From Profusion to Confusion: The Saga of Managing Hypertension in Chronic Kidney Disease!

Hypertension (HTN), through its high incidence, prevalence, and dire consequences, remains a major contributor to the global burden of disease. The noncommunicable disease burden now exceeds that of infectious disease even in the developing world, with precious few resources anywhere to manage this burgeoning challenge.1 Nevertheless, HTN control rates remain unacceptably low. Currently, approximately 73 million Americans have HTN, and blood pressure (BP) is controlled in only around 50% of the cases.2 Between 1988–1994 and 2007–2010, the prevalence of uncontrolled high BP declined for all age groups. However, in 2007–2010, nearly one half of adults with HTN continued to have uncontrolled high BP.3 Good, clear guidance about how to screen for, detect, and treat HTN is needed for patients, health-care providers, insurance companies, public health bodies, agencies, and governments. The question we posed in 2014 was whether we have this guidance or whether the multiple overlapping and sometimes even contradictory statements recently issued do not in fact provide a perfect storm of confusion. The first report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) was published in 1977 and was based on rather limited and inconclusive (available in the mid-1970s) clinical information from a modern point of view. Currently, a total of eight JNC reports have been issued. They are briefly summarized in Table 1. No systolic blood pressure (SBP) in its classification system; Drug therapy was recommended for patients with diastolic blood pressure (DBP) ≥105 mm Hg; Therapy “could be considered” even for patients with DBP between 90 mm Hg and 104 mm Hg; First-line medication: thiazide-type diuretic No SBP in the new classification system; Introduced the terms “mild,” “moderate,” and “severe hypertension” Addressed SBP, only as isolated systolic hypertension (≥160 mm Hg) or borderline isolated systolic hypertension; The first report recognizing the terms “high normal” when SBP was <140 mm Hg and that these patients could be at “some risk”; β-Blockers were added for first-line medication SBP was included in a better-defined classification system; The first report that established the “high-risk” patient concept (for patients with diabetes or chronic kidney disease) Suggested that any of the seven types of antihypertensive drugs could be used for initial treatment; Reduced the number of BP stages from four to three; Settled the term “goal BP”; Introduced the term “compelling indication” Classification reduced the hypertension stages to two; Introduced the term “prehypertension” for patients with BP <140/90 mm Hg; Reduced the BP goal to ≤130/80 mm Hg; Treatment was stratified in accordance with target organ damage and high-risk populations; Highlighted the importance of lifestyle changes; First-line therapy recommendations were consistent with various types of populations with compelling indications The guidelines industry was founded, and then flourished, with departmental, hospital, regional, national (eg, National Institute for Health and Clinical Excellence [NICE]), international-local (eg, North America, Australia, Europe), and then fully international guidelines groups and bodies, all highly active in assembling evidence and then analyzing and disseminating care instructions. Furthermore, each medical condition had its own guidelines, eg, dyslipidemia, HTN, kidney disease, and diabetes. Little initial effort was expended on appreciating that many real-life subjects often had more than one “risk factor” (eg, obesity, diabetes, HTN) and that the presence of these other comorbidities would likely affect therapeutic options and outcomes. In contrast to the early JNC times, we are now experiencing an era of “too much information.” This is because in 2014 we were faced with six “guidance protocols,” essentially covering the same topic(s): detection and treatment of HTN. It is clear that these guidelines have different incentives (see below) and that they should give an exhaustive algorithm about how to treat HTN, but it is also clear that in some important areas there appears to be disagreement among these recommendations. The collision of these new recent guidelines has now made every clinical decision harder, so, the “new-old ironclad” question remains: “What should we do?” To misquote by paraphrasing St Francis of Assisi “where there was certainty, let us now sow doubt.” A number of articles had been issued on this matter highlighting the most important discrepancies, particularly the increase in threshold BP value for initiation of pharmacologic therapy.13-16 Indeed, as mentioned above, these guidelines were intended for different audiences and were written with different motivations. The ESH/ESC guideline evaluates all the relevant literature across the spectrum of HTN and provides concise recommendations that can be easily and rapidly consulted by physicians in their routine practice.6 ASH/ISH is a brief curriculum and set of recommendations that can be useful for all practitioners, not only for primary care physicians or medical students.7 CHEP is a national program that targets various health-care professionals in clinical and community settings. Its standardized recommendations and clinical practice guidelines are updated annually and then translated and adapted into educational materials for patients and providers.9 NICE was composed primarily to address cost-effectiveness issues in HTN.10 Although, or even because of this, it was based on a systematic review including only randomized controlled trials, the most controversial guideline in the current setting is clearly JNC 8.8 This is because of the major changes introduced that differentiate JNC 8 from JNC 7,17 specifically the introduction of an increase of the target systolic BP from 140 mm Hg to 150 mm Hg in patients 60 years and older without diabetes mellitus or chronic kidney disease (CKD). A minority of authors in the guideline development panel disagreed with this new systolic BP target.8, 18 Finally, a full 60% of recommendations were based on expert opinion, while just 10% were based on clinical trial evidence. Following is a comparison of all of the recently published guidelines, underlining the key differences between the different guideline recommendations and focusing on two critical areas: first, the definition and classification of HTN, and, second, special considerations for patients with CKD (Figure). Apparently, three guidelines skipped this basic important step: JNC 8 and AHA/ACC/CDC did not provide a proper and clear threshold for HTN definition and JNC 8, AHA/ACC/CDC, and CHEP did not state a grade classification of HTN.8, 9, 12 In addition, the definition of “elderly” is different between the ASH/ISH, CHEP, and NICE guidelines (age ≥80 years) and the JNC 8 guideline (age ≥60 years), and the AHA/ACC/CDC guideline did not provide any definition or special guidance for the elderly patient.7, 10, 12 In addition to not presenting an adequate definition of the elderly, the ESH/ESC guideline exerts a confusing effect by referring to this category of patients both in terms of older than 65 years and 80 years and older.6 Also, the ASH/ISH guideline considers first-line medication in patients stratified as younger than 60 years and 60 years and older.7 This is not a trivial issue since in the United States alone there are 7.4 million patients 60 years and older who could be included in a group with BP between 140/90 mm Hg and 149/90 mm Hg.15 For a schematic comparison between these guidelines, see Table 2 and 3. SBP 140–159 mm Hg or DBP 90–99 mm Hg (grade 1 HTN) in patients at low to moderate risk (IIa, B) SBP 160–179 mm Hg or DBP 100–109 mm Hg (grade 2 HTN) and SBP ≥180 mm Hg or DBP ≥110 mm Hg (grade 3 HTN) in patients with any level of CV risk, a few weeks after or simultaneously with initiation of lifestyle changes (I, A) BP >140/90 mm Hg and lifestyle changes not effective BP ≥160/100 mm Hg (grade 2 HTN), drug treatment should be started immediately Drug treatment can be started immediately in all HTN patients in whom the practitioner believes it is necessary to achieve more rapid control of BP SBP ≥140 mm Hg, DBP ≥90 (expert opinion, grade E) SBP ≥160 mm Hg or DBP ≥100, in patients without macrovascular TOD or other CV risk factors (grade A) SBP ≥140 mm Hg and DBP ≥90 mm Hg, in patients with macrovascular target organ damage or other independent CV risk factors (grade A for DBP, grade C for SBP 140–160 mm Hg, grade A for SBP >160 mm Hg) BP ≥140/90 in patients with ≥1 of the following: TOD, CVD, CKD, DM, 10-year CV risk ≥20% BP ≥160/100 mm Hg and subsequent average ABPM/HBPM ≥150/95 mm Hg For patients younger than 40 years and stage 1 hypertension with no evidence of TOD, CVD, renal disease, or DM, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of potential TOD In fit elderly patients younger than 80 years: SBP <140 mm Hg if treatment is well tolerated (IIb, C) In patients 80 years and older: SBP between 150 mm Hg and 140 mm Hg, if they are in good physical and mental condition (I, B) For most patients: BP <140/90 mm Hg In patients 80 years and older: BP <150/90 mm Hg who do not have CKD or DM; (in case of DM or CKD, BP <140/90 mm Hg can be considered) SBP <150 mm Hg DBP <90 mm Hg (strong recommendation, grade A) For patients younger than 80 years: BP <140/90 mm Hg For patients 80 years and older: BP <150/90 mm Hg SBP goal <140 mm Hg (I, A) DBP goal <85 mm Hg (I, A) SBP <140 mm Hg and DBP <90 mm Hg (expert opinion, grade E) <140 mm Hg should be considered (IIa, B) When overt proteinuria is present, SBP values <130 mm Hg may be considered, provided that changes in eGFR are monitored (IIb, B) SBP <140 mm Hg and DBP <90 mm Hg (expert opinion, grade E) ASH/ACC, JNC 8, and NICE made special considerations for non-black and black populations, ESH/ESC, CHEP, and AHA/ACC/CDC failed to include black patients in their recommendations.6-9, 12 We acknowledge the lack of recommendations regarding other populations, such as Asian and Hispanic patients. For example, Asian patients, especially those with CKD, are more likely to develop end-stage renal disease than cardiovascular death compared with Caucasian patients,19 so that BP threshold and goal and first-line therapy might be different in order to prevent the most significant outcomes. New HTN guidelines have been developed in Asian20 and Hispanic21 areas, but the complete analysis of all available regional guidelines, frequently based on limited scientific data, is beyond the scope of this article. Since patients with CKD are at high risk for developing CVD with increasing risk of cardiovascular mortality, adequate BP control could translate into immense benefit.22 However, the following crucial question naturally emerges from the beginning: what is the BP treatment threshold value and what is the BP treatment goal value in these patients? Not all of the guidelines specifically address patients with CKD, in contrast to the interest shown to other high-risk and prevalent populations (those with diabetes and stroke). The most explicit in this regard is KDIGO.11 The KDIGO guidelines stratify therapeutic strategies according to urine albumin excretion: when this value is <30 mg/24 h, the guidelines recommend a systolic BP (SBP) threshold of >140 mm Hg and a diastolic BP (DBP) of >90 mm Hg, and when the value is between 30 mg/24 h and 300 mg/24 h or ≥300 mg/24 h, the guidelines recommend an SBP threshold of >130 mm Hg and DBP >80 mm Hg.11 In addition, in terms of BP treatment goal value, KDIGO uses the same classification system: when the urine albumin excretion is <30 mg/24 h, the SBP target is ≤140 mm Hg and the DBP is ≤90 mm Hg, and when it is between 30 mg/24 h and 300 mg/24 h or >300 mg/24 h, the SBP target is ≤130 mm Hg and the DBP is ≤80 mm Hg.11 For initial choice of drug, this protocol recommends, regardless of urine albumin excretion, an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor.11 The ESH/ESC guidelines recommend that an SBP goal of <140 mm Hg should be considered, except in the case of proteinuria, in which the goal could be reduced to <130 mm Hg. For first-line medication, the protocol suggests that renin-angiotensin system blockers may be more effective than other antihypertensive drugs in reducing albuminuria. They also state that in case of a CKD patient with isolated systolic HTN, a calcium channel blocker might be preferred.6 ASH/ISH settled for a BP goal of <140/90 mm Hg, considering the lack of evidence for a specific target value. However, the authors considered this is an important modification, because, until now, the BP goal for these patients was <130/80 mm Hg. In the presence of albuminuria, a lowered BP goal could be considered (<130/80 mm Hg). In terms of threshold BP value, the guidelines consider that, in elderly patients with CKD, the limit should be lowered to ≥140/90 mm Hg for initiation of treatment, in opposite to BP ≥150/90 mm Hg, settled in the general elderly population. For first-line therapeutic intervention, the guidelines recommend an ARB or ACE inhibitor.7 JNC 8 established an SBP goal of <140 mm Hg and a DBP goal of <90 mm Hg for hypertensive CKD patients. They recommend the initiation of treatment with an ACE inhibitor or ARB, regardless of diabetes status.8 The AHA/ACC/CDC guidelines are not specific in determining a precise value for BP treatment goal in CKD patients; nevertheless, the BP goal of <140/90 mm Hg is appropriate. The guidelines do not provide a clear, evidence-based statement for pharmacologic intervention but suggest that ACE inhibitors or ARBs should be considered for hypertensive patients with CKD.12 The CHEP guidelines recommend, in the presence of nondiabetic CKD with proteinuria (defined as urinary protein >500 mg/24 h or albumin to creatinine ratio >30 mg/mmol) that initial therapy should be started with an ACE inhibitor or an ARB if an ACE inhibitor is not well tolerated, aiming for a BP target of <140/90 mm Hg. The protocol considers diuretics as an additive therapy (and loop diuretics for patients with CKD and volume overload).9 The 2011 NICE HTN guidelines assert that hypertensive patients younger than 80 years receive medication starting with grade 1 HTN if they have renal disease. They do not offer a first-line agent for treatment.10 Since there are no particular endorsements in the latest NICE HTN guidelines, we refer to recommendations made by the NICE CKD guidelines issued in 2008: “In people with CKD aim to keep the systolic BP below 140 mm Hg (target range 120–139 mm Hg) and the diastolic BP below 90 mm Hg.”23 Finally, what about renal patients who are receiving renal replacement therapy (CKD-5D)? This is an extremely complicated and challenging question, given the fact that specific BP targets derived from randomized controlled trials are lacking.24 The prevalence of HTN in patients undergoing dialysis is about 90% and is associated with an annual mortality rate of 23%, primarily from CV complications.25 Therefore, achieving optimal BP control in patients on dialysis is of major importance. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines suggest that pre-hemodialysis and post-hemodialysis BP should be 140/90 mm Hg and 130/80 mm Hg, respectively, but these targets were mainly based only on the expert judgment of the working group, applying weak evidence.24 BP in the CKD-5D population is multifactorial, determined by the interconnection between the renin-angiotensin system and sympathetic nervous system, fluid volume and sodium load, postdialysis target weight, dialysate composition, and arterial stiffness.24 This “complex brew” requires a strict individualization of BP targets and therapy regimen. The BP ranges associated with the minimal risk related to self-measured home BP monitoring (the “between-dialysis sessions control of BP”) are currently not known in CKD stage 5D patients. In the only study published so far on the topic, the best outcome was observed with a self-measured home SBP range between 120 mm Hg and 145 mm Hg.24 The main conclusion that emerges from these several detailed comparisons is actually quite simple and touches the very definition of a guideline. Health-care providers should always remember that these protocols are here merely to provide guidance and they should certainly not be considered as a set of abiding laws. A clinician's discernment about his individual patient must be superior to the recommendations of a committee that has not seen that specific patient and has not evaluated the individual's overall state of health, comorbidities, or needs and priorities (and indeed, the needs and priorities of the country and region of medical practice). The doctor should follow the appropriate BP treatment goal, stratified accordingly to specific risk factors and distinct features for each patient in particular, establishing and dealing with identifiable causes of HTN. We also need to suggest a world body agreement statement to reconcile the major confusion currently felt by practicing physicians, carriers, patients, payers, and all other concerned parties. Therefore, an international consensus conference that will include physicians, bioethicists, and medical economists from various countries should be established in order to institute a universal and integrated guideline for HTN management. Undoubtedly, the medical delegate committee should include not only cardiologists but also nephrologists, neurologists, primary care physicians, and diabetes specialists with extensive clinical and methodological experience. Broadly, the meeting should cover interactive discussions on the existing sets of guidelines and their differences, the evidence-based search strategy and a detailed review of all available literature, and a unanimous settlement on a personalized optimal approach for clinical decision-making according to various subgroups of population. Separate processing groups should effectively achieve in the end a final international consensus. None.