patients. However, it is unclear whether carotid IMT is useful for the prediction of cardiovascular events in predialysis patients with CKD. The prediction power of carotid ultrasonography for cardiovascular event, rate of renal function decline, and all-cause mortality was tested in a cohort of 203 Chinese patients with stages 3 to 4 CKD. The average IMT was 0.808 +/- 0.196 mm; 121 (59.6%) patients had atherosclerotic plaques visualized. IMT correlated with patient age (r = 0.373, P < 0.001), serum LDL level (r = 0.164, P = 0.021), Charlson's comorbidity score (r = 0.260, P < 0.001), and serum C-reactive protein (r = 0.279, P < 0.001). Carotid IMT was significantly higher in patients with diabetes than in those without diabetes (0.930 +/- 0.254 versus 0.794 +/- 0.184; P = 0.002). At 48 mo, the cardiovascular event-free survival was 94.4, 89.8, 77.7, and 65.9% for IMT quartiles I, II, III, and IV, respectively (log rank test, P = 0.006). By multivariate analysis with the Cox proportional hazard model, each higher quartile of IMT conferred 41.6% (95% confidence interval 6.4 to 88.4%; P = 0.017) excess hazard for developing cardiovascular event. The actuarial survival at 48 mo was 96.3, 98.0, 95.7, and 85.7% for IMT quartiles I, II, III and IV, respectively (log rank test, P = 0.127), and the difference was not statistically significant after Cox proportional hazard model to adjust for confounders. Carotid IMT did not correlate with the rate of renal function decline in these patients. Carotid IMT is a strong predictor of cardiovascular disease in Chinese predialysis patients and may be usefully applied for risk stratification in this group of patients.