Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care.

Patients with advanced chronic kidney disease (CKD) have a high burden of physical and psychosocial symptoms, poor outcomes, and high costs of care. Current paradigms of care for this highly vulnerable population are variable, prognostic and assessment tools are limited, and quality of care, particularly regarding conservative and palliative care, is suboptimal. The KDIGO Controversies Conference on Supportive Care in CKD reviewed the current state of knowledge in order to define a roadmap to guide clinical and research activities focused on improving the outcomes of people living with advanced CKD, including those on dialysis. An international group of multidisciplinary experts in CKD, palliative care, methodology, economics, and education identified the key issues related to palliative care in this population. The conference led to a working plan to address outstanding issues in this arena, and this executive summary serves as an output to guide future work, including the development of globally applicable guidelines.

Knowing what we do and doing what we should: quality assurance in hemodialysis.

An international group of around 50 nephrologists and scientists, including representatives from large dialysis provider organisations, formulated recommendations on how to develop and implement quality assurance measures to improve individual hemodialysis patient care, population health and cost effectiveness. Discussed were methods thought to be of highest priority, those clinical indicators which might be most related to meaningful patient outcomes, tools to control treatment delivery and the role of facilitating computerized expert systems. Emphasis was given to the use of new technologies such as measurement of online dialysance and ways of assessing fluid status. The current evidence linking achievement of quality criteria with patient outcomes was reviewed. This paper summarizes useful processes and quality measures supporting quality assurance that have been agreed across the expert panel. It also notes areas where more understanding is required.

Estimating the financial cost of chronic kidney disease to the NHS in England.

BACKGROUND: Chronic kidney disease (CKD) is a major challenge for health care systems around the world, and the prevalence rates appear to be increasing. We estimate the costs of CKD in a universal health care system. METHODS: Economic modelling was used to estimate the annual cost of Stages 3-5 CKD to the National Health Service (NHS) in England, including CKD-related prescribing and care, renal replacement therapy (RRT), and excess strokes, myocardial infarctions (MIs) and Methicillin-Resistant Staphylococcus Aureus (MRSA) infections in people with CKD. RESULTS: The cost of CKD to the English NHS in 2009-10 is estimated at £ 1.44 to £ 1.45 billion, which is ≈ 1.3% of all NHS spending in that year. More than half this sum was spent on RRT, which was provided for 2% of the CKD population. The economic model estimates that ≈ 7000 excess strokes and 12 000 excess MIs occurred in the CKD population in 2009-10, relative to an age- and gender-matched population without CKD. The cost of excess strokes and MIs is estimated at £ 174-£ 178 million. CONCLUSIONS: The financial impact of CKD is large, with particularly high costs relating to RRT and cardiovascular complications. It is hoped that these detailed cost estimates will be useful in analysing the cost-effectiveness of treatments for CKD.

Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults. METHODS: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as ΔeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance. RESULTS: In the groups as a whole, no relationship between BMI and ΔeGFR was shown. Dividing the subjects into obese (BMI≥30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and ΔeGFR. Univariate analysis of variance was used. CONCLUSIONS: Neither BMI as a continuous variable nor obesity (BMI≥30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population.

The use of eGFR and ACR to predict decline in renal function in people with diabetes.

BACKGROUND: There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria. METHODS: Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood. RESULTS: For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001). CONCLUSIONS: The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria.

Factors associated with kidney disease progression and mortality in a referred CKD population.

BACKGROUND: Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. PREDICTORS: CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². OUTCOMES: Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. RESULTS: During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. LIMITATIONS: Single-center observational study. CONCLUSION: This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.

Community Health Care Quality Standards to Prevent Acute Kidney Injury and Its Consequences.

As the incidence of acute kidney injury (AKI) increases, prevention strategies are needed across the health care continuum, which begins in the community. Recognizing this knowledge gap, the 22nd Acute Disease Quality Initiative (ADQI) was tasked to discuss the evidence for quality-of-care measurement and care processes to prevent AKI and its consequences in the community. Using a modified Delphi process, an international and interdisciplinary group provided a framework to identify and monitor patients with AKI in the community. The recommendations propose that risk stratification involve both susceptibilities (eg, chronic kidney disease) and exposures (eg, coronary angiography), with the latter triggering a Kidney Health Assessment. This assessment should include blood pressure, serum creatinine, and urine dipstick, followed by a Kidney Health Response to prevent AKI that encompasses cessation of unnecessary medications, minimization of nephrotoxins, patient education, and ongoing monitoring until the exposure resolves. These recommendations give community health care providers and health systems a starting point for quality improvement initiatives to prevent AKI and its consequences in the community.

The influence of multiple episodes of acute kidney injury on survival and progression to end stage kidney disease in patients with chronic kidney disease.

BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort. METHODS: Patients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients' first, second, and third or more AKI episodes. RESULTS: A total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient [IQR 6-26]). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years [IQR 1.1-3.2]. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 [HR 2.04, p 0.01]. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT [HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI]. However, suffering one or more AKI events was not associated with an increased risk of mortality. CONCLUSIONS: AKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.

Quality Improvement Goals for Acute Kidney Injury.

AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.

Closing the gap between evidence and practice in chronic kidney disease.

There are major gaps between our growing knowledge of effective treatments for chronic kidney disease (CKD), and the delivery of evidence-based therapies to populations around the world. Although there remains a need for new, effective therapies, current evidence suggests that many patients with CKD are yet to fully realize the benefits of blood pressure-lowering drugs (with and without reducing proteinuria with renin-angiotensin system blockade), wider use of statins to reduce atherosclerotic cardiovascular disease events, and better glycemic control in both type 1 and type 2 diabetes. There are many barriers to optimizing evidence-based nephrology care around the world, including access to health care, affordability of treatments, consumer attitudes and circumstances, the dissemination of appropriate knowledge, the availability of expertise and structural impediments in the delivery of health care. Further investment in implementation science that addresses the major barriers to effective care in a cost-effective manner could yield both local and global benefits.

Strategies to improve monitoring disease progression, assessing cardiovascular risk, and defining prognostic biomarkers in chronic kidney disease.

Chronic kidney disease (CKD) is a major global public health problem with significant gaps in research, care, and policy. In order to mitigate the risks and adverse effects of CKD, the International Society of Nephrology has created a cohesive set of activities to improve the global outcomes of people living with CKD. Improving monitoring of renal disease progression can be done by screening and monitoring albuminuria and estimated glomerular filtration rate in primary care. Consensus on how many times and how often albuminuria and estimated glomerular filtration rate are measured should be defined. Meaningful changes in both renal biomarkers should be determined in order to ascertain what is clinically relevant. Increasing social awareness of CKD and partnering with the technological community may be ways to engage patients. Furthermore, improving the prediction of cardiovascular events in patients with CKD can be achieved by including the renal risk markers albuminuria and estimated glomerular filtration rate in cardiovascular risk algorithms and by encouraging uptake of assessing cardiovascular risk by general practitioners and nephrologists. Finally, examining ways to further validate and implement novel biomarkers for CKD will help mitigate the global problem of CKD. The more frequent use of renal biopsy will facilitate further knowledge into the underlying etiologies of CKD and help put new biomarkers into biological context. Real-world assessments of these biomarkers in existing cohorts is important, as well as obtaining regulatory approval to use these biomarkers in clinical practice. Collaborations among academia, physician and patient groups, industry, payer organizations, and regulatory authorities will help improve the global outcomes of people living with CKD.

Early chronic kidney disease: diagnosis, management and models of care.

Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt.

Conservative care for ESRD in the United Kingdom: a national survey.

BACKGROUND AND OBJECTIVES: Conservative kidney management (CKM) has been developed in the United Kingdom (UK) as an alternative to dialysis for older patients with stage 5 CKD (CKD5) and multiple comorbidities. This national survey sought to describe the current scale and pattern of delivery of conservative care in UK renal units and identify their priorities for its future development. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A survey on practice patterns of CKM for patients age 75 and older with CKD5 was sent to clinical directors of all 71 adult renal units in the UK in March 2013. RESULTS: Sixty-seven units (94%) responded. All but one unit reported providing CKM for some patients. Terminology varied, although "conservative management" was the most frequently used term (46%). Lack of an agreed-upon definition of when a patient is receiving CKM made it difficult to obtain meaningful data on the numbers of such patients. Fifty-two percent provided the number of CKM patients age ≥ 75 years in 2012; the median was 45 per unit (interquartile range [IQR], 20-83). The median number of symptomatic CKM patients who would otherwise have started dialysis was eight (IQR, 4.5-22). CKM practice patterns varied: 35% had a written guideline, 23% had dedicated CKM clinics, 45% had dedicated staff, and 50% provided staff training on CKM. Most units (88%) provided primary care clinicians with information/advice regarding CKM. Eighty percent identified a need for better evidence comparing outcomes on CKM versus dialysis, and 65% considered it appropriate to enter patients into a randomized trial. CONCLUSIONS: CKM is provided in almost all UK renal units, but scale and organization vary widely. Lack of common terminology and definitions hinders the development and assessment of CKM. Many survey respondents expressed support for further research comparing outcomes with conservative care versus dialysis.

A prospective study of the determinants of renal functional outcome and mortality in atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARVD) commonly causes renal failure and hypertension and is accompanied by high cardiovascular comorbidity and mortality. Interrelationships between these factors remain poorly understood. Patients with ARVD presenting to a single center between 1995 and 1999 were followed up, with prospective collection of clinical and biochemical data. Fifty men and 48 women were identified. Mean age at entry was 68.7 +/- 8.3 (SD) years, and baseline creatinine clearance (CrCl) was 35.5 +/- 20.7 mL/min. During follow-up (27.7 +/- 18.7 months), 10 patients required dialysis therapy, 11 patients underwent revascularization, and 35 patients (36%) died. Patients in whom renal function deteriorated during follow-up (n = 61) had similar ages, baseline CrCls, blood pressures, and comorbidities compared to patients with stable function. Mortality (55.7% versus 27.0%; P < 0.01) and proteinuria (protein, 1.3 +/- 1.6 versus 0.3 +/- 0.4 g/24 h; P < 0.001) were greater in patients with declining function. Baseline renal function was not significantly related to blood pressure, proteinuria, or change in renal function during follow-up (change in CrCl), but patients with a lower CrCl had increased mortality. There was no increase in cardiovascular comorbidity in groups with lower renal function. Patients with the most severe anatomic ARVD had worse hypertension and increased mortality, but severity of ARVD was unrelated to extent of renal dysfunction and proteinuria at baseline. Lack of correlation between renal artery anatomy and baseline renal function or functional outcome and correlation between renal functional outcome and proteinuria suggest that renal parenchymal damage is a major determinant of renal dysfunction and outcome in ARVD.

Serious adverse incidents with the usage of low molecular weight heparins in patients with chronic kidney disease.

BACKGROUND: The aim of the study is to describe serious adverse events in patients with renal insufficiency administered low molecular weight heparins (LMWHs). METHODS: Systematic case note review from July 2002 to March 2003, Hope Hospital, Salford, UK, was used. RESULTS: Ten patients experienced an adverse incident on LMWH therapy. Five patients were on maintenance hemodialysis therapy, and 1 patient was on continuous ambulatory peritoneal dialysis therapy. Three patients had calculated creatinine clearances of 5, 11, and 33 mL/min (0.08, 0.18, and 0.55 mL/s), and 1 patient had an estimated glomerular filtration rate of 12 mL/min. Age range was 45 to 89 years. Indications for anticoagulation were suspected pulmonary embolism (1 patient), acute coronary syndrome (7 patients), severe nephrotic syndrome (1 patient), and postoperative venous thromboembolic prophylaxis (1 patient). Three patients also were administered aspirin; 1 patient, clopidogrel; and 3 patients, aspirin and clopidogrel. LMWHs used were enoxaparin (6 patients), tinzaparin (3 patients), and dalteparin sodium (1 patient). Bleeding sources were retroperitoneal (1 patient), spontaneous soft tissue (3 patients), gastrointestinal (2 patients), dialysis catheter and cannula sites (2 patients), hemorrhagic pericardial effusion (1 patient), and intracranial (1 patient). Activated partial thromboplastin time was prolonged in 7 of 10 patients, with no other identifiable cause found. Three patients died despite aggressive resuscitation, including packed red blood cell infusions and protamine sulfate administration. Eight of the 10 prescriptions for LMWHs were either started or continued within our directorate, giving an approximate incidence of major hemorrhagic events in patients with chronic kidney disease of 7.8%. CONCLUSION: LMWHs administered at fixed-weight doses and without monitoring show unpredictable anticoagulant effects in patients with chronic kidney disease stages 4 and 5, leading to serious and even fatal adverse incidents.

Anaemia in patients with diabetes: unrecognised, undetected and untreated?

BACKGROUND: Diabetes mellitus is one of the two most common causes of end-stage renal disease and significant proportions of patients with diabetes mellitus develop renal complications. Anaemia is a key indicator of renal disease yet most patients with diabetes are rarely tested for anaemia and are unaware of the link between anaemia and kidney disease. PATIENTS AND METHODS: A pan-European study was undertaken to assess patients' level of awareness and understanding of anaemia and of the complications of diabetes mellitus, and to determine the impact of anaemia on quality of life. The study comprised a questionnaire-based interview with 1,054 respondents from six countries (Belgium, France, Germany, Greece, Italy and the UK). Ages ranged from 18 to 85, the average duration of diabetes was 15 years and 69% of respondents had type 2 diabetes mellitus. RESULTS: Only 32% of respondents had been given information about anaemia, although 83% had heard of anaemia. Less than half were aware of being tested for anaemia and only 14% attributed anaemia to diabetes. Of 1,054 respondents, 132 were known to be anaemic, one-fifth had received no treatment, 12 had received blood transfusions, five were receiving erythropoietin therapy and the remainder had been given iron and/or vitamin supplementation. Perceived state of health was worse in those with anaemia, 47% had either experienced periods of ill health or were feeling in poor health generally compared with only 28% of those without anaemia. Tiredness and lethargy were more marked in those with anaemia, 74% feeling tired and lethargic considerably more often or somewhat more often than others compared with only 52% of those without anaemia. With respect to complications of diabetes, respondents were most concerned about retinopathy (40%) but 23% were concerned about developing nephropathy. Only 46% had received information about renal complications. CONCLUSIONS: Anaemia has a significant impact on the quality of life of patients with diabetes. Although patients are aware of anaemia, their awareness of being tested for anaemia is low. A significant number of those in whom anaemia was detected received no treatment. It is likely that anaemia in patients with diabetes is unrecognised, undetected and untreated.

Predictive value of myocardial and coronary imaging in the long-term outcome of potential renal transplant recipients.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality in renal transplant recipients, but there is no agreed screening protocol. The value of myocardial perfusion imaging (MPI) and coronary angiography (CA) in predicting future cardiovascular events and mortality in unselected dialysis patients was studied. METHODS: Forty seven patients (mean age 51±14 years, 37 males), underwent both CA and MPI as part of pre-renal transplant assessment between 1995 and 1999. Follow-up period was 75±132 (range 3 to 143) months. RESULTS: Twenty-two (46.8%) patients had >50% stenosis of at least one major coronary artery (CAD), only 10 patients had abnormal MPI. Positive CA was found in all patients with angina and in 80% of diabetics. During follow-up 18 (38.3%) patients received a transplant and 28 (59.6%) patients died, of which 16 were proven or suspected cardiac deaths. Survival was significantly longer in patients with negative MPI or CA (92 and 96 versus 29 and 54 months for positive studies, respectively). CA had PPV of 95.7% and NPV of 54.2% for predicting the combined outcome of death and cardiovascular events whereas for MPI and MUGA, PPVs were 90.9% and 73.3% and NPVs 37.8% and 30%, respectively. CONCLUSIONS: Although MPI had a high specificity for CAD detection, its sensitivity appears limited in dialysis patients. The study suggests that those with angina and/or diabetes should undergo CA because of the high incidence of CAD in these groups, but MPI was at least as important as CA in overall mortality prediction over a long follow-up.

Serum phosphate and mortality in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. RESULTS: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. CONCLUSIONS: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.