The Work Group believed that the data for reducing usual systolic BP to r140 mm Hg and diastolic BP to r90 mm Hg were strong, on the basis of the data presented above, as well as the clear relationship between BP levels and the risk of cardiovascular and kidney out- comes consistently noted in observational studies in both the and in patients with diabetes with a systolic BP 4140 mm Hg and a diastolic BP Further support is provided by reports from a number of clinical trials or trial subgroups demonstrat- ing that BP-lowering therapy prevents cardiovascular and kidney events in patients with diabetes, most of whom had BP levels 4140/90 mm Hg at trial entry.183,219,221,223,232 There are few data for individuals with diabetes and CKD, but those that are available have reported broadly consistent findings.234 The Work Group does not believe that the evidence is sufficiently strong to support a lower target BP level for all patients with diabetes and CKD. Some support for lower BP targets is provided by the ACCORD and ABCD trials population. However in ACCORD, these benefits must be balanced against the increased risk of adverse events. As a result, it was felt that the risk-to-benefit ratio is likely to be unfavorable for at least some groups of individuals with diabetes and CKD. These include patients with diabetes and non-albuminuric CKD, who may be likely to have additional co-morbidities; the elderly, who are prone to falls; patients with marked systolic hypertension; and those with severe autonomic neuropathy. Such patients may have been under- represented in the RCTs and observational studies. A target BP of r140 systolic and r90 mm Hg diastolic may appear to require less aggressive therapy than the targets recommended in some other guidelines for patients with diabetes. However, whether this is true depends on how targets are interpreted by clinicians. There is extensive evidence from routine clinical practice that many patients do not achieve the targets set in guidelines; instead, achieved values often have a normal distribution around the target.22 This distribution of values is the reason for the wording we have chosen for the recommendation statements: that BP be consistently below a given level. For instance, to account for random fluctuations in resting office BP over time, the intervention threshold needs to be significantly o130 mm Hg to achieve a systolic BP consistently o130 mm Hg. The Work Group, therefore, is confident that most individuals with diabetes and CKD should have their usual BP lowered to be consistently r140/90 mm Hg (hence the grade of 1B for recommendation 4.1), and that targets lower than r140/90 mm Hg could be considered on an individual basis for patients believed to be more likely to benefit than to be harmed by the treatment (e.g., patients not already on several BP-lowering agents, younger individuals, or persons at high risk of stroke). Overall, the evidence supporting the statement that systolic BP should be lowered to r140 mm Hg is at least level B. However, the evidence supporting the implication that systolic BP needs to be lowered further, for instance to r130 mm Hg, is weaker. This grading should not, therefore, be taken to imply that no further research is required on the question of lower BP targets in this group. Comparison with current guidelines. Recommendation 4.1 is consistent with recommendations made by numerous international and national guidelines for the general popula- all of which agree on a treatment goal of r140/ 90 mm Hg on the grounds that BP-lowering drugs reduce the risk of all-cause and cardiovascular mortality in people whose BP is 4140/90 mmHg. There is no reason to expect that patients with diabetes and CKD are less likely to have a benefit. Although there is observational evidence that the risk of CVD is higher among diabetic patients than non-diabetic patients at any given BP, these findings do not, in the absence of RCT evidence, support a recommendation that BP should be lowered further than is recommended in diabetic patients. The Work Group is aware that this recommendation appears more conservative than the recommendations of some other international and national guidelines that recommend a BP target r130/80 mm Hg for patients with diabetes and CKD.1,9,30,237 240,243,245 247 However, there is insufficient high-quality evidence from RCTs to support a lower target for patients with diabetes and CKD (which we ) who do not have an increased urinary AER. All other guidelines have relied on observational evidence to support a lower systolic BP threshold for patients with diabetes. The Work Group did not consider the evidence from the HOT220 trials strong enough to justify a recommendation to lower the target diastolic BP to r80 mm Hg. The Work Group analyzed the evidence base for the existing guidelines carefully to ensure that the apparent departure from accepted wisdom was justified. Few existing guidelines specify how patients with normoalbuminuric CKD and diabetes should be treated with BP-lowering drugs, with the majority advising a BP target of r130/80 mmHg for all patients with diabetes, irrespective of GFR or albuminuria. Although the grades (and grading system) of these recommendations vary, all supporting statements acknowledge that the evidence is largely observational. For instance, many guidelines refer back to JNC 7,9 which qualified the recommendation with the caveat, although available data are somewhat sparse to justify the low target level of 130/80 mmHg y. The JNC 7 goes on to cite the American Diabetes Association guidelines245 and the supporting literature analysis,235 which rely on the HOT for justification of the 80 mmHg diastolic BP and on Systolic Hypertension in the Elderly Program and Systolic Hypertension in Europe (Syst-Eur) (both studies of the general population) for the 140 mmHg systolic BP target. Finally, the JNC 7 states that Epidemiological studies indicate that there is a benefit to reducing systolic BP still further to 130 mm Hg or below , citing two references, UKPDS 36229 and a study from Allegheny County that contains no data on BP.249 We have not made recommendations about the choice of the BP-lowering drug to be used in patients with CKD and diabetes who do not have elevated rates of urinary albumin excretion. Although there is some evidence that inhibitors of the renin angiotensin system might prevent an increase in particularly in the presence of higher and might also reduce cardiovascular risk, such studies have not been performed in patients with reduced GFR but normal urinary albumin excretion. In such patients, the balance of risks and benefits of the use of ACE-Is or ARBs may well differ from the balance of their use for primary prevention of diabetic kidney disease. Considerations. Most interpretations of the observational evidence predict that achieved BPs below a target of r140/ 90 mm Hg in patients with CKD and diabetes would be associated with additional benefit in the prevention of both progressive kidney disease and cardiovascular events. However, no RCTs have demonstrated such a benefit. It remains possible that clinical harm could be done, at least in some subgroups, by attempting to reach lower BPs. Achieving lower BPs would require multiple drug treatments in the majority of patients with CKD and diabetes, particularly those with high pulse pressures. This has implications both for adherence and for the cost of treatment, of which the latter is particularly important in resource-poor settings. 4.2: We suggest that adults with diabetes and CKD ND with urine albumin excretion 430 mg per 24 hours (or equivalent*) whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r130 mm Hg systolic and r80 mm Hg diastolic. (2D) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Observational studies show that the level of urine albumin predicts the risk of adverse cardiovascular and kidney outcomes. K BP lowering reduces the rate of urinary albumin excretion, which may in turn lead to a reduced risk of both kidney and cardiovascular events, although this has not been shown in RCTs. RCTs. The Work Group found only one RCT, from the Steno Diabetes Centre in Copenhagen (Intensified Multi- factorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria [Steno-2 study]) in which diabetic patients with high urine albumin were selected and randomized to two BP targets.209,211,253 In the Steno-2 study, 160 adults with microalbuminuria and type 2 diabetes were randomized to intensive multifactorial intervention or to conventional therapy. The intensive-care arm received ACE-I or ARB irrespective of BP and had a BP target that was initially 140/85 mm Hg but was reduced to 130/80 mm Hg during the study, as compared to o160/95 mm Hg which was subsequently reduced to o135/85 mm Hg in the conven- tional arm. However, intensive intervention also included dietary advice, exercise, lipid-lowering treatment, help with smoking cessation, vitamin supplementation, aspirin, and intensified glycemic control. This intensive therapy was shown to be associated with a reduced risk of CVD, nephropathy, retinopathy, and autonomic neuropathy. The improvements seen in the intensive-therapy group were mostly in BP and the lipid profile, with only minor differences between the two groups in glycemic control and no differences in smoking, exercise measures, or body Observational evidence. There is strong observational evidence of an association between higher BP and an increased risk of worsening kidney function.148,201,225,254,255 Diabetic patients with microalbuminuria are at increased risk of both and progressive kidney disease as compared to diabetic patients with normal albumin excretion.256 258 Reduction of the rate of urinary albumin excretion during treatment is associated with a better kidney and cardiovascular However, these associations do not prove causation, and it remains possible, albeit highly unlikely, that patients in whom the rate of urine albumin excretion declines, either spontaneously or in response to treatment, have intrinsically less severe disease than those in whom no remission occurs. RCTs examining the effects of targeting certain levels of urine albumin on clinically relevant end points are needed before it can be concluded that treatment to reduce the rate of urinary albumin excretion will improve prognosis. The Work Group therefore felt that benefits of targeting lower BP levels were likely to be greater for individuals with micro- or macroalbuminuria, so a target BP of r130/ 80 mm Hg is suggested; however, stronger evidence is required in this population, hence the grade of 2D. 4.3: We suggest that an ARB or ACE-I be used in adults with diabetes and CKD ND with urine albumin excretion of *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Patients with diabetes and microalbuminuria are at increased risk of kidney failure and cardiovascular events. K ACE-Is and ARBs reduce the level of urine albumin in patients with diabetes and microalbuminuria at baseline, but data regarding the effects on kidney failure or cardiovascular outcomes are limited. Microalbuminuria is much more common than frank proteinuria or albuminuria in patients with diabetes, but it is also associated with an increased risk of kidney and cardiovascular events. Several trials have shown a benefit of ACE-Is or ARBs over placebo in patients with microalbumi- nuria, irrespective of pre-treatment BP (See Supplementary All of these trials studied the effects of treatment on surrogate outcomes, most commonly the transition to overt proteinuria; none demonstrate conclu- sively that these improvements are associated with a reduction in hard end points in this population, although this may be the result of low event rates, inadequate statistical power, and short follow-up times. The Work Group believes that ACE-Is and ARBs should be the preferred classes of BP-lowering agent used in patients with diabetes and microalbuminuria, although the relatively weak available evidence is reflected in the poor grade assigned to this guideline statement (2D). We have not made statements about prevention of microalbuminuria as this topic will be addressed in the forthcoming KDOQI Diabetes guideline update.268 4.4: We recommend that an ARB or ACE-I be used in adults with diabetes and CKD ND with urine albumin excretion 4300mg per 24 hours (or equivalent*). (1B) *Approximate equivalents for albumin excretion rate per 24 hours expressed as protein excretion rate per 24 hours, albumin/creatinine ratio, protein/creatinine ratio, and protein reagent strip results are given in Table 1, Chapter 1. RATIONALE K Patients with diabetes and high levels of urine albumin are at a particularly high risk of adverse cardiovascular and kidney outcomes. K There is strong evidence from RCTs conducted in patients with diabetes and CKD demonstrating that ACE-Is and ARBs protect against kidney failure and increases in albumin levels. Individuals with elevated levels of urinary albumin or protein and diabetes have some of the highest rates of cardiovascular events and kidney failure of any group with CKD. For example, in IDNT and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, the annual risk of the kidney and cardio- vascular end points all approached 10%.182,184,259 261 RCTs. Several RCTs have provided high-quality evidence, both in type 1 diabetes269 that ARBs and ACE-Is reduce the risk of kidney outcomes270 as compared to placebo or a dihydropyridine calcium-channel although no clear effect on cardiovascular out- comes has been established (possibly due to inadequate power) (see Supplementary Tables 37 42 online). How- ever, applicability of study findings to the entire CKD and diabetes population is somewhat limited, because major studies have excluded patients with clinically significant CVD. There is high-quality evidence from trials of high-risk individuals from the general population showing that ARBs and ACE-Is improve cardiovascular outcomes,185,271 276 including in patients with diabetes.277,278 But these studies did not focus on patients with clinically significant albuminuria. In contrast, there was no benefit of ACE-Is as compared to diuretic therapy in the CKD and diabetic subgroups in ALLHAT,279 although, again, few of the study patients were likely to have had frank albuminuria. Moreover, ALLHAT showed clear BP differences in favor of diuretic therapy over ACE-Is, making the comparison between the two groups somewhat difficult. As the RCT data in this population is strong and consistent, the level of evidence is high (see Supplementary Table 37 online). The decision on the grade of this recommendation statement (1B) was made by a majority vote. The minority of Work Group members supported an evidence grade of A. The choice between an ACE-I and an ARB in CKD patients is controversial. In general, the evidence for kidney outcomes that supports the use of ACE-Is is older and applies largely to type 1 diabetes, whereas the evidence supporting the use of ARB comes from more recent trials in type 2 diabetes. For cardiovascular protection in patients with diabetes, the evidence largely points to ACE-Is. The available data are consistent, suggesting the effects of both classes of agents are likely to be similar. Cost and availability may be an important consideration in some countries. However, extra- polations within and between drug classes must be made with care: within-class effects on hard outcomes may differ substantially and may depend on the dose, making extrapolation to other drug classes problematic. A 2004 meta-analysis concluded that there was insufficient evidence on the relative effects of ACE-Is versus ARBs on survival.280 We were unable to find trials directly comparing ACE-Is and ARBs in patients with diabetes and albuminuria. No clear difference between the effects of the two classes of drugs was found in the large Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET) trial involving people at high cardiovascular risk, including subgroups with diabetes or CKD.281,282 However, this study was not powered to make this comparison, so a real difference remains possible. The data are even more scarce regarding the effects of other drug classes on outcomes in patients with diabetes and proteinuria. In IDNT, patients with proteinuria were rando- mized to irbesartan, amlodipine, or placebo. Amlodipine did not significantly affect the risk of kidney or cardiovascular events as compared to placebo and was clearly inferior to irbesartan for the prevention of kidney outcomes.184 Aldoster- one antagonists can reduce the risk of proteinuria in non- diabetic CKD patients109,283 and in patients with diabetic but adequately powered studies are lacking. In the opinion of the Work Group, ACE-Is and ARBs are likely to be similarly effective in improving outcomes in patients with diabetes and proteinuria. Practitioners should therefore base prescribing decisions on the evidence available for each class, the risk of side effects, and cost considerations. RESEARCH RECOMMENDATIONS K Prospective RCTs of a risk-based approach to the reduction of cardiovascular risk and kidney end points are encouraged. K Studies comparing various BP intervention thresholds and targets among patients with diabetes, with or without an increased urinary AER, and with or without a reduced GFR are needed. K Studies in which drug dose is titrated on the basis of the urine albumin level (or change in GFR) are needed. K Studies on the effects of non-dihydropyridine calcium- channel blockers on long-term outcomes are needed. K Prospective studies of add-on therapy (consisting of thiazides, aldosterone antagonists, or DRIs) and reduc- tion of sodium chloride intake on the effects of ACE-Is or ARBs in patients with diabetes and CKD are encouraged. K Prospective studies of the combination of ACE-Is and ARBs in patients with diabetes and CKD are encouraged. K Prospective studies of different target BP levels stratified by GFR are encouraged. 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 contribu- tor, 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 37. Evidence profile of RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM. Supplementary Table 38. RCTs examining the effect of ACEI or ARB vs. placebo in patients with CKD and DM [categorical outcomes]. Supplementary Table 39. RCTs examining the effect of ACEI or ARB vs. placebo in patient with CKD and DM [continuous outcomes]. Supplementary Table 40. Evidence profile of RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM. Supplementary Table 41. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 42. RCTs examining the effect of ACEI or ARB vs. dihydropyridine CCB in patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 43. Evidence profile of RCTs examining the effect of ACEI vs. ARB in patients with Type 2 DKD. Supplementary Table 44. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 45. RCTs examining the effect of ACEI vs. ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 46. Evidence profile of RCTs examining the effect of ARB vs. ARB in patients with CKD and DM. Supplementary Table 47. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 48. RCTs examining the effect of ARB vs. ARB in overtly albuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 49. RCTs examining the effect of DRI ARB vs. placebo ARB in microalbuminuric patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 50. RCTs examining the effect of dihydropyridine CCB vs. placebo in overtly albuminuric patients with CKD and Type 2 DM [categorical outcomes]. Supplementary Table 51. RCTs examining the effect of aldosterone antagonist ACEI vs. placebo ACEI in patients with CKD and Type 2 DM [continuous outcomes]. Supplementary Table 52. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [categorical outcomes]. Supplementary Table 53. RCTs examining the effect of endothelin antagonist vs. endothelin antagonist in patients with CKD with Type 2 DM [continuous outcomes]. Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/bp.php Chapter 5: Blood pressure management in kidney transplant recipients (CKD T) INTRODUCTION This chapter addresses the management of BP in adults with non dialysis-dependent CKD who have received a kidney transplant (CKD T). There is insufficient evidence to make recommendations specific to children with a kidney transplant. 5.1: We suggest that adult kidney transplant recipients whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg diastolic be treated to maintain a BP that is consistently r130 mm Hg systolic and r80 mm Hg diastolic, irrespective of the level of urine albumin excretion. (2D) RATIONALE In adult kidney transplant recipients we consider two primary outcomes from the standpoint of BP: graft function and CVD. High BP is well recognized as an important risk factor for both decline in graft function and develop- ment of CVD.153,284 288 Increased levels of both systolic and diastolic BP are associated with worse graft survival over a 7-year period after transplantation,289 and maintaining a systolic BP o140 mm Hg at 3 years after transplantation is associated with improved graft survival and reduced cardiovascular mortality at 10 years.290 Similarly, high BP is associated with an increased risk of graft loss and all-cause Although no RCT defines BP targets in adult kidney transplant recipients for clinically important end points such as graft survival, cardiovascular events, or all-cause mortality, our suggestion is that the BP target should not deviate from the recommended target of r130/80 mm Hg as defined in the recent KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients,292 since there have been no recent data to contradict this recommendation. Although the European Best Practice Guidelines for Renal Transplantation 2002 recommended a target BP r125/ 75 mm Hg in proteinuric patients, there is no evidence to differentiate BP target based on albumin excretion in renal Because adult CKD T patients are at high risk for both graft loss and development of CVD,284 288 we favor a target of r130/80 mm Hg rather than a target of r140/90 mm Hg. We recognize that this recommendation is based on observational data and have therefore given it a grade of 2D. 5.2: In adult kidney transplant recipients, choose a BP- lowering agent after taking into account the time after transplantation, use of calcineurin inhibitors, presence or absence of persistent albuminuria, and other co-morbid conditions. (Not Graded) RATIONALE BP-lowering agents are prescribed in 70 to 90% of kidney transplant recipients, according to both registry reports and There are many considerations in choosing anti- hypertensive drugs for use in adult kidney transplant recipients. These include side effects that are also seen in the general population, side effects particular to kidney transplant patients (e.g., increased propensity to hyperkalemia or anemia with ACE-Is or ARBs), level of urine albumin, degree of hemodynamic stability and the associated potential to alter graft perfusion (especially in a period soon after transplanta- tion), co-morbid conditions that may indicate or preclude certain agents, interactions with immunosuppressive medica- tions or other medications unique to patients with kidney transplant patients, and long-term impact on graft function, CVD, and all-cause mortality.296 Because of these considera- tions and the absence of large trials with clinically important outcomes, there is marked variability in the prescription of cardioprotective medications after transplantation.294 Short-term RCTs (of duration r2 years) suggest a beneficial effect of calcium-channel blockers, as compared with either placebo or ACE-Is, with regard to level of kidney In addition, a recent meta-analysis of RCTs indicated that the use of calcium-channel blockers, versus placebo or no treatment (plus additional agents in either arm, as needed) was associated with a 25% lower rate of graft loss (relative risk [RR] 0.75; 95% CI 0.57 0.99) and higher These findings prompted the Canadian Society of Transplantation and Canadian Society of Nephrology to question the recommen- dation from the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients to use any class of antihypertensive agent after kidney transplantation.292,302 Most transplantation centers prefer to use dihydropyridine calcium-channel blockers for initial therapy after transplan- tation, since these agents dilate afferent arterioles and counteract the vasoconstrictive effect of CNIs298,303 (Supple- mentary Tables 54 59 online). However, non-dihydropy- ridines might interfere with the metabolism and excretion of chapter 5 http://www.kidney-international.org & 2012 KDIGO the CNIs cyclosporine and tacrolimus, as well as the mTOR inhibitors sirolimus and everolimus. When renal transplant recipients are prescribed non-dihydropyridine calcium- channel blockers, careful monitoring of CNIs and mTOR inhibitors blood levels is required if drugs or dosages are changed. ACE-Is and ARBs are known to have acute hemodynamic effects, resulting in an increase in SCr level, and are therefore frequently avoided within the first 3 to 4 months after transplantation, when acute rejection is a strong possibility, and an increase in creatinine level can be difficult to Side effects of ACE-Is and ARBs when used soon after transplantation include increased creatinine levels, hyperkalemia, and anemia. One study showed that although 44% of patients were receiving ACE-Is or ARBs at the time of transplantation, the proportion dropped to 12% at 1 month and subsequently increased to 24% at 6 months.294 In the longer term, especially in kidney-transplant patients with persistent albuminuria, ARBs and ACE-Is should be considered. Two analyses of registry data have been published, with one showing a benefit and the other no benefit with the use of ACE-Is or ARBs for graft and patient Small trials have examined various agents to lower BP in kidney-transplant patients. One examined losartan, captopril, and amlodipine and noted no change in BP or kidney function between baseline and end of follow-up. ACE-Is and ARBs did, however, reduce the risk of proteinuria, as compared with a calcium-channel blocker308 (Supplementary Table 60 online). The Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) was an RCT of candesartan The primary outcome was all-cause mortality, cardiovascular morbidity, or graft failure. Enroll- ment of 700 patients was planned, but unfortunately, the study was terminated prematurely due to lower-than- expected event rates after enrollment of 502 participants because only 26 events took place in the 20 months of follow- up (with no difference in frequency between the two arms), whereas 210 events had been predicted over 3 years. Although there was slightly better BP control in the active group versus the control group (mean BP, 131/80 mm Hg vs. 137/ 83 mm Hg, respectively), the relatively tight BP control in both arms might have contributed to the low event rate. The protein excretion rate decreased in the ARB arm and increased in the placebo arm, but this difference may have been influenced by the different achieved BP levels (Supple- mentary Tables 61 62 online). A large Canadian RCT of ramipril versus placebo is It will enroll 528 kidney-transplant patients who underwent transplantation 46 months previously, have protein excretion of 40.2 g per 24 hours, and have a GFR . Outcomes will include doubling of SCr level, kidney failure, and death. Because no large studies with clinically important out- comes have been completed, we have chosen to follow the recommendations of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients292 and to provide an ungraded statement. RESEARCH RECOMMENDATIONS RCTs are needed to determine: K The optimal target BP for adult patients with kidney transplants with a focus on clinically important outcomes such as graft survival, CVD, and mortality. K The effects of ACE-Is and ARBs versus placebo, ACE-Is and ARBs versus calcium-channel blockers, and calcium- channel blockers versus placebo regarding long-term graft survival, CVD, and patient survival. 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 54. Evidence profile of RCTs examining the effect of ACEI or ARB vs. CCB in transplant recipients without DM. Supplementary Table 55. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [categorical outcomes]. Supplementary Table 56. RCTs examining the effect of ACE or ARB vs. CCB in transplant recipients with CKD without DM [continuous outcomes]. Supplementary Table 57. Evidence profile of RCTs examining the effect of CCB vs. placebo in transplant recipients without DM. Supplementary Table 58. RCTs examining the effect of CCB vs. placebo in transplant recipients [categorical outcome]. Supplementary Table 59. RCTs examining the effect of CCB vs. placebo in transplant recipients without DM [continuous outcome]. Supplementary Table 60. RCTs examining the effect of ACE vs. ARB in hypertensive transplant recipients without DM [continuous out- comes]. Supplementary Table 61. RCTs examining the effect of ARB vs. placebo in transplant recipients [categorical outcome]. Supplementary Table 62. RCTs examining the effect of ARB vs. placebo in transplant recipients 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 6: Blood pressure management in children with CKD ND INTRODUCTION This chapter addresses the management of BP in children (defined as 18 years or younger, although chronological age does not necessarily parallel biological or social development). Children with non-dialysis-dependent CKD (CKD ND) differ from adults in the etiologies of CKD, definition of hyperten- sion, and CKD associated co-morbidities. As cardiovascular end points such as myocardial infarction, stroke, or cardio- vascular death are rare, effects of high BP and its treatment on kidney outcomes (e.g., lowering of GFR, initiation of dialysis, or transplantation) and target-organ damage are relevant end points in studies of children with CKD, although in the longer-term, CVD has a more important role. Elevated BP and high BP are common in children with CKD, but RCTs of various treatment agents or targets are scarce. Observational studies and registry data311 315 demon- strate that more than half of children with CKD have high BP based upon a casual BP reading. Observational data also suggest that hypertensive children with CKD progress to kidney failure significantly faster than normotensive children In studies of young adults with kidney failure whose kidney disease began in childhood, the risk of cardiovascular death is extremely high.316,317 Sudden cardiac death is the main cause of cardiac death in these In light of the high prevalence and substantial morbidity associated with elevated BP in children with CKD, we systematically reviewed the existing literature and previously published guideline statements regarding the management of elevated BP in this vulnerable population. As RCTs are considered to provide the strongest evidence for CPGs, we reviewed RCTs with kidney and cardiovascular outcomes in which children with CKD was the study population. We supplemented this limited RCT evidence with information obtained from case series, cohort studies, and previous guideline statements on BP in healthy children and children with CKD. We further described the evidence base in detail in the narrative following each recommendation statement. The strict evidence-based approach of formulating recommendations may have resulted in statements that do not include some commonly accepted treatment practices in children. The rationale for this approach is that we do not wish to provide guideline recommendations and discourage research in areas where evidence is weak. The research recommendations listed at the end of the chapter illustrate areas where more evidence is needed. BACKGROUND Definitions. For this Guideline, the age range for children is defined as from birth through 18 years. The preferred method of BP measurement in children is auscultation, and reference tables for BP percentiles for age, sex, and height can be accessed at the National Heart, Lung, and Blood Institute s Fourth Report on the Diagnosis, Evaluation, and Treatment of High BP in Children and Adolescents at http://www.nhlbi. Throughout this guideline when we refer to thresholds or targets for BP therapy, we are referring to manual, auscultatory measurements of both systolic and diastolic BP unless otherwise specified. Correct BP measurement requires a cuff that is appropriate to the size of the child s upper arm and elevated BP must be confirmed on repeated visits. In deciding on treatment, unless severe hypertension is present, an individual s BP level should be determined as an average of multiple BP measurements taken over weeks Current recommendations suggest that measurements obtained by oscillometric devices that exceed the 90th percentile for age, sex, and height should be repeated by auscultation.319 Detailed descriptions of appropriate BP measurement techniques in children and the strengths and limitations of various BP measure- ment methods in children with CKD have been detailed previously in the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease, Guideline 13: Special Considerations in Although there is insufficient trial evidence to recommend the use of ABPM in this Guideline, by virtue of frequent measurement and recording, ABPM allows the practitioner to compute the mean BP during the day, night, and over 24 hours, as well as to assess the time in which BP exceeds the upper limit of the normal range (i.e., the BP load). A number of reviews and guidelines suggest that in children with CKD, ABPM is a particularly useful tool to assess BP patterns.320 322 In children, ABPM can be particularly useful, as a significant number of patients have masked hypertension and would not be recognized as having hypertension based on the outpatient measurements only. A few studies using ABPM in patients with CKD suggest that it may give a better measure of overall BP and better indicate risk for kidney disease progression than office BP measurement.12,77,323 In fact, the only large RCT of BP control in children with CKD used ABPM as the method for BP assessment.14 Further research may elucidate chapter 6 http://www.kidney-international.org & 2012 KDIGO that future guidelines for therapy should be based on ABPM, rather than office based measures that are commonly used today. We have not recommended ABPM targets in this Guideline as ABPM is currently expensive and not readily available as routine clinical care in many settings. 6.1: We recommend that in children with CKD ND, BP- lowering treatment is started when BP is consistently above the 90th percentile for age, sex, and height. (1C) RATIONALE CVD has long been recognized as a substantial cause of late morbidity and mortality in individuals with onset of CKD The majority of children with CKD are and a substantial proportion show evidence of target-organ damage associated with both masked and confirmed hypertension in a dose dependent fashion.325 However, few RCTs directly comparing thresholds for initiation of BP treatment (vs. no treatment) or targets of BP treatment to prevent or reverse target-organ damage have ever been performed in children with CKD. Observational studies of healthy children suggest that persistent elevations in BP are associated with significant late sequelae. In cross-sectional studies, elevated BP is associated with evidence of target-organ damage, including left ventricular hypertrophy and increased carotid intimal medial In longitudinal analysis from the Bogalusa Heart Study, high systolic or diastolic BP was associated with an increased risk of developing kidney failure during long-term and high childhood BP was an independent predictor of increased ankle brachial pulse wave velocity in Persistently elevated BP in the young has been associated with decreased measures of carotid artery In healthy children, in the absence of long-term data linking specific BP levels with adverse cardiovascular or kidney events, hypertension is defined on the basis of a population-based distribution. Specifically, hypertension is defined as average systolic BP or diastolic BP that is greater than or equal to the percentile for sex, age, and height on three or more In healthy children, the goal of anti-hypertensive treatment is reduction of the BP to below the 95th percentile, unless concurrent conditions are present. CKD is considered such a concurrent condition. In children with CKD, according to the Fourth Report on the Diagnosis, Evaluation, and Treat- ment of High BP in Children and Adolescents, the BP should be lowered to below the 90th percentile (http://www.nhlbi.nih. The rationale for this approach is similar to the recommended treatment of hypertension in adults with additional cardiovascular risk factors or co-morbid conditions. A number of expert panels have reviewed the existing literature and made similar recommendations. The National High Blood Pressure Education Program Working Group on High BP in Children and Adolescents has recommended initiating pharmacologic therapy for BP above the 90th percentile if a compelling indication such as CKD is In 2004, the NKF KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease1 recommended that the target BP in children with CKD should be lower than the 90th percentile for normal values adjusted for age, sex, and height or o130/ 80 mm Hg, whichever is lower. Similarly, the Cardiovascular Risk Reduction in High-Risk Pediatric Patients report330 listed children with CKD or kidney failure as a pediatric population at high risk for CVD, for which a target BP below percentile for age, sex, and height is suggested. According to that consensus statement, CKD is considered a coronary heart disease equivalent for which the treatment recommendations are similar to those in secondary preven- tion guidelines for adults with established coronary disease. Among children with CKD, observational data have shown that those with hypertension (i.e., BP above the 95th percentile) have a more rapid decline in estimated GFR than those without hypertension.313,331 In a study by the European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood, children with a systolic BP 4120 mm Hg had a significantly faster decline in GFR.332 In children who have received a kidney transplant, hyperten- sion is a strong predictor of accelerated GFR decline333 and Preliminary data from the ongoing observa- tional Chronic Kidney Disease in Children (CKiD) study show that, among 425 children with repeated measures of GFR, having systolic BP above the 90th percentile for age, sex, and height is associated with faster progression of CKD as compared with lower BP.336 In this cohort, the annualized percent change in GFR among those with systolic BP above with systolic BP between the 50th percentiles and 2.5 (95% CI 8.9 3.9) in those with systolic BP below the percentile. In the ESCAPE trial (described in detail in the next section), the kidney survival rate was 66% during follow-up among those with systolic BP below the 90th percentile but only 41% among those with systolic BP above percentile (P 0.0002). In ESCAPE, a diastolic BP below the 90th percentile was associated with a kidney survival rate of 67%, compared to 28% among those with diastolic BP above the 90th (F. Schaefer and E. Wuhl, personal communication). On the basis of the RCT evidence, observational data, and other guidelines, the Work Group graded this recommendation as 1C. The quality of evidence was graded as C because the RCT evidence is limited to inferred evidence from one trial. 6.2: We suggest that in children with CKD ND (parti- cularly those with proteinuria), BP is lowered to consistently achieve systolic and diastolic readings less than or equal to the 50th percentile for age, sex, and height, unless achieving these targets is limited by signs or symptoms of hypotension. (2D) RATIONALE The evidence for this recommendation comes largely from the which showed a benefit in slowing CKD progression by targeting 24-hour MAP by ABPM to less than percentile for age, height and sex. Secondary analysis of the data suggested the effect was stronger in proteinuric children with CKD. (See Supplementary Tables 63 64 online). Based largely on the ESCAPE results, the European Society of Hypertension guidelines recently recommended that in children with CKD, BP targets should be below the 50th percentile in the presence of proteinuria and below the 75th percentile in the absence of proteinuria.337 In the European Society of Hypertension guidelines, the rationale for choosing percentile as a threshold in children with CKD without proteinuria is based on a re-analysis of ESCAPE results, examining kidney outcomes according to achieved 24-hour mean BP level. Since the 75th percentile was not an original targeted intervention in the ESCAPE trial, and the trial was not powered to detect differences by levels of proteinuria in recruited subjects, we have not made a separate specific recommendation distinguishing between the presence and absence of proteinuria for target BP levels for children with CKD, but this is an important area for future study. Our guideline includes a statement of caution in aggressively pursuing low BP targets in children with CKD. We recognize that children are particularly susceptible to intercurrent illnesses, gastroenteritis and dehydration, and aggressive use of BP lowering medications in polyuric and dehydrated patients can lead to hypotension and alterations in renal perfusion. Clinicians who prescribe anti-hypertensive medications, particularly ACE-Is and ARBs in children need to be aware of the risk of drug toxicity in children susceptible to intravascular dehydration. Clinicians should consider discontinuing the drugs in the presence of acute diarrhea.338 Additionally we recognize that reaching a target of less than percentile BP may be quite difficult in some children with CKD. The risks of polypharmacy have to be weighed against the potential benefits of achieving lowered BP. In the ESCAPE trial,14 468 hypertensive children with a 24-hour MAP above the 95th percentile for age, sex, and height, and a GFR (based on the Schwartz formula) of , received ramipril at a fixed dose of /day and were randomized to target a 24-hour MAP, measured by means of ABPM, of either between the 50th and percentile or below the 50th percentile. Additional anti- hypertensive agents, except for other antagonists of the RAAS, were added at the discretion of the local provider to achieve the target BP. In this study the largest prospective RCT of BP therapy in children with CKD to date fixed-dose ramipril and a lower therapeutic BP target (MAP below the 50th percentile for age, sex, and height by ABPM delayed the progression to kidney failure. There were no differences in the frequency or types of adverse events between the intensified and conven- tional BP target arms in the trial. In subsequent stratified analyses, the effects were more pronounced in children with glomerulopathy and kidney hypodysplasia or dysplasia. There was no evidence of improved outcomes in individuals with hereditary nephropathies or other congenital causes of kidney disease other than aplasia or dysplasia, although there were relatively few individuals in these subgroups. Additionally, in stratified analyses, the efficacy of the intensified BP control intervention was most marked in children with a urine PCR of 4150 mg/g (415 mg/mmol) (see supplement of Wuhl ). Data presented at the American Society of Nephrology 2010 annual meeting from the observational CKiD study336 also shows slower progression of decline in kidney function in individuals with auscultatory manual BP below the 50th percentile for age, sex, and height as compared to individuals with BP between the 50th percentile and those with BP above the 90th percentile. BP in this study is measured according to a standard protocol at annual study visits with an aneroid device. BP targets in children with CKD should be individualized on the basis of susceptibility to hypotension. Many causes of childhood CKD include diagnoses associated with salt and water losses in the urine. As such, the risk of hypotension associated with aggressive BP control should temper the ramping-up of BP-lowering medication to reach a low BP target. 6.3: We suggest that an ARB or ACE-I be used in children with CKD ND in whom treatment with BP-lowering drugs is indicated, irrespective of the level of RATIONALE This recommendation is based on published experience with these agents in children with hypertension, showing the drugs to be safe and effective in lowering BP and to confer a benefit for slowing CKD and reducing urine protein levels in adults with CKD. However in teenage girls, pregnancy testing and the use of birth control prior to and during ACE-I/ARB therapy need to be considered. Additionally, as mentioned above, discontinuing these agents during episodes of diarrheal illness and dehydration should be considered.338 ACE-Is or ARBs should be the preferred choice in treating proteinuric CKD (see Chapters 3 and 4). Multiple studies in adults with CKD have shown renoprotection with the use of ACE-Is or ARBs. RAAS antagonists preserve kidney function not only by lowering BP but also by means of anti-proteinuric, anti-fibrotic, and anti-inflammatory properties. In the ESCAPE trial described above, on the basis of previous research in adults, the children in both arms of the intervention received a fixed, maximum dose of the ACE-I ramipril.323 Further BP lowering was achieved through the addition of other medica- tions at the discretion of the local provider. Others have recommended ACE-Is or ARBs as first-line agents in treating children with CKD and high BP,339 particularly in those with proteinuria.340 The recently released European Society of Hypertension guidelines337 assert that it is reasonable to recommend agents blocking the renin angiotensin system as first choice in proteinuric, and also in non-proteinuric patients with CKD. How- ever, limited direct evidence from clinical trials is available with which to assess the efficacy of RAAS in children with CKD. In healthy children with hypertension, a number of clinical trials have examined the safety and efficacy of Small, uncontrolled studies have shown stable kidney function in children with CKD treated with ACE-Is Kidney dysfunction that is hemodynamic in origin has been more commonly associated with the use of ACE-Is and ARBs than with other anti-hypertensive agents. Additionally, since elevations in serum potassium levels have also been observed, counselling about potassium intake and addition of thiazide or loop diuretics are sometimes Although analysis of registry data from the ItalKid Project database failed to show clear evidence of ACE-I efficacy in slowing the progression of CKD,311 other observational evidence shows that ACE-Is are associated with lower urine protein levels349 and that BP control in childhood CKD is superior with anti-hypertensive regimens containing an ACE-I or ARB.312 In a small trial, an ARB was more effective at lowering urine protein levels than a calcium- The only study to date that has compared ACE-Is and ARBs in children found that urine protein levels were similarly reduced with the ACE-I enalapril and the ARB As in adults, ARBs may be more tolerable than ACE-Is in children, with fewer adverse events such as cough, angio- neurotic edema, and hyperkalemia but this has not been systematically studied in large trials. 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. 