Combination therapy with ACE-Is and ARBs may be used for additive anti- proteinuric and renoprotective effects, but this approach has rarely been studied in children. Small randomized trials of combinations of ACE-Is and ARBs in children with CKD demonstrate significant reductions in urine protein levels as compared to the use of only one of the drug classes.335,352 However, further study of long-term outcomes and safety data are necessary. Use of ACE-Is and ARBs should be individualized on the basis of susceptibility to hypotension and of the risk of pregnancy in young women of child-bearing age. ACE-Is and ARBs are labelled by the US FDA as pregnancy category C for the first 3 months of pregnancy and category D for the last 6 months (the second and third trimesters). Pregnancy category C means that a risk may exist but its magnitude is unknown because of a lack of trustworthy studies in pregnant women, and animal studies either have shown risk in pregnancy or have not been performed. Pregnancy category D means that there have been studies in pregnant women showing that the drug is associated with some risk for the fetus, but the benefit of the drug may still outweigh that risk for some patients.84,85 Monitoring for hyperkalemia may be considered in high- risk children as kidney function declines. In the ESCAPE individuals with CKD receiving a high-dose ACE-I had an increase in mean ( standard deviation [SD]) serum potassium levels from 4.31 0.52 mmol/l to 4.71 0.57 mmol/l. The upper limit of the normal range for children (5.6 mmol/l) was exceeded in 3.3% of tests. In all but 5 patients, medical management through adjustment of diet, addition of a diuretic, or prescription of potassium- exchange resins resulted in persistent normalization of serum potassium levels while the child remained on ACE-I therapy. ACE-Is and ARBs have similar hemodynamic effects in the kidney which leads to decrease in GFR. It has been stated that increases of the SCr level by up to 30% should be expected and tolerated after initiating therapy with ACE-Is or ARBs in adults with chronic kidney failure, but children have not been prospectively studied in this regard.88 Few direct comparisons of classes of anti-hypertensive agents have been performed in children with CKD. Extensive reviews of different drugs and classes of anti-hypertensive agents in children with CKD have recently been pub- There is no clear evidence that one second-line BP agent is superior to the another in children. In the calcium-channel blockers were used as first- choice anti-hypertensive co-medication (in 38% of patients), followed by diuretics (in 36%) and beta-blockers (in 26%), without differences between the randomization groups. Other guidelines suggest diuretics or calcium-channel block- ers as the most suitable second-line agents.353 LIMITATIONS In children with CKD, there is a dearth of RCTs; in fact, the recommendations in this chapter are largely based on a single trial, ESCAPE, which limits the quality of the evidence and the strength of the recommendations. The ESCAPE trial was performed in a predominantly Caucasian population. There- fore, the generalization of these findings to other populations is uncertain. RESEARCH RECOMMENDATIONS K Further RCTs are needed to replicate the findings from ESCAPE and to examine the safety and efficacy of intensified BP control on slowing CKD progression and incidence of CVD in children with CKD. K Studies addressing BP targets and comparing home BP monitoring via oscillometric devices, ABPM, and clinic- based BP monitoring are needed, as are robust ABPM reference measures in populations of various races and ethnicities. K Long-term observational studies of the onset of target- organ damage in children with CKD are necessary to obtain evidence on which to base thresholds for BP treatment and targets rather than relying on population- based percentiles. Large, long-term randomized trials addressing targets and comparing various agents to prevent target-organ damage are also necessary to improve knowledge of the advantages and disadvantages of specific doses and classes of anti-hypertensive agents in this population. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contri- butor, copyright holder, or advertiser concerned. Accord- ingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplementary Table 63. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [categorical outcome]. Supplementary Table 64. RCTs examining the effect of intensified vs. conventional BP control on children with CKD without DM [continuous outcome]. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Chapter 7: Blood pressure management in elderly persons with CKD ND INTRODUCTION This chapter specifically addresses the BP management of older patients with CKD that is non-dialysis-dependent (i.e., CKD ND), many of whom have accumulated co-morbidities associated with aging, including vascular disease, osteoporo- sis, and general frailty. The term elderly is used for persons whereas very elderly is reserved for persons 480 years of age, consistent with the terminology used in the literature reviewed in this chapter.43,149,355,356 In using these definitions, we recognize that chronological age is used as a surrogate for biological age, although this relationship is highly variable. The elderly comprise the most rapidly growing proportion of the population in most parts of the world.357 From 30 to 40 years of age, the GFR generally (but not invariably) declines, and in the older person, tubular and endocrine dysfunction in the kidney are common.358,359 Combine this with the increased prevalence of type 2 diabetes mellitus and high BP among older persons, it is not surprising that the elderly constitute the most rapidly growing population of CKD patients. In population health surveys, a large proportion of the elderly have a reduced GFR. In the United States, NHANES 1999 2004 data showed that 37.8% of subjects 470 years had (measured using the MDRD equation); this prevalence had increased from 27.8% in the Nearly 50% of United States veterans aged 485 years fulfilled the definition for CKD.362 Similarly in China,363 a high prevalence of CKD has been found in older populations. With greater access to health care among the elderly, this group is the fastest-growing population requiring dialysis, with 25% and 21.3% of dialysis patients in the United States and Australia, respectively, being Z75 years of age366,367 and between 31 and 36% of patients receiving renal replacement therapy in different regions of the United Kingdom being 7.1: Tailor BP treatment regimens in elderly patients with CKD ND by carefully considering age, co-morbidities and other therapies, with gradual escalation of treatment and close attention to adverse events related to BP treatment, including electrolyte dis- orders, acute deterioration in kidney function, orthostatic hypotension and drug side effects. (Not Graded) RATIONALE The relationships between CKD and BP in the elderly in the United States have recently been reviewed in detail.369 Among NHANES III (1988 1994) subjects aged Z60 years of age, either treated or not treated for a high BP, there was a J-shaped relationship between BP and CKD prevalence. Thus, persons with a systolic BP of 120 to 159 mm Hg or a diastolic BP of 80 to 99 mm Hg had the lowest CKD prevalence, with a higher prevalence associated with a systolic BP o120 mm Hg or diastolic BP o80 mm Hg and a systolic BP Z160 mm Hg or a diastolic BP Z100 mm Hg.361 Analyses of data from the Kidney Early Evaluation Program (KEEP), as well as NHANES, indicate that with increasing age, there is an increase in the prevalence and severity of CKD, confirming the strong relationship between BP and CKD in the elderly.370,371 Despite these findings, there is little evidence on which to base recommendations for BP management in elderly patients with CKD. Systematic assessment of the evidence base underpinning this Guideline shows that many RCTs excluded patients 470 years of age. The mean age of participants rarely exceed 65 years with the upper limit of the 95% CI (i.e., the mean 2 SD) very uncommonly being Z85 years, meaning no more than about 2.5% of the study population had an age above this cut-off point (Supplemen- tary Table 65 online). We therefore cannot draw much direct evidence from these RCTs to indicate how to properly manage BP in elderly CKD patients, although some inferences might be drawn from BP studies in elderly populations not specifically chosen for the presence of CKD. Measurement of BP in the elderly. Assessment of BP in the elderly is made more difficult by such common issues as the presence of atrial fibrillation (as seen in 25% of patients Z 70 years in the Chronic Renal Insufficiency Cohort (CRIC) ), orthostatic hypotension44,45 and the tendency for pulse pressure to widen with arterial stiffening, resulting in The literature on management of elderly patients has thus been focused more on systolic than diastolic BP. There is relevant observational evidence from the SHEP study.374 In an analysis of 2181 persons 465 years of age in the placebo arm of this study, systolic BP was more predictive of decline in kidney function (i.e., rise in SCr by Z0.4 mg/dl [35.4 mmol/l] over 5 years) than diastolic BP, pulse pressure, or MAP. The mean age was 72 years and patients with renal http://www.kidney-international.org chapter 7 & 2012 KDIGO failure were excluded. Among those enrolled, the initial SCr level was 1.04 0.23 mg/dl (92 20 mmol/l). Hence, most subjects probably had normal kidney function or CKD stages 1 3. CKD in the elderly. There are clear differences in the causes of CKD when comparing elderly and younger cohorts.375 Autopsy studies indicate that arteriolar sclerosis, global glomerulosclerosis, and tubular atrophy are more common in the elderly, as are renal artery stenosis and cholesterol Although selection bias is likely, a kidney biopsy series of 413 patients aged 66 to 79 years and 100 patients aged 80 to 89 years showed nephrosclerosis in 34% of patients 480 years and in 7% of those 66 to 79 yrs.356 According to registries of kidney failure patients, arterio- pathic disease was the diagnosis in 17 to 38% of patients commencing dialysis on three continents.375 Although a discussion as to whether or not nephrosclerosis is an aspect of kidney aging is beyond the scope of this Guideline, vascular disease within the kidney is often regarded as a major factor contributing to decline in kidney function. This predisposi- tion to vascular disease may influence the response of the aging kidney to low BP and renin angiotensin blockade, with the attendant risks of acute reduction in GFR and hyperkalemia. This has led to questions regarding the safety of renin angiotensin-blocking agents such as ACE-Is and ARBs in the elderly.377 379 GFR estimation in the elderly. Most equations used to estimate GFR have been primarily developed in younger populations, although subgroup analyses show that these equations perform reasonably well in older people380,381 . Co-morbidities. Co-morbidities are frequently present in the elderly and may influence BP management. Macrovascular disease is particularly common. This might influence BP targets or the preferred agents use to control BP, especially if heart failure, angina, cerebral vascular insufficiency, or peripheral vascular diseases are prominent. The presence of heart failure or cardiomyopathy may lead clinicians to initiate or diuretics independently of BP treatment. Similarly, angina may be an indication for beta-blockers or calcium-channel blockers. Hypotension (orthostatic or persistent) due to BP-lowering treatment may exacerbate the risk of falls and fractures in the elderly, especially in patients with co-morbidities such as cerebrovas- cular disease, osteoporosis, or vitamin D deficiency. Drugs and the elderly. The pharmacology and pharmaco- dynamics of BP drugs also change with age, mainly because of reduced GFR, but also due to changes in hepatic function, volume of distribution, and other issues that are less well Side-effect profiles may also vary, either owing to altered end-organ sensitivity to the drugs, co- morbidities, or interactions with other medications, such as diuretics, NSAIDs and COX-2 inhibitors which may accentuate the adverse kidney effects of renin angiotensin blockade.384 Goals of BP management in the elderly. It is particularly important to individualize care in the elderly, bearing co- morbidities in mind. A philosophy of patient-centered care (rather than disease-directed care) is particularly relevant as the elderly become very elderly.385 The high likelihood of elderly patients developing cardiac and cerebrovascular complications in the context of a high BP, along with evidence that kidney function may decline more slowly in the elderly than in younger patients (particularly when the GFR should lead to a greater emphasis on vascular rather than kidney outcomes. More- over, particularly in the very elderly, possible beneficial effects of therapy on morbidity and mortality should be balanced against any negative effects on quality of life.388 BP TARGETS IN THE ELDERLY Although there have been many studies of treatment of high BP in the elderly, there is little evidence specific to the elderly with known CKD. Most relevant information comes from observational studies and RCTs involving entire populations of older hypertensive patients not specifically chosen on the basis of kidney function (Supplementary Table 66 online). Renal failure or a designated upper limit for the SCr concentration have been an exclusion criterion in many studies, reducing the applicability of the data to CKD patients. A meta-analysis of observational studies conducted prior to 2002, including nearly 1 million subjects selected for having no previously known vascular disease, indicated that the rates of stroke, ischemic heart disease, and overall mortality increased with increasing BP, even among subjects 60 to 89 years of age, although the RR decreased with increasing age.21 RCTs involving elderly patients not selected for having CKD indicate that it is beneficial to treat high BP in patients 460 years of age. A 2009 Cochrane review of 15 RCTs in which persons 460 years of age with a systolic BP Z140 mm Hg or a diastolic BP Z90 mm Hg at baseline received either placebo or a BP-lowering agent indicated that active treatment reduced total mortality (RR 0.90; 95% CI 0.84 0.97) and total cardiovascular mortality and morbidity (RR 0.72; 95% CI 0.68 0.77), particularly due to a reduction in the incidence of stroke.389 Withdrawals due to adverse events were poorly documented, but in three RCTs that did report these data, treatment was associated with 111 events/ 1000 patient-years, as compared with 65 events/1000 patient- years with placebo (RR 1.71; 95% CI 1.45 2.00). Although these findings support treatment of high BP in subjects 460 years of age, they do not inform us specifically about patients with CKD nor about the target BP and they suggest that some patients will have adverse reactions to drug therapy. Of concern is that in this Cochrane review,389 when patients aged Z80 years were specifically considered, there was no overall reduction in the risk of total mortality with treatment of BP vs. no treatment (RR 1.01; 95% CI 0.90 1.13), although the reduction in risk of cardiovascular mortality (RR 0.75; 95% CI 0.65 0.87) was similar to that seen in patients 60 to 80 years of age. This is in accordance with a 1999 subgroup meta-analysis of seven RCTs represent- ing 1670 patients aged Z80 years (who had participated in trials of anti-hypertensive agents) indicating that treatment vs. no treatment was associated with a decrease in the rates of strokes, major cardiovascular events and heart failure but, similar to the Cochrane findings, there was no benefit of treatment in terms of cardiovascular death or overall Similarly, a 2010 meta-analysis of 8 RCTs involving treatment of BP in subjects 80 years and older found that treatment of high BP reduced the risk of stroke, cardiovascular events and heart failure, but had no effect on Meta-regression analysis suggested that mortality reduction was achieved in the trials with the least BP reductions and lowest intensity of therapy. These findings suggest that there might be deleterious effects resulting from BP treatment in the very elderly undermining the advantages brought about by the reduced risk of cardiovascular events. An observational cohort study involving 4071 hyper- tensive individuals aged 80 years or older (mainly men, since they were recruited from the Veterans Affairs Administra- tion) supports this notion.43 All subjects were classified as hypertensive according to the International Classification of Diseases (ICD-9) code, 9.9% as having chronic renal failure, and 84.5% were taking anti-hypertensive medica- tions. A J-shaped relationship between BP and survival was seen. Patients with BP o130 139 mm Hg systolic or o70 79 mm Hg diastolic were more likely to die during 5 years of follow-up than those with BP 130 139 mm Hg systolic or 70 79 mm Hg diastolic. With each further 10 mm Hg decrease in systolic or diastolic BP to o100 mm Hg systolic or o50 diastolic the risk increased, suggesting that overly aggressive BP control might be harmful in this age group. A series of retrospective analyses of INVEST has further highlighted the issue of J-shaped relationships between systolic BP, diastolic BP and outcomes in elderly hypertensive patients with CAD.40,42,231 The risk of all cause mortality and myocardial infarction, but not stroke, increased with reductions in diastolic BP in the patient group as a whole, all of whom had CAD and were being treated for high BP.40 In elderly patients included in the study, nadirs of risk occurred at particular systolic and diastolic BP levels, with the nadirs generally increasing with age. In patients aged 70 to 80 years, risk increased once systolic BP was less than 135 mm Hg or diastolic BP o75 mm Hg, while the risk increasing when systolic BP was o140 mm Hg or diastolic BP These relationships may be due to confounding and should not be used to set BP targets in this population. In preparing the evidence review for this guideline, the ERT found four studies involving elderly patients in which treating to differing targets for BP was part of the study design (Supplementary Table 67 online).149,389,391 393 The Shanghai Trial of Nifedipine in the Elderly (STONE) involved 1632 patients aged 60 79 years with a systolic BP Z160 mm Hg, or a diastolic BP Z96 mm Hg, who were randomized to nifedipine or placebo.392 The mean achieved BP was 147/85 mm Hg in the nifedipine group and 156/ 92 mm Hg in the placebo group and although there was no significant difference in all-cause mortality, there were reductions in the rates of stroke and severe arrythmia in the lower-BP nifedipine treated group. Exclusion criteria included secondary hypertension and a blood urea nitrogen level Z40 mg/dl (14.3 mmol/l). The Hypertension in the Very Elderly Trial (HYVET), involving patients 80 years of age or older, provided further assurance that BP lowering treatment of very elderly patients with a sustained BP of Z160 mm Hg is beneficial.149,391 Aiming to treat to a target BP of systolic o150 mm Hg and diastolic o80 mm Hg in the active-treatment group, the investigators achieved a BP of 145/79 mm Hg with indapa- mide plus perindopril (if needed), compared to 159/ 83 mm Hg with placebo. They demonstrated a reduction in the rates of all-cause mortality and stroke in the low-BP active-treatment group over a median 1.8 years of follow-up. Patients were withdrawn if systolic BP fell to o110 mm Hg. However, exclusion criteria included secondary hypertension (which might be of kidney origin) and a SCr level 41.7 mg/ dl (4150 mmol/l) (which represents a GFR of 39 or 37 ml/ for an 80-year-old white man, as estimated by either the MDRD or CKD Epidemiology Collaboration (CKD-EPI) equation, respectively and a GFR of 29 or for an 80-year-old white woman as esti- mated by the MDRD and CKD-EPI equations, respectively). The mean baseline creatinine levels were 88.6 mmol/l (1.0 mg/ dl) and 89.2 mmol/L (1.0 mg/dl) in the active-treatment and placebo groups, respectively which were well below the exclusion level. Accordingly, direct extrapolation of these data to patients with known advanced CKD is not possible. Although this evidence provides some reassurance regard- ing treatment of high BP in the very elderly, it only does so with respect to treatment to a BP target level of 150/80 mm Hg, and it does not specifically address CKD for men and women, respectively. Very importantly, however, the evidence challenges any tendency toward therapeutic nihilism in the very elderly with high BP and CKD 1 3. Two Japanese studies failed to show any benefit or harm from reducing systolic BP to o140 mm Hg in otherwise healthy elderly patients.393,394 The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) aimed to assess optimal systolic BP in elderly hypertensive patients and randomized 4418 patients with essential hypertension aged 65 to 85 years with a systolic BP 4160 mm Hg to strict BP control (target systolic BP o140 mm Hg) or mild BP control (target systolic Patients with SCr of Z1.5 mg/dl (133 mmol/l) were excluded, as were patients with multiple co-morbidities. Achieved mean SD systolic BP was 135.9 11.7 mm Hg in the strict-control group and 145.6 11.1 in the mild-control group (Po0.001), with significantly more drugs required in the strict-control group. There was no difference in cerebrovascular, cardiac, or kidney end points, nor in total mortality between the two groups at 2 years of follow-up. Renal failure occurred in 8 and 9 patients, respectively. Rates of treatment withdrawal due to adverse events did not differ between the groups. The Valsartan in Elderly Isolated Systolic Hypertension (VALISH) study involved 3260 Japanese participants aged 70 to 84 years, with systolic BP Z160 mm Hg.394 this study did not demonstrate any differences in outcomes or adverse events between the strict-control group (systolic BP goal o140 mm Hg, achieved mean systolic BP was 136.6 mm Hg) and the moderate-control group (systolic BP goal 140 150 mm Hg, achieved mean systolic BP was 142.0 mm Hg) after a median follow-up period of 3.07 Although 43 of the 3260 patients had kidney insufficiency (undefined) at study entry, none had a SCr level Z2 mg/dl (177 mmol/l) since this was an exclusion criterion, as were many other co-morbidities. Doubling of the SCr, an increase in the SCr level to 2.0 mg/dl (177 mmol/l), or dialysis occurred in 5 and 2 patients, respectively (non-significant). The authors concluded that in relatively healthy elderly Japanese patients, a BP o140 mm Hg is safely achievable, but that the trial was underpowered to assess outcome benefits. No difference was seen between the two groups in terms of adverse event rates (18.2% with strict control and 17.9% with mild control, P 0.851). Thus BP targets in the elderly, with or without CKD, should be set only after consideration of co-morbidities and should be achieved gradually. Based on the evidence on BP in the elderly (not selected for CKD), recent guidelines and consensus documents generally agree that o140/90 mm Hg should be the target in uncomplicated hypertension.117,395,396 The American College of Cardiology Foundation and American Heart Association (ACCF/AHA), in collaboration with a large group of other American and European bodies, acknowledge in their consensus document on hypertension in the elderly that although there is limited information for evidence-based guidelines to manage older hypertensive patients, a target of o140/90 mm Hg is recommended in uncomplicated hypertension for the age range 65 79 years.395 This document acknowledges that the target for 480 years is unclear, and refers to expert opinion and observational data (including KDOQI 2002 and JNC 7) suggesting o130/ 80 mm Hg as a target in CKD, irrespective of albuminuria. From the UK, NICE has published a comprehensive guideline for management of hypertension in adults which also recommends BP o140/90 mm Hg for primary hyperten- sion up to 80 years of age, and for those over 80 years who are Caution is recommended when starting BP medications in those over 80 years of age, and no recommendation is given with respect to the elderly with CKD. Although intuitively there must be a lower limit for safe BP control in the elderly and very elderly, there will probably never be an RCT designed specifically to address this limit in these populations. We can, however, gain insights from observations among elderly patients on treatment as outlined While these date do not allow us to recommend a lower BP limit on treatment, they do suggest that in the elderly, it may be prudent not to reduce BP much below the target BP o140/90 mm Hg as recommended by ACCF/AHA In addressing the risks associated with low BP in the elderly, it is relevant that orthostatic hypotension is more common than in younger populations, particularly among those treated for high BP or diabetes and those receiving As well as causing postural dizziness, low BP is associated with a higher risk of falls and fractures in elderly persons in studies that are likely to have included individuals with and without CKD.9,10,358,397 An additional consideration when treating elderly CKD patients is that they may differ from those with well preserved kidney function in terms of their response to BP lowering agents. The Work Group decided that it was not possible to recommend specific BP targets in the elderly with CKD. A reasonable approach might be to use BP targets as recom- mended in the younger CKD population (r140/90 mm Hg in non-albuminuric CKD and r130/80 mm Hg in albumi- nuric CKD as in Chapters 3 and 4), but to reach these targets gradually, bearing in mind that they may not be achievable without adverse effects particularly in a patient with multiple age-related co-morbidities. It is even more difficult to make recommendations in patients over 80 years of age with CKD due to the lack of evidence. With consideration given to the adverse effects of treatment, the Work Group felt that it was good practice to ask elderly patients treated for high BP about postural dizziness and to measure BP immediately (within 1 minute) and a few minutes after standing as well as in the sitting position.44 METHODS FOR BP REDUCTION IN THE ELDERLY Lifestyle modifications in the elderly, although often recommended, can compromise quality of life and may impair nutrition. The place of salt restriction, exercise and weight control is detailed in the aforementioned ACCF/AHA Given that there is very little evidence to support lifestyle modifications in the treatment of BP in CKD patients in general, the Work Group decided not to make any such recommendations in the elderly with CKD. Although salt restriction might seem to be the most attractive intervention, it may impact the quality of life, particularly enjoyment of food. A recent observational study of elderly persons (Z65 years of age) does not support alcohol restriction as an intervention to reduce decline in GFR.398 The Work Group felt that drug regimens should be tailored by carefully considering the elderly patient s co-morbidities and any changes in treatment should be very gradual. Close attention should be paid to potential adverse events related to BP treatment, including electrolyte disorders, acute deteriora- tion in kidney function and orthostatic hypotension. Although many elderly patients with CKD will require several agents, studies comparing use of various agents in the elderly without CKD have produced somewhat conflicting results (see Supple- mentary Tables 66 68 online). The ability of the patient to adhere to complex poly-pharmacy should be taken into consi- deration. Some clinicians have expressed concerns about the use of drugs that block the renin angiotensin system in the elderly This concern is largely due to the perceived potential for these agents to cause more frequent adverse events in this population. A recent Cochrane review addressing pharmacotherapy of all types for treatment of hypertension in the elderly reported an increased risk of withdrawals due to adverse effects (RR 1.71; 95% CI 1.45 2.00).389 Since quality of life is particularly important in the elderly, it may be worth avoiding drugs that may have negative quality of life implications, but no clear advice can be given.388,399 Thus given the many differences between the elderly (particularly the very elderly) with CKD and younger patients with CKD, it is not possible to recommend any particular drug class for the reduction of BP in older CKD patients. However, it is advisable to consider the severity of CKD, presence of albuminuria, and co-morbidities and their treatment when prescribing. Therapeutic changes should be made gradually, with close monitoring for adverse effects due to low BP or side effects from prescribed agents. RESEARCH RECOMMENDATIONS An important NIH funded trial- SPRINT- is currently ongoing in the United States randomizing patients without diabetes or significant proteinuria to a systolic BP of o140 mmHg or o120 mm Hg. Since it contains both elderly patients and those with CKD, it is likely to provide important evidence to guide BP management in this subpopulation.171,172 A workshop on kidney disease including the American Society of Nephrology, the National Institute on Aging, the American Geriatrics Society, and the National Institute of Diabetes and Digestive and Kidney Diseases resulted in the 2009 publication of a list of priority areas for research in kidney disease in the elderly (Table 3).400 Although BP was not specifically addressed, it highlighted the many areas of ignorance regarding CKD in the elderly. Important areas for future research suggested by this KDIGO Work Group include: K The effects of different BP targets (e.g., 150/90 mm Hg vs. 140/90 mm Hg) in elderly and very elderly patients with advanced CKD (CKD 3 4) should be assessed by pros- pective RCTs using a fixed-sequential BP-agent protocol (e.g., diuretic, ACE-I or ARB, beta-blocker, and calcium- channel blocker) excluding only patients with angina or cardiomyopathy. K The effect of various combinations of agents in the elderly and very elderly populations should be examined. DISCLAIMER While every effort is made by the publishers, editorial board, and ISN to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor, copyright holder, or advertiser concerned. Accordingly, the publishers and the ISN, the editorial board and their respective employers, office and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with the drug manufacturer s own published literature. SUPPLEMENTARY MATERIAL Supplementary Table 65. Age restriction in all RCTs for DM CKD, non- DM CKD, Transplant and CKD subgroups. Supplementary Table 66. PICO criteria for blood pressure targets in elderly studies. Supplementary Table 67. Ages and BP targets in elderly studies. Supplementary Table 68. PICO criteria for blood pressure agents in elderly studies. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Table 3 | Questions for future research Mechanisms and biology Is CKD in elderly people the same condition as CKD in young adults? How do age-related mechanisms such as fibrosis and cellular senescence interact with mechanisms underlying CKD progression? How much risk for CKD progression is determined by age versus factors such as AKI? How does fibrosis versus vessel dropout change with age? Do age- and CKD-associated changes in vascular biology differ from other parenchymal kidney disease changes associated with age? Measurement and prognosis Are there better ways to estimate GFR in older adults to identify CKD? What are the morphologic correlates of CKD in elderly people? Are there other markers that can contribute to assessment of CKD prognosis in elderly people, beyond GFR and cystatin? CVD How do age-related changes in vascular biology contribute to CKD- associated increases in cardiovascular risk? What are the age-related changes in non-traditional cardiovascular risk factors in patients with CKD? Other comorbidities How do comorbidities differ during the transition from CKD to kidney failure and need for dialysis? Can the deterioration in physical functioning and subsequent frailty in patients with CKD be prevented by physical activity interventions? How does age interact with exercise in prevention or reduction of comorbidities associated with CKD progression? What is the natural history of cognitive impairment associated with CKD progression, and what happens to cognitive function with the start of dialysis? What mechanisms link CKD with cognitive impairment in elderly people? Are there any interventions to attenuate the development of cognitive impairment in patients with CKD? How does preclinical kidney disease relate to other prefrailty risk factors? Management and care How can geriatricians, internists, general family practitioners, and nephrologists work together to optimize the care of elderly patients with CKD and kidney failure? Can age-related declines in kidney function and progression to CKD be modulated? AKI, acute kidney injury; CKD chronic kidney disease; GFR, glomerular filtration rate. Adapted from Anderson S, Halter JB, Hazzard WR et al. Prediction, progression, and outcomes of chronic kidney disease in older adults. J Am Soc Nephrol 2009; 20: 1199 209 with permission from American Society of Nephrology400 conveyed through Copyright Clearance Center, Inc.; accessed http://jasn.asnjournals.org/ content/20/6/1199.long. Chapter 8: Future directions and controversies INTRODUCTION In this chapter, we discuss issues regarding BP management and the use of BP-lowering drugs in CKD patients that are currently the subject of ongoing research or controversy and for which there is insufficient evidence upon which to base a recommendation at this time. 8.1: ASSESSMENT OF BP The RCTs on which this Guideline is based involved standard office BP measurements, with the exception of the ESCAPE trial in children.14 In clinical practice BP assessment typically involves measurements made in the clinic or office. In RCTs, the protocols for BP measurement usually require one or more BP readings taken after a period of rest and avoiding prior activities that may have effects on BP. As far as it is possible these protocols should be followed in clinical practice if this evidence is used to guide management. The techniques for office BP measurement and associated problems are well described in the hypertension litera- There is no reason to believe that office BP measurement should be performed differently in CKD patients than in non-CKD patients, other than a strong emphasis be placed on measuring supine or sitting and standing BP because of the increased likelihood of orthostatic hypotension associated with volume depletion, autonomic neuropathy, older age, and drug effects.44,45,374,375 Measuring BP in the general community and in particular, patients with essential hypertension, is becoming increasingly sophisticated. Examples include technologies that assess usual BP as distinct from the BP measured at an office visit and new ways of measuring BP, beyond just systolic and diastolic pressures. Gradually, these advances are being implemented in research and BP management in CKD patients. Ambulatory BP monitoring and self-monitoring at home. There is a long history of assessing BP by means other than the BP measurement taken at an office visit. The gold standard is automated ABPM, the techniques for which have been well described,10,143,401 and self-monitoring using automated devices, which is increasingly used. Recommen- dations and guidelines for the use of ABPM and self- monitoring are accumulating in the hypertension literature (Table 4). There have been a limited number of studies conducted in CKD patients but data suggest that in CKD, high ABPM systolic pressures, and nocturnal non-dipping (i.e., the absence of a drop in BP during sleep) are associated with increased risks of mortality (as in other populations) and of decline in GFR or kidney failure.11,77,78 As has been found for non-CKD patients, office BP measurements are commonly overestimates (in the case of white-coat hypertension) or underestimates (in the case of masked hypertension) of usual BP when compared with ambulatory BP assessments. A recent paper highlights the interest in ABPM in CKD.79 436 hypertensive CKD patients were prospectively followed using ABPM and this was shown to be much more accurate in predicting both renal and cardiovascular outcomes than office BP. White coat hypertension was common, and ABPM indicated that non-dipping and reverse dipping of nocturnal BP were particularly predictive of cardiovascular and renal outcomes. Future trials are needed to assess the best means of measuring BP in CKD patients by randomizing patients to ABPM, home BP or office BP directed therapy and to address whether evening dosing to encourage dipping is advanta- geous as recently demonstrated in non-CKD hypertensive Given the technical and economic barriers to routine measurement of ambulatory BP, self-BP recording using automated BP devices has been introduced because these give readings that are more in line than with ABPM than those achieved by office BP measurements.12,402,403 Self-BP measurement and ABPM are being used increas- ingly in BP management and the devices for measuring them usually rely on oscillometric assessment of BP at the elbow. Atrial fibrillation and very high pulse pressures can lead to inaccuracies and hence, re-calibration against traditional methods of BP measurement is important.402 While it is unlikely that self-BP monitoring or ABPM will become part of mainstream CKD montoring in developing countries in the near future, they are likely to become more widely used if further research indicates the value of these techniques in CKD management. Measurement of pulse pressure and pulse wave velocity. The stiffening of arterial walls that accompanies CKD (as well as aging and chronic high BP) causes a loss of the volume compliance in the large arteries such as the aorta, reducing their ability to effectively buffer the systolic pressure wave generated by the left ventricle and thus resulting in higher systolic BP. In diastole, the loss of elastic recoil leads to a reduced diastolic pressure. These changes together contribute to a higher pulse pressure and faster pulse wave velocity, since the pulse wave travels more rapidly when the larger arteries are less compliant. Measurement of pulse pressure or pulse wave velocity can therefore offer insights into vascular structure and function.32,373 Studies of pulse pressure or chapter 8 http://www.kidney-international.org & 2012 KDIGO Table 4 | Existing guidelines on ambulatory BP monitoring (ABPM) and home BP monitoring Society or authors Measurement recommendations British Hypertension Home BP monitoring: Accuracy of at-home recordings can be improved by calibration of the home instrument with a known standard, but even so, a lower threshold for treatment is recommended (i.e., less than 135/85 mm Hg) because of inaccuracies in home measurements and the tendency for home readings to be lower than office readings. ABPM: Recommended levels of normality for ambulatory BP BP levels (mm Hg) Optimal Normal Abnormal Japanese Society of Hypertension Guidelines for self-monitoring of BP Home BP monitoring: 1. Arm-cuff devices based on the cuff-oscillometric method that have been validated officially and the accuracy of which has been confirmed in each individual should be used for home BP measurement. 2. The BP should be measured at the upper arm. Finger-cuff devices and wrist-cuff devices should not be used for home BP measurements. 3. Devices for home BP measurement should be adapted to the American Association for Medical Instrumentation standards and the British Hypertension Society guidelines. In addition, the difference between the BP measured by the auscultatory method and the device should be within 5 mm Hg in each individual. The home measurement device should be validated before use and at regular intervals during use. 4. Home BP should be monitored under the following conditions: The morning measurement should be made within 1 h after waking, after micturition, sitting after 1 to 2 min of rest, before drug ingestion, and before breakfast. The evening measurement should be made just before going to bed, sitting after 1 to 2 min of rest. 5. Home BP should be measured at least once in the morning and once in the evening. 6. All home BP measurements should be documented without selection, together with the date, time, and pulse rate. Use of devices with a printer or an integrated circuit memory is useful to avoid selection bias. 7. The home BP in the morning and evening should be averaged separately for a certain period. The first measurement on each occasion should be used for totaling. 8. Home BP values averaged for a certain period Z135/80 mm Hg indicate hypertension and Z135/85 mm Hg, definite hypertension. Normotension is defined as less an average BP o125/80 mm Hg and definite normotension as o125/75 mm Hg. American Society of ABPM: Ambulatory BP monitors measure BP by means of auscultatory or oscillometric methods. Auscultatory monitors use a microphone on the bladder cuff to detect the Korotkoff sounds. The advantage of this technique is that arm movement does not interfere with the recording; however, these monitors are sensitive to background noise. Oscillometric monitors sense arterial pressure vibrations and calculate systolic and diastolic values using an algorithmic approach. They are unaffected by background noise, but arm movement can cause errant readings. Both types of monitors are validated by the British Hypertension Society and the Association for the Advancement of Medical Instrumentation. Patients wear the monitor for a 24-hour period, usually a workday. The monitor is preprogrammed to record BP, usually every 15 to 20minutes during daytime hours and every 20 to 30minutes during night-time hours. Patients are instructed to keep an activity log throughout the testing period for evaluation of stress- and activity-related BP changes. Pickering et al.409 ABPM: Currently available ambulatory monitors are fully automatic and can record BP for 24 hours or longer while patients go about their normal daily activities. Most monitors use the oscillometric technique. They can be worn on a belt or in a pouch and are connected to a sphygmomanometer cuff on the upper arm by a plastic tube. Subjects are asked to keep their arm still while the cuff is inflating and to avoid excessive physical exertion during monitoring. The monitors are programmed to take a reading every 15 to 30 minutes throughout the day and night. At the end of the recording period, the readings are downloaded into a computer. Standard protocols are used to evaluate the accuracy of the monitors, and approved devices are usually accurate to within 5 mm Hg of readings taken with a mercury sphygmomanometer. The daytime level of ambulatory BP that is usually considered the upper limit of the normal range is 135/85 mm Hg. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure143 ABPM is warranted for evaluation of white-coat hypertension in the absence of target-organ injury. It is also helpful in patients with apparent drug resistance, hypotensive symptoms with antihypertensive medications, episodic hypertension, or autonomic dysfunction. Ambulatory BP values are usually lower than office readings. Individuals with hypertension have an average BP of 4135/85 mm Hg when awake and 4120/75 mm Hg during sleep. The level of BP measurement by using ABPM correlates better than office measurements in patients with target organ injury. ABPM also provides data on the percentage of BP readings that are elevated, the overall BP load, and the extent of BP reduction during sleep. In most individuals, BP decreases by 10 to 20% during the night; those in whom such reductions are not present are at increased risk for cardiovascular events. Home BP monitoring: Home measurement devices should be checked regularly for accuracy. European Society of 1. Refers to http://www.dableducational.org/ for UK available ABPM and home measuring devices. 2. Details proper equipment and technique. 3. Outlines accepted and potential clinical indications for ABPM. Out-of-office BP measurements are now recommended as part of the proper diagnosis of hypertension. ABPM should be offered to confirm the diagnosis of hypertension if two BP measurements during an office consultation are X140/90 mm Hg. If ABPM is used, at least two measurements per hour must be taken during waking hours (08:00 to 22:00). The average value at least 14 measurements taken during the waking hours is needed to confirm the diagnosis of hypertension. Home BP monitoring is a suitable alternative to ABPM and requires two consecutive BP measurements a minute apart in the seated position, taken twice daily (usually morning and evening) for at least 4 days (but ideally 7). The first day s measurements are discarded and the average of the remaining measurements are used to confirm a diagnosis of hypertension. Stage 1 hypertension is diagnosed if average BP from ABPM or home monitoring is Z135/85 mm Hg. When using ABPM or home BP monitoring to assess response to treatment, the target average BP during waking hours should be o135/85 mm Hg for people aged under 80 years and o145/85 mm Hg for people aged Z80 years. ABPM, ambulatory blood pressure monitoring; BP, blood pressure. pulse wave velocity have been widely performed in the general, hypertensive, and diabetic populations as well as to a limited extent, in hemodialysis patients, in whom the correlation of pulse wave velocity with mortality has been Pulse wave velocity may be increased in early CKD34,404,405 but it is unclear what this means in terms of CVD risk and kidney-disease prognosis. It is also unclear whether treatment of BP will alter pulse wave velocity in the longer term for CKD 1-5 patients and if so, whether this might influence the prognosis. While sophisticated studies such as pulse wave velocity are unlikely to become widespread in the global CKD community, especially in less economically advanced com- munities, further research is likely to lead to better use of this tool for assessment of BP related changes in the cardiovas- cular system in CKD patients and possibly to treatment changes based on pulse wave velocity indices. 8.2: IS THERE AN EVIDENCE-BASED LOWER LIMIT FOR BP REDUCTION? The Work Group discussed whether it would be preferable to recommend a target range (lowest to highest) for BP rather than just a single target for highest acceptable BP. Although the benefits of lowering BP in CKD have been demonstrated, allowing us to recommend that we should aim for BP consis- tently r140/90 mm Hg when albumin excretion is o30 mg per 24 hours and r130/80 mm Hg if albumin excretion is Z30 mg per 24 hours in both non-diabetic (Chapter 3) and diabetic (Chapter 4) adults with CKD ND, we were unable to give any recommendations for a lower BP target level due to a lack of evidence. There are observational data that support the intuitive notion that excessive BP reduction might be harmful, at least in trials that have not specifically recruited CKD patients. In a cohort of 4071 very elderly (Z80 years) ambulatory American veterans (hence 96.6% males) with hypertension on 1.7 1.2 (mean SD) antihypertensive medication classes, a J-shaped survival curve was noted when the relationship between both systolic and diastolic pressure and survival was examined. The optimum survival was associated with the ranges of diastolic BP between 70 79mm Hg and systolic BP between 130- In another smaller study (n 331) of mortality with 2 year follow-up in elderly hospitalized subjects 470 years with vascular disease or hypertension, the longest survival was observed when diastolic BP was in the range 71 80mm Hg, with a pronounced increase in risk with diastolic BP r60mmHg.410 Further evidence to discourage aggressive reduction in BP in high risk groups comes from secondary analyses of outcomes associated with achieved BPs in the context of large RCTs. Such analyses are retrospective in nature and the trials themselves have not specifically recruited (and often excluded) patients with reduced GFR, so they cannot be used to formulate a guideline for a lower BP target in the context of CKD. One example of such a study is a retrospective analysis of the active treatment group of the SHEP trial. In this study, 4736 subjects aged Z60 years with a systolic BP 4160mmHg and diastolic o90mmHg were randomized to placebo or BP reduction with chlorthalidone with or without atenolol to reduce systolic BP. Perhaps surprisingly, a low diastolic BP on treatment was associated with an increased risk of stroke, coronary heart disease and CVD.41 Likewise in INVEST, a multi-national RCT comparing verapamil sustained-release and atenolol-based treatment in 22,576 patients with hypertension and CAD, BP control and outcomes were equivalent between the groups, but the risk of the primary outcome (all-cause death, non-fatal myocardial infarction and non-fatal stroke) progressively increased with a BP lower than 119/84mmHg, although taken alone, stroke risk did not increase with lower BP. After adjustment for multiple variables the relationship between low diastolic BP and primary outcome Further analysis of the above association including only the 2699 patients with peripheral artery disease also showed a J-shaped relationship, such that the primary outcome occurred least frequently at a systolic BP of 135-145mmHg and a diastolic BP of 60-90mmHg, with the effect most strongly related to Stratifying patients into those aged o60, 60 to o70, 70 to o80 and Z80 years and plotting survival versus diastolic BP produced a pronounced J-curve effect with a HR nadir at 75mmHg up to 80 years, then 70mmHg for subjects 480 years. For systolic BP the HR nadir increased with increasing age: 115mmHg up to 70 years, 135mmHg for In ONTARGET involving 25,588 patients with athero- sclerotic disease or diabetes with organ damage, a J-shaped relationship between on-treatment systolic BP (nadir around 130 mm Hg) and all outcomes except stroke was observed in a Data from IDNT showed that a systolic BP below 120 mmHg was associated with an increased risk of cardiovascular deaths and congestive heart failure, but not myocardial infarction in hypertensive type 2 diabetics.228 Finally, in the ACCORD study, while targeting a systolic BP of o120 mm Hg rather than o140 mm Hg did not reduce cardiovascular outcomes, serious adverse events occurred in 3.3% of the lower BP group compared with 1.3% (po0.001) in the higher BP target group indicating the potential penalty paid for aggressive BP reduction.159 In CKD ND patients, there is observational evidence from two community-based longitudinal studies including 1549 subjects with CKD 3-4. In one study, a J-shaped relationship between stroke and systolic BP was observed, with lowest stroke risk in the range of systolic BP between 120 and 129 mm Hg, and higher risk above and below this.158 A cohort study of 860 US veterans (comprising mainly men) with CKD (GFR o60 and a subset with GFR o30 ml/min/ ) showed greater mortality when systolic BP was o133 mm Hg or diastolic BP o65 mm Hg, although it appeared that the association might not be causal but instead related to atherosclerotic CVD as a co-morbidity.413 In summary, with respect to a lowest BP target, most of the relevant evidence is observational, derived from retro- spective analyses, and nearly all involves non-CKD popula- tions. No studies to date have specifically tested a strategy of reducing blood-pressure-lowering drug treatment if the BP falls below a certain limit. We anticipate that there would be major practical difficulties in implementing such a practice, particularly in patients with reduced conduit artery com- pliance and consequent increased pulse pressure (in whom a lower limit for diastolic BP might entail accepting an systolic BP much higher than the current targets). Although the available evidence is enough to support our guideline statements advising caution in those with co-morbidity, we do not consider it is robust enough to allow us to specify a lower limit for either systolic BP or diastolic BP, even though other organizations have done so.396 Although inferences can be drawn when treatment-related BP is too low, especially in patients with diabetes, the elderly and those with CVD, we are left without a lowest BP target. The NIH funded SPRINT trial currently recruiting patients in the US may clarify this issue. It will randomize over 7500 patients with systolic BP to targets of o140mmHg or o120mmHg, deliberately including approximately 1750 patients over 75, and followed for cardiovascular, cognitive and kidney end points over a period of 9 years, commencing 2010.171,172 8.3: SHOULD A REDUCTION IN ALBUMINURIA BE A TARGET FOR TREATMENT WITH AGENTS THAT MODIFY BP? As outlined elsewhere in this Guideline, RAAS intervention is effective in not only lowering BP but also protecting individual patients with CKD from further decline in kidney function. Although the BP-lowering effect of RAAS inhibi- tion contributes to renoprotection, a component of the protective effect may be independent of the effect on BP. Thus, to achieve maximum renoprotection using a RAAS inhibitor, the clinician might consider monitoring the reduction in urine albumin excretion (an off target effect). This is particularly important in macroalbuminuric and microalbuminuric hypertensive subjects with type 2 diabetes, in whom the BP response to RAAS inhibitors may be discordant with the anti-albuminuric response.414,415 Studies in such patients indicate that those in whom urine albumin was lowered without significant lowering of BP gained some renoprotection, whereas patients who did not have urine albumin lowered in spite of BP-lowering did not have Thus, albuminuria may be an independent factor in renoprotection. In a prospective study supporting this concept, Hou et al.416 detected nearly 50% additional renoprotection with a dose of a RAAS inhibitor titrated to maximally reduce urine albumin levels as compared to a standard dose used for the BP lowering effect. There have been no RCTs assessing hard renal or cardio- vascular outcomes, in which patients have been randomized to different targets of urinary albumin excretion irrespective of BP. 8.4: SHOULD RAAS INHIBITION BE MAXIMIZED IN CKD PATIENTS? Accepting that RAAS inhibitors may be used to both lower BP and urine albumin excretion, options are available to optimize the albuminuria lowering effect of these agents. For example, it is well recognized that co-administration of a low-sodium or the addition of a diuretic63,66,419 enhances the effect of both ACE-Is and ARBs on lowering urine albumin excretion. Such therapeutic combinations make good sense and are unlikely to be associated with harmful side effects. Whether more aggressive blockade of the RAAS using supramaximal doses of ACE-Is or ARBs is beneficial is less certain. Recently, Burgess et al.420 showed that increasing the dose of candesartan well beyond the guideline-recommended dose for BP-lowering resulted in further reduction of the urine albumin levels. The substantial evidence suggesting that RAAS inhibition using ACE-Is or ARBs has renoprotective effects when these agents are used individually has led to the hypothesis that combining the two classes of agents, or adding an aldosterone antagonist or a DRI, may provide additional benefit. Interest in this approach has been increased by the evidence that individuals treated with ACE-Is may have aldosterone breakthrough 89 with angiotensin I to angiotensin II conversion occurring via other and by the fact that there may be other active receptors for angiotensin II422 that may have a range of roles. A number of moderate-sized studies, mostly in patients with diabetes, have demonstrated that proteinuria levels may be further lowered by combining ACE-Is and ARBs than by using each agent alone.423 Aldosterone antagonists may substantially lower proteinuria when used on top of ACE-Is Similarly when the DRI, aliskiren, was added to proteinuria was reduced. The optimism generated by these findings has recently been seriously dampened. The ONTARGET trial did not demonstrate any cardiovascular benefit for dual RAAS blockade (with the ACE-I ramipril and the ARB telmisartan), in a population at high risk of CVD, but did suggest an increased risk of major renal outcomes with dual RAAS blockade.281 This finding has been questioned for a range of reasons, and it has been suggested that the result may have been different if the population included a greater number of patients with CKD.425 The ALTITUDE trial randomized type 2 diabetic partici- pants to receive either aliskiren or matching placebo on top of an ACE-I or ARB113 and included a large number of diabetic individuals with CKD.426 Although the results have not been published at the time of writing this Guideline, the trial was recently stopped early due to a low likelihood of ever demonstrating benefit and a suggestion of an increased risk of some adverse outcomes, including non-fatal stroke, renal complications, hyperkalemia and hypotension,427 resulting in the US FDA counselling against this practice.114 As a result, any benefits of combined blockade of the RAAS for clinically important renal outcomes currently remain unproven, and the safety issues should be taken into account prior to using this therapeutic approach. 8.5: SHOULD ACE-IS AND ARBS BE DISCONTINUED IN CKD 5 BECAUSE THEY COMPROMISE RESIDUAL KIDNEY FUNCTION? It has long been recognized that commencing ACE-Is and ARBs can lead to an acute reduction in GFR that may be reversed if the dose is reduced or if the drug is discontinued. This phenomenon has been observed in the context of RCTs such as the RENAAL trial. In a post hoc analysis of this study, an initial fall in GFR was found to predict better long-term Such acute changes in GFR are likely to reflect the hemodynamic changes that accompany initiation of RAAS blockade.88,428 However, since a reduction in GFR is not usually considered beneficial, observers have recently questioned the value of commencing or continuing BP- lowering regimens based on an ACE-I or ARB in elderly patients with advanced CKD and have specifically suggested that use of such agents in CKD 4 5 patients may compromise residual kidney function or even accelerate its rate of decline in both diabetic429 and non-diabetic patients.430 This opinion is based on uncontrolled observations and is contrary to the observations made from the RENAAL RCT in patients approaching renal replacement therapy.431 For example in one such observational study, discontinuation of ACE-Is and ARBs in 52 patients with CKD 4 5 was followed by a greater than 25% increase in the GFR in 61.5% of patients, and a greater than 50% increase in 36.5% of An RCT that specifically randomized patients with advanced CKD to benzapril or placebo did not support The study reported that 112 predominantly CKD 4 patients with a mean GFR of 26 ml/min/1.73 m2 receiving benzapril had a lower risk of doubling of SCr, kidney failure, or death compared with the same number of patients receiving placebo. A small study of 60 peritoneal dialysis patients showed better preservation of residual kidney function among patients randomized to ramipril as com- pared to no treatment.432 Thus, the current evidence does not support the discontinuing ACE-Is and ARBs in patients with advanced CKD in an effort to preserve residual kidney function, although hyperkalemia or hypotension may be a specific reason for discontinuation in some patients. 8.6: ETHNICITY, RACE, AND GENES In this Guideline, the individualization of BP control is emphasized, yet specific advice to tailor therapy according to ethnicity, race, or genetic influences is not available. In lieu of such advice, we have drawn on RCTs specific to various racial and ethnic populations: African-American, Chinese, Japa- nese, Pakistani, and European whites (sometimes from a single country). We have generalized the observations derived from these ethnicity- or race-specific RCTs to management advice applicable to all ethnic and racial groups. However, there is good reason but not good evidence to believe that ethnicity, race, and genotype influence elevated BP and CKD, with familial aggregation and ethnic racial disparities in both conditions. Currently, it is difficult to disentangle ethnic - racial disparities from social, economic, and environmental disparities. The evidence for ethnic or racial influence on CKD is mainly epidemiological. 