commentary
In sum, even when compared with a population enriched for CVD and CVD risk factors, individuals with CKD performed modestly worse on a cognitive battery testing multiple domains. Despite the many caveats associated with a crosssectional study as well as this study’s modest sample size, these findings, when viewed in the context of existing data, suggest that risk factors for cerebrovascular disease may be particularly important in the pathogenesis of cognitive impairment in people with CKD. Critically, clinicians should be aware of the high rates of cognitive impairment that occur even in earlier stages of CKD. Although initial cognitive deficits may be subtle, these deficits may herald future, more debilitating impairment. Future studies should evaluate whether treatments targeting vascular disease risk factors, possibly including inflammation, can prevent or slow the development of cognitive impairment in individuals with CKD. DISCLOSURE
The authors declared no competing interests. ACKNOWLEDGMENTS
D.A.D is funded by the American Society of Nephrology Research Fellowship Program. D.E.W work on cognition in kidney disease is funded via National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) grant R01-DK090401.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Griva K, Stygall J, Hankins M et al. Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 2010; 56: 693–703. Kurella M, Chertow GM, Luan J et al. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 2004; 52: 1863–1869. Sarnak MJ, Tighiouart H, Scott TM et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013; 80: 471–480. Murray AM, Tupper DE, Knopman DS et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006; 67: 216–223. Seliger SL, Siscovick DS, Stehman-Breen CO et al. Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 2004; 15: 1904–1911. Drew DA, Bhadelia R, Tighiouart H et al. Anatomic brain disease in hemodialysis patients: a cross-sectional study. Am J Kidney Dis 2013; 61: 271–278. Weiner DE, Scott TM, Giang LM et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011; 58: 773–781.
Kidney International (2014) 85
8.
9.
10.
11.
12.
13.
Kalirao P, Pederson S, Foley RN et al. Cognitive impairment in peritoneal dialysis patients. Am J Kidney Dis 2011; 57: 612–620. Weiner DE, Bartolomei K, Scott T et al. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009; 53: 438–447. Barzilay JI, Fitzpatrick AL, Luchsinger J et al. Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008; 52: 216–226. Kurella Tamura M, Unruh ML, Nissenson AR et al. Effect of more frequent hemodialysis on cognitive function in the Frequent Hemodialysis Network Trials. Am J Kidney Dis 2013; 61: 228–237. Seidel UK, Gronewold J, Volsek M et al. The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease. Kidney Int 2014; 85: 693–702. Sorensen EP, Sarnak MJ, Tighiouart H et al. The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients. Am J Kidney Dis 2012; 60: 417–426.
14.
15.
16.
17.
18.
19.
Agganis BT, Weiner DE, Giang LM et al. Depression and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2010; 56: 704–712. Chen H-Y, Cheng I-C, Pan Y-J et al. Cognitivebehavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. Kidney Int 2011; 80: 415–422. Peacock T, Shihabi Z, Bleyer A et al. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73: 1062–1068. van Oijen M, Witteman JC, Hofman A et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005; 36: 2637–2641. Weiner DE, Tighiouart H, Elsayed EF et al. The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD. Am J Kidney Dis 2008; 51: 212–223. Jenny NS, French B, Arnold AM et al. Longterm assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. J Gerontol A Biol Sci Med Sci 2012; 67: 970–976.
see clinical investigation on page 686
Better prevention than cure: optimal patient preparation for renal replacement therapy Xiaoyan Huang1,2 and Juan Jesu´s Carrero1,3 A generous proportion of end-stage renal disease patients may not be adequately prepared for initiation of renal replacement therapy (RRT). Here we review potential benefits of early patient referral to nephrologists and optimal preparation for RRT. We place this evidence in the context of the epidemiological study by Kurella Tamura et al., which shows that voluntary community kidney disease screening and education is associated with better patient preparation and, importantly, improved survival upon initiation of RRT. Kidney International (2014) 85, 507–510. doi:10.1038/ki.2013.438
1 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 2Division of Nephrology, Peking University Shenzhen Hospital, Peking University, Shenzhen, China and 3Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence: Juan Jesu´s Carrero, Divisions of Renal Medicine and Baxter Novum, Karolinska University Hospital at Huddinge K56, Karolinska Institutet, SE-14186 Stockholm, Sweden. E-mail: [email protected]
The population prevalence of chronic kidney disease (CKD) exceeds 12% and is more than 50% in high-risk subpopulations. Nonetheless, awareness remains low in the community and among many physicians. In patients who progress to end-stage renal disease (ESRD), renal replacement therapy (RRT) is a life-saving necessity. Preparation for ESRD initiation has received increasing attention for disease 507
commentary
Screening and monitoring of CKD
Early referral to a nephrologist
Multidisciplinary strategies: • Dietary instruction • Modality education • Treatment of comorbidities • Control of complications • Early placement of permanent dialysis access • Timely initiation of dialysis • Preemptive kidney transplantation
Benefits (before RRT): • Retard decline in kidney function • Reduced death and hospitalization before reaching ESRD
Benefits (on RRT): • Better status at initiation of RRT • High rate of transplantation • Reduced death and hospitalization on RRT
Potential harms: • False-positive diagnosis, overdiagnosis • Anxiety • Unnecessary visits, tests, and treatments • Hyperkalemia • Costs
Figure 1 | The early screening and monitoring program for chronic kidney disease, subsequent multidisciplinary strategies, and their benefits and potential harms. In an early screening and monitoring program, participants with chronic kidney disease are informed and counseled to timely refer to a nephrologist. Optimal preparation for end-stage renal disease includes the multidisciplinary strategies listed, which are associated with a number of benefits before and after initiation of renal replacement therapy and potential harms. CKD, chronic kidney disease; ESRD, end-stage renal disease; RRT, renal replacement therapy.
prevention since the publication of disappointing figures regarding high rates of hospitalization and death on RRT due to suboptimal patient preparation. There has been general consensus that patients with CKD should receive multidisciplinary comprehensive clinical management by nephrologists for at least 6 months before initiation of RRT.1 Current guidelines recommend dietary instruction, modality education, treatment of comorbidities, and prevention and control of complications. In addition, specific preparation for forthcoming RRT is emphasized, including but not limited to planned early placement of permanent dialysis access and, if possible, assessment and referral for preemptive transplantation (Figure 1). Despite these efforts, data from the United States suggest that a big gap 508
remains in care for the transitioning of patients with advanced CKD to RRT.2,3 One-third of patients do not see a nephrologist and only 13% have seen a dietitian before initiation of RRT. More than 50% of potentially eligible patients do not even receive information about the possibility of peritoneal dialysis or transplantation. In 2010, only 36% of incident hemodialysis patients had an arteriovenous access in use or maturing during their first outpatient dialysis treatment. These realities are not limited to the United States but extend to many other countries, as highlighted by the Dialysis Outcomes and Practice Patterns Study (DOPPS):4 Approximately 20% of patients starting hemodialysis in countries participating in DOPPS (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand,
Spain, Sweden, the United Kingdom, and the United States) have not seen a nephrologist before approaching dialysis (o1 month); and preceding control of CKD risk factors such as diabetes, hypertension, dyslipidemia, anemia, malnutrition, or mineral and bone disorder was also far from acceptable levels of recommended care. The primary barrier to improving outcomes is failure to deliver ideal care to those who need it.5 Although no randomized controlled trials so far exist, a body of observational evidence supports several benefits linked with adequate ESRD patient preparation, such as better control of nutritional status, anemia, osteodystrophy, or acidosis. During predialytic stages of CKD, patients under multidisciplinary educational programs and team care exhibit slower decline in kidney function and, ultimately, are more likely to initiate RRT instead of dying before reaching ESRD.6 Early referral to nephrologists is associated with a higher likelihood of predialytic transplantation, better metabolic status at start of RRT, and a shorter duration of the initial hospital stay.7 After initiation of RRT, patients referred earlier to specialist care have decreased risks of mortality and hospitalization.8 In August 2000, the US National Kidney Foundation (NKF) launched the Kidney Early Evaluation Program (KEEP).9 KEEP is a screening program for CKD in high-risk individuals, including adults with a history of diabetes or hypertension or who have a family history of these conditions and/or of kidney disease. KEEP now serves as a voluntary free communitybased health screening program, providing early CKD detection and raising public awareness of CKD and its risk factors. The evaluation process consists of six stations: registration; consent and screening questionnaire; physical measurements; urine and blood testing; clinician consultation; and screening review. Laboratory results are reviewed by NKF medical staff, and participants with abnormal results are directly contacted. For participants with manifest CKD, information regarding treatment Kidney International (2014) 85
commentary
of complications is given to physicians involved. This program is complemented with follow-up questionnaires to evaluate the effectiveness of the screening, increase awareness of CKD, and guarantee the clinical findings as actionable for participants and physicians. In June 2008, KEEP developed into a longitudinal program involving annual reexaminations for changes in risk factors, disease state, and CKD progression. Owing to its success, KEEP has been recognized as a model of ‘best practice’ in chronic disease screening by the US Centers for Disease Control and Prevention, and it is being replicated or emulated in other countries, such as Australia, Mexico, and Japan. Kurella Tamura et al.10 (this issue) report an observational study comparing ESRD preparation and survival between KEEP participants and control (supposedly unprepared) patients. A total of 595 adults who developed ESRD between 2005 and 2010 after participating in KEEP were selected. From the US Renal Data System database, the investigators identified nonKEEP adult patients who developed ESRD during the same period and lived in the same regions as KEEP participants. To their credit, the investigators constructed a propensity score model to estimate the likelihood of KEEP enrollment based on demographic and clinical characteristics. Using the propensity scores, they randomly matched each KEEP participant to five non-KEEP patients who had the same or a similar probability of KEEP enrollment. The study thus included 595 KEEP and 2975 non-KEEP patients. The main outcomes were indicators of ESRD preparation and mortality after ESRD. Participation in KEEP was associated with significantly higher rates of pre-ESRD nephrologist care, peritoneal dialysis as a modality choice, preemptive transplant wait-listing, and transplantation through end of followup. KEEP participants were also more likely to use an arteriovenous fistula or graft and to have a maturing arteriovenous fistula or graft at the first outpatient dialysis. Rates of preemptive transplantation were not significantly Kidney International (2014) 85
different between the two groups. During a median follow-up of 1.6 years after the onset of ESRD, there were 175 and 1037 deaths among KEEP and non-KEEP patients, respectively (hazard ratio 0.80, 95% confidence interval 0.68–0.94). This difference in mortality was at least partly explained by ESRD preparation. Unfortunately, potential harms of the CKD screening and education program (such as psychological distress and increased burden of medical visits and tests), as well as the costs, were not evaluated in the present study, making it impossible to fully ascertain the benefits, risks, and cost-effectiveness of this program. These observational data do tell an informative and optimistic story of ESRD preparation and reduction in ESRD mortality through improved preESRD care. Whereas previous studies have mainly focused on prevention during predialytic stages, these findings add to and broaden the reach of preESRD education efforts. One clinically relevant implication of this study is that CKD screening and education programs may improve ESRD preparation, as evidenced by several clinical domains spanning from pre-ESRD nephrology care and use of peritoneal dialysis to access to kidney transplantation, most of which have been proposed as approaches to reduce mortality of ESRD patients. More inspiring is the observation that KEEP participation was associated with a 5.4% absolute reduction in mortality over a median 1.6 years of follow-up from RRT initiation. Albeit relatively simple, such a preventive strategy could improve patient outcomes, implying clinical applicability. Despite this, indicators of ESRD preparation even in KEEP participants were still not optimal: Strikingly, there were still around 25% of patients who had not been cared for by a nephrologist when they progressed to ESRD. The rate of preemptive transplantation remained low, although the overall rates of transplantation were higher among KEEP versus non-KEEP patients. Also, only approximately 25% of patients had a functioning arteriovenous fistula or graft at first outpatient
hemodialysis; nonetheless, an additional 20% of patients already had a maturing arteriovenous fistula or graft at that time. Although the latter may reflect reimbursement policies in the United States, one should consider that preparation of patients, despite using a catheter for access, still leads to an improvement in patient survival. This then raises the interesting question of whether catheter use per se is such a risk factor for death, or whether the increased risk of death reported with catheters has been, in part, confounded by unplanned starters. From a patient perspective, a recent US single-center study11 demonstrated that the majority of patients still feel unprepared and illinformed about the initiation of dialysis, especially concerning the risks and burdens of dialysis or the option of not starting the therapy. About onethird of the patients perceived that the decision to start dialysis and the decision of the modality were made by the doctor. All in all, the study by Kurella Tamura et al.10 brings optimism and fresh air to the issue of the value of screening and disease educational preventive strategies. Although such observations may, for some, be considered a truism, there is a compelling (human) need to remind us that increased screening and patient preparation certainly pay off in the fight against disease. Originating from the ancient Chinese masterpiece the Suwen of the Huangdi Neijing, the principle of ‘preventive treatment of disease’ has been a medical axiom for more than two millennia. Nevertheless, appropriately designed interventional trials may be needed to prove a causal effect of patient preparation on survival after dialysis initiation. In this regard the study by Kurella Tamura et al.10 provides valuable sample-size estimations, as, for an intervention with this size effect, the number needed to treat to prevent one ESRD death would be 18. More stringent efforts are certainly needed from all involved in nephrology care and community screening policies. DISCLOSURE
The authors declared no competing interests. 509
commentary
ACKNOWLEDGMENTS
The authors acknowledge grant support from the Swedish Research Council and the Centre for Gender Medicine at Karolinska Institutet.
5. 6.
7.
REFERENCES 1.
2.
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4.
Bolton WK. Renal physicians association clinical practice guideline: appropriate patient preparation for renal replacement therapy: guideline number 3. J Am Soc Nephrol 2003; 14: 1406–1410. Mehrotra R, Marsh D, Vonesh E et al. Patient education and access of ESRD patients to renal replacement therapies beyond in-center hemodialysis. Kidney Int 2005; 68: 378–390. Renal US. Data System. 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health: Bethesda, MD, USA, 2012. Hasegawa T, Bragg-Gresham JL, Yamazaki S et al. Greater first-year survival on hemodialysis in facilities in which patients are provided earlier and more frequent pre-nephrology visits. Clin J Am Soc Nephrol 2009; 4: 595–602.
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Narva AS. Optimal preparation for ESRD. Clin J Am Soc Nephrol 2009; 4(Suppl 1): S110–S113. Chen YR, Yang Y, Wang SC et al. Effectiveness of multidisciplinary care for chronic kidney disease in Taiwan: a 3-year prospective cohort study. Nephrol Dial Transplant 2013; 28: 671–682. Goransson LG, Bergrem H. Consequences of late referral of patients with end-stage renal disease. J Intern Med 2001; 250: 154–159. Smart NA, Titus TT. Outcomes of early versus late nephrology referral in chronic kidney disease: a systematic review. Am J Med 2011; 124: e2. McCullough PA, Brown WW, Gannon MR et al. Sustainable community-based CKD screening methods employed by the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2011; 57: S4–S8. Kurella Tamura M, Li S, Chen S-C et al. Educational programs improve the preparation for dialysis and survival of patients with chronic kidney disease. Kidney Int 2014; 85: 686–692. Song MK, Lin FC, Gilet CA et al. Patient perspectives on informed decision-making surrounding dialysis initiation. Nephrol Dial Transplant 2013; 28: 2815–2823.
see clinical investigation on page 703
Extracellular hydration, cardiovascular risk, and the interstitium: a three-dimensional view Sandip Mitra1 Volume expansion is a major contributor to poor cardiovascular outcomes in kidney disease. The relationship of extracellular volume (ECV) overload to cardiovascular changes in chronic kidney disease (CKD) remains speculative. Recent studies are challenging traditional concepts and providing new insight into mechanisms and the relationship of ECV to cardiovascular health. A dynamic role of the extracellular interstitium in inducing cardiovascular risk is emerging in CKD. Kidney International (2014) 85, 510–512. doi:10.1038/ki.2013.481
fluid (in up to 80% patients) has been demonstrated consistently. Fluid overload is a condition linked to increased morbidity and mortality in patients with chronic kidney disease (CKD),1 acute kidney injury, or heart failure and in the critically ill.2 Effective salt and water management improves survival in patients on dialysis,3 and in acutely ill patients in intensive care. It is traditionally believed that failure of natriuresis and volume overload directly induce vascular remodeling, hypertension, left ventricular hypertrophy, heart failure, and vascular events such as strokes and myocardial infarction. The burden of cardiovascular disease in stages of CKD could therefore be considered a direct result of loss of salt and water autoregulation by the kidney. Hung et al.4 (this issue) describe subclinical and relatively modest extracellular overhydration (41.1 liters) as a strong risk factor for poor cardiovascular outcomes, in an observational study in 338 Taiwanese patients with stage 3–5 CKD and a mean age of 65.7±13.5 years, followed up in outpatient clinics with the use of body composition measurements. Overhydration is shown to be strongly related to cardiovascular dysfunction with an independent association with clinical factors (diabetes mellitus, systolic blood pressure, male gender, and preexisting cardiovascular disease) and biomarkers (albumin, N-terminal prohormone brain natriuretic peptide, ln tumor necrosis factor-a, and ln urine protein creatinine ratio). The association of subclinical overload with cardiovascular risk is striking in this clinical setting. However, the findings do not represent causality and highlight several issues that deserve consideration. DETECTION OF SUBCLINICAL FLUID OVERLOAD
1
Department of Renal Medicine, Manchester Academic Health Science Centre, Biomedical Research Centre, Central Manchester Foundation Trust and University of Manchester, Manchester, UK Correspondence: Sandip Mitra, Department of Renal Medicine, Central Manchester Foundation Trust, Manchester Academy Health Science Centre, Oxford Road, Manchester M139WL, UK. E-mail: [email protected] 510
The accumulation of excess body fluid (previously termed ‘dropsy’) is depicted in many ancient paintings. The Egyptians called it ‘flooding of the heart’ and recognized that excess fluid was at its origin. End-stage kidney failure has been the most common disease model in which such overwhelming retention of
Detection of subclinical extracellular volume (ECV) overload poses a particular challenge. Edema is the classical sign but lacks sensitivity and specificity. With failure of homeostatic control by the kidneys, plasma volume expands. The rise in intravascular hydrostatic pressure causes an imbalance of Kidney International (2014) 85
In sum, even when compared with a population enriched for CVD and CVD risk factors, individuals with CKD performed modestly worse on a cognitive battery testing multiple domains. Despite the many caveats associated with a crosssectional study as well as this study’s modest sample size, these findings, when viewed in the context of existing data, suggest that risk factors for cerebrovascular disease may be particularly important in the pathogenesis of cognitive impairment in people with CKD. Critically, clinicians should be aware of the high rates of cognitive impairment that occur even in earlier stages of CKD. Although initial cognitive deficits may be subtle, these deficits may herald future, more debilitating impairment. Future studies should evaluate whether treatments targeting vascular disease risk factors, possibly including inflammation, can prevent or slow the development of cognitive impairment in individuals with CKD. DISCLOSURE
The authors declared no competing interests. ACKNOWLEDGMENTS
D.A.D is funded by the American Society of Nephrology Research Fellowship Program. D.E.W work on cognition in kidney disease is funded via National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) grant R01-DK090401.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Griva K, Stygall J, Hankins M et al. Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 2010; 56: 693–703. Kurella M, Chertow GM, Luan J et al. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 2004; 52: 1863–1869. Sarnak MJ, Tighiouart H, Scott TM et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013; 80: 471–480. Murray AM, Tupper DE, Knopman DS et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006; 67: 216–223. Seliger SL, Siscovick DS, Stehman-Breen CO et al. Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 2004; 15: 1904–1911. Drew DA, Bhadelia R, Tighiouart H et al. Anatomic brain disease in hemodialysis patients: a cross-sectional study. Am J Kidney Dis 2013; 61: 271–278. Weiner DE, Scott TM, Giang LM et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011; 58: 773–781.
Kidney International (2014) 85
8.
9.
10.
11.
12.
13.
Kalirao P, Pederson S, Foley RN et al. Cognitive impairment in peritoneal dialysis patients. Am J Kidney Dis 2011; 57: 612–620. Weiner DE, Bartolomei K, Scott T et al. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009; 53: 438–447. Barzilay JI, Fitzpatrick AL, Luchsinger J et al. Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008; 52: 216–226. Kurella Tamura M, Unruh ML, Nissenson AR et al. Effect of more frequent hemodialysis on cognitive function in the Frequent Hemodialysis Network Trials. Am J Kidney Dis 2013; 61: 228–237. Seidel UK, Gronewold J, Volsek M et al. The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease. Kidney Int 2014; 85: 693–702. Sorensen EP, Sarnak MJ, Tighiouart H et al. The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients. Am J Kidney Dis 2012; 60: 417–426.
14.
15.
16.
17.
18.
19.
Agganis BT, Weiner DE, Giang LM et al. Depression and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2010; 56: 704–712. Chen H-Y, Cheng I-C, Pan Y-J et al. Cognitivebehavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. Kidney Int 2011; 80: 415–422. Peacock T, Shihabi Z, Bleyer A et al. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73: 1062–1068. van Oijen M, Witteman JC, Hofman A et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005; 36: 2637–2641. Weiner DE, Tighiouart H, Elsayed EF et al. The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD. Am J Kidney Dis 2008; 51: 212–223. Jenny NS, French B, Arnold AM et al. Longterm assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. J Gerontol A Biol Sci Med Sci 2012; 67: 970–976.
see clinical investigation on page 686
Better prevention than cure: optimal patient preparation for renal replacement therapy Xiaoyan Huang1,2 and Juan Jesu´s Carrero1,3 A generous proportion of end-stage renal disease patients may not be adequately prepared for initiation of renal replacement therapy (RRT). Here we review potential benefits of early patient referral to nephrologists and optimal preparation for RRT. We place this evidence in the context of the epidemiological study by Kurella Tamura et al., which shows that voluntary community kidney disease screening and education is associated with better patient preparation and, importantly, improved survival upon initiation of RRT. Kidney International (2014) 85, 507–510. doi:10.1038/ki.2013.438
1 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 2Division of Nephrology, Peking University Shenzhen Hospital, Peking University, Shenzhen, China and 3Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence: Juan Jesu´s Carrero, Divisions of Renal Medicine and Baxter Novum, Karolinska University Hospital at Huddinge K56, Karolinska Institutet, SE-14186 Stockholm, Sweden. E-mail: [email protected]
The population prevalence of chronic kidney disease (CKD) exceeds 12% and is more than 50% in high-risk subpopulations. Nonetheless, awareness remains low in the community and among many physicians. In patients who progress to end-stage renal disease (ESRD), renal replacement therapy (RRT) is a life-saving necessity. Preparation for ESRD initiation has received increasing attention for disease 507
commentary
Screening and monitoring of CKD
Early referral to a nephrologist
Multidisciplinary strategies: • Dietary instruction • Modality education • Treatment of comorbidities • Control of complications • Early placement of permanent dialysis access • Timely initiation of dialysis • Preemptive kidney transplantation
Benefits (before RRT): • Retard decline in kidney function • Reduced death and hospitalization before reaching ESRD
Benefits (on RRT): • Better status at initiation of RRT • High rate of transplantation • Reduced death and hospitalization on RRT
Potential harms: • False-positive diagnosis, overdiagnosis • Anxiety • Unnecessary visits, tests, and treatments • Hyperkalemia • Costs
Figure 1 | The early screening and monitoring program for chronic kidney disease, subsequent multidisciplinary strategies, and their benefits and potential harms. In an early screening and monitoring program, participants with chronic kidney disease are informed and counseled to timely refer to a nephrologist. Optimal preparation for end-stage renal disease includes the multidisciplinary strategies listed, which are associated with a number of benefits before and after initiation of renal replacement therapy and potential harms. CKD, chronic kidney disease; ESRD, end-stage renal disease; RRT, renal replacement therapy.
prevention since the publication of disappointing figures regarding high rates of hospitalization and death on RRT due to suboptimal patient preparation. There has been general consensus that patients with CKD should receive multidisciplinary comprehensive clinical management by nephrologists for at least 6 months before initiation of RRT.1 Current guidelines recommend dietary instruction, modality education, treatment of comorbidities, and prevention and control of complications. In addition, specific preparation for forthcoming RRT is emphasized, including but not limited to planned early placement of permanent dialysis access and, if possible, assessment and referral for preemptive transplantation (Figure 1). Despite these efforts, data from the United States suggest that a big gap 508
remains in care for the transitioning of patients with advanced CKD to RRT.2,3 One-third of patients do not see a nephrologist and only 13% have seen a dietitian before initiation of RRT. More than 50% of potentially eligible patients do not even receive information about the possibility of peritoneal dialysis or transplantation. In 2010, only 36% of incident hemodialysis patients had an arteriovenous access in use or maturing during their first outpatient dialysis treatment. These realities are not limited to the United States but extend to many other countries, as highlighted by the Dialysis Outcomes and Practice Patterns Study (DOPPS):4 Approximately 20% of patients starting hemodialysis in countries participating in DOPPS (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand,
Spain, Sweden, the United Kingdom, and the United States) have not seen a nephrologist before approaching dialysis (o1 month); and preceding control of CKD risk factors such as diabetes, hypertension, dyslipidemia, anemia, malnutrition, or mineral and bone disorder was also far from acceptable levels of recommended care. The primary barrier to improving outcomes is failure to deliver ideal care to those who need it.5 Although no randomized controlled trials so far exist, a body of observational evidence supports several benefits linked with adequate ESRD patient preparation, such as better control of nutritional status, anemia, osteodystrophy, or acidosis. During predialytic stages of CKD, patients under multidisciplinary educational programs and team care exhibit slower decline in kidney function and, ultimately, are more likely to initiate RRT instead of dying before reaching ESRD.6 Early referral to nephrologists is associated with a higher likelihood of predialytic transplantation, better metabolic status at start of RRT, and a shorter duration of the initial hospital stay.7 After initiation of RRT, patients referred earlier to specialist care have decreased risks of mortality and hospitalization.8 In August 2000, the US National Kidney Foundation (NKF) launched the Kidney Early Evaluation Program (KEEP).9 KEEP is a screening program for CKD in high-risk individuals, including adults with a history of diabetes or hypertension or who have a family history of these conditions and/or of kidney disease. KEEP now serves as a voluntary free communitybased health screening program, providing early CKD detection and raising public awareness of CKD and its risk factors. The evaluation process consists of six stations: registration; consent and screening questionnaire; physical measurements; urine and blood testing; clinician consultation; and screening review. Laboratory results are reviewed by NKF medical staff, and participants with abnormal results are directly contacted. For participants with manifest CKD, information regarding treatment Kidney International (2014) 85
commentary
of complications is given to physicians involved. This program is complemented with follow-up questionnaires to evaluate the effectiveness of the screening, increase awareness of CKD, and guarantee the clinical findings as actionable for participants and physicians. In June 2008, KEEP developed into a longitudinal program involving annual reexaminations for changes in risk factors, disease state, and CKD progression. Owing to its success, KEEP has been recognized as a model of ‘best practice’ in chronic disease screening by the US Centers for Disease Control and Prevention, and it is being replicated or emulated in other countries, such as Australia, Mexico, and Japan. Kurella Tamura et al.10 (this issue) report an observational study comparing ESRD preparation and survival between KEEP participants and control (supposedly unprepared) patients. A total of 595 adults who developed ESRD between 2005 and 2010 after participating in KEEP were selected. From the US Renal Data System database, the investigators identified nonKEEP adult patients who developed ESRD during the same period and lived in the same regions as KEEP participants. To their credit, the investigators constructed a propensity score model to estimate the likelihood of KEEP enrollment based on demographic and clinical characteristics. Using the propensity scores, they randomly matched each KEEP participant to five non-KEEP patients who had the same or a similar probability of KEEP enrollment. The study thus included 595 KEEP and 2975 non-KEEP patients. The main outcomes were indicators of ESRD preparation and mortality after ESRD. Participation in KEEP was associated with significantly higher rates of pre-ESRD nephrologist care, peritoneal dialysis as a modality choice, preemptive transplant wait-listing, and transplantation through end of followup. KEEP participants were also more likely to use an arteriovenous fistula or graft and to have a maturing arteriovenous fistula or graft at the first outpatient dialysis. Rates of preemptive transplantation were not significantly Kidney International (2014) 85
different between the two groups. During a median follow-up of 1.6 years after the onset of ESRD, there were 175 and 1037 deaths among KEEP and non-KEEP patients, respectively (hazard ratio 0.80, 95% confidence interval 0.68–0.94). This difference in mortality was at least partly explained by ESRD preparation. Unfortunately, potential harms of the CKD screening and education program (such as psychological distress and increased burden of medical visits and tests), as well as the costs, were not evaluated in the present study, making it impossible to fully ascertain the benefits, risks, and cost-effectiveness of this program. These observational data do tell an informative and optimistic story of ESRD preparation and reduction in ESRD mortality through improved preESRD care. Whereas previous studies have mainly focused on prevention during predialytic stages, these findings add to and broaden the reach of preESRD education efforts. One clinically relevant implication of this study is that CKD screening and education programs may improve ESRD preparation, as evidenced by several clinical domains spanning from pre-ESRD nephrology care and use of peritoneal dialysis to access to kidney transplantation, most of which have been proposed as approaches to reduce mortality of ESRD patients. More inspiring is the observation that KEEP participation was associated with a 5.4% absolute reduction in mortality over a median 1.6 years of follow-up from RRT initiation. Albeit relatively simple, such a preventive strategy could improve patient outcomes, implying clinical applicability. Despite this, indicators of ESRD preparation even in KEEP participants were still not optimal: Strikingly, there were still around 25% of patients who had not been cared for by a nephrologist when they progressed to ESRD. The rate of preemptive transplantation remained low, although the overall rates of transplantation were higher among KEEP versus non-KEEP patients. Also, only approximately 25% of patients had a functioning arteriovenous fistula or graft at first outpatient
hemodialysis; nonetheless, an additional 20% of patients already had a maturing arteriovenous fistula or graft at that time. Although the latter may reflect reimbursement policies in the United States, one should consider that preparation of patients, despite using a catheter for access, still leads to an improvement in patient survival. This then raises the interesting question of whether catheter use per se is such a risk factor for death, or whether the increased risk of death reported with catheters has been, in part, confounded by unplanned starters. From a patient perspective, a recent US single-center study11 demonstrated that the majority of patients still feel unprepared and illinformed about the initiation of dialysis, especially concerning the risks and burdens of dialysis or the option of not starting the therapy. About onethird of the patients perceived that the decision to start dialysis and the decision of the modality were made by the doctor. All in all, the study by Kurella Tamura et al.10 brings optimism and fresh air to the issue of the value of screening and disease educational preventive strategies. Although such observations may, for some, be considered a truism, there is a compelling (human) need to remind us that increased screening and patient preparation certainly pay off in the fight against disease. Originating from the ancient Chinese masterpiece the Suwen of the Huangdi Neijing, the principle of ‘preventive treatment of disease’ has been a medical axiom for more than two millennia. Nevertheless, appropriately designed interventional trials may be needed to prove a causal effect of patient preparation on survival after dialysis initiation. In this regard the study by Kurella Tamura et al.10 provides valuable sample-size estimations, as, for an intervention with this size effect, the number needed to treat to prevent one ESRD death would be 18. More stringent efforts are certainly needed from all involved in nephrology care and community screening policies. DISCLOSURE
The authors declared no competing interests. 509
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ACKNOWLEDGMENTS
The authors acknowledge grant support from the Swedish Research Council and the Centre for Gender Medicine at Karolinska Institutet.
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see clinical investigation on page 703
Extracellular hydration, cardiovascular risk, and the interstitium: a three-dimensional view Sandip Mitra1 Volume expansion is a major contributor to poor cardiovascular outcomes in kidney disease. The relationship of extracellular volume (ECV) overload to cardiovascular changes in chronic kidney disease (CKD) remains speculative. Recent studies are challenging traditional concepts and providing new insight into mechanisms and the relationship of ECV to cardiovascular health. A dynamic role of the extracellular interstitium in inducing cardiovascular risk is emerging in CKD. Kidney International (2014) 85, 510–512. doi:10.1038/ki.2013.481
fluid (in up to 80% patients) has been demonstrated consistently. Fluid overload is a condition linked to increased morbidity and mortality in patients with chronic kidney disease (CKD),1 acute kidney injury, or heart failure and in the critically ill.2 Effective salt and water management improves survival in patients on dialysis,3 and in acutely ill patients in intensive care. It is traditionally believed that failure of natriuresis and volume overload directly induce vascular remodeling, hypertension, left ventricular hypertrophy, heart failure, and vascular events such as strokes and myocardial infarction. The burden of cardiovascular disease in stages of CKD could therefore be considered a direct result of loss of salt and water autoregulation by the kidney. Hung et al.4 (this issue) describe subclinical and relatively modest extracellular overhydration (41.1 liters) as a strong risk factor for poor cardiovascular outcomes, in an observational study in 338 Taiwanese patients with stage 3–5 CKD and a mean age of 65.7±13.5 years, followed up in outpatient clinics with the use of body composition measurements. Overhydration is shown to be strongly related to cardiovascular dysfunction with an independent association with clinical factors (diabetes mellitus, systolic blood pressure, male gender, and preexisting cardiovascular disease) and biomarkers (albumin, N-terminal prohormone brain natriuretic peptide, ln tumor necrosis factor-a, and ln urine protein creatinine ratio). The association of subclinical overload with cardiovascular risk is striking in this clinical setting. However, the findings do not represent causality and highlight several issues that deserve consideration. DETECTION OF SUBCLINICAL FLUID OVERLOAD
1
Department of Renal Medicine, Manchester Academic Health Science Centre, Biomedical Research Centre, Central Manchester Foundation Trust and University of Manchester, Manchester, UK Correspondence: Sandip Mitra, Department of Renal Medicine, Central Manchester Foundation Trust, Manchester Academy Health Science Centre, Oxford Road, Manchester M139WL, UK. E-mail: [email protected] 510
The accumulation of excess body fluid (previously termed ‘dropsy’) is depicted in many ancient paintings. The Egyptians called it ‘flooding of the heart’ and recognized that excess fluid was at its origin. End-stage kidney failure has been the most common disease model in which such overwhelming retention of
Detection of subclinical extracellular volume (ECV) overload poses a particular challenge. Edema is the classical sign but lacks sensitivity and specificity. With failure of homeostatic control by the kidneys, plasma volume expands. The rise in intravascular hydrostatic pressure causes an imbalance of Kidney International (2014) 85
