A feared combination: Hypertension and chronic kidney disease

The prevalence of arterial hypertension is approximately 30% around the world, with an unacceptable lack of blood pressure (BP) control considering the recommended therapeutic targets.1 Even though the great effort of the international medical societies to create new guidelines about the detection and therapeutic management of hypertension, and to encourage a proactive behavior of the clinicians, the statistics remain unsatisfactory. Therapeutic inertia and lack of follow-up of the clinical guidelines in the real-world setting remain as important causes of inadequate BP control.2, 3 Moreover, the presence of comorbidities in the hypertensive patient makes it more difficult to achieve BP targets and decrease cardiovascular risk. Chronic kidney disease (CKD) is one of the most feared comorbidities owing to the interdependence between hypertension and renal disease. Among hypertensive patients, 16% have CKD based on 2017 ACC/AHA guidelines.3 These hypertensive patients represent the subpopulation with the highest prevalence of resistant hypertension and renal and cardiovascular events.4 At the same time, the prevalence of hypertension in patients with CKD rises with the advancing stages of the disease and it ranges from 67% to 92%.3, 5 Combination of hypertension and renal disease is deleterious because hypertension promotes endothelial dysfunction and an increase of intraglomerular pressure; on the other side, renal disease interferes with the physiological mechanisms of volume and sodium homeostasis, activates sympathetic nervous system and promotes vasoconstriction by several pathways. Thus, it is logical that comorbidities such as hypertension and CKD associate so closely.6, 7 Despite this relationship, clinical trials in hypertension and BP control have historically excluded CKD patients. It is for this reason that the study by Magvanjav and colleagues in this issue of the Journal of Clinical Hypertension, contributes to the medical community, firstly considering the high number of patients included and thereafter, because of the interesting analysis on the antihypertensive therapy prescribing patterns.8 The findings reported by the study regarding antihypertensive therapy in ambulatory CKD patients are useful. Updated data regarding management of hypertension treatment in CKD patients are requested so much for nephrologists and cardiologists. As the authors stated, the data were obtained through electronic health records analysis on 5658 ambulatory CKD patients with stages between 1 and 4, which reflects a spontaneous management, that is without apparent bias given by therapeutic obligatory protocols demanded by randomized clinical trials, reflecting real-life medical management. An unexpected information of prescribed antihypertensive therapy is that one-third of these CKD patients were not prescribed any angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), including those with documented proteinuria, and in spite of what guidelines recommend. The use of renin-angiotensin blockade in subjects with hypertension and CKD is well established.9 A recognized meta-analysis reported less renal disease progression when ACEI or ARBs were used for hypertension treatment in patients with CKD, especially if the patient had more than 1 g/d of proteinuria.10 Unfortunately, the present study lacks the information about the reasons making the physicians not to prescribe ACEI/ARBs, or if these drugs had been prescribed, why they would have been discontinued. At least, the authors indicate that the history of kalemia >5.5 mEq/L did not seem to have been the cause of the absence of its indication. Moreover, CKD patients with history of cough, angioedema, and/or severe hyperkalemia were not included in this report. One fact in this regard is that this paper confirms that some doctors do not follow clinical guidelines, considering that 91% of the patients were in a stage ≤3 of CKD, and so, adequate to receive and ACE or an ARB. As the authors did state, these findings promote a call to action to clinicians to be aware of the nephropathy condition of their patients, making them more proactive to an early indication of an intraglomerular protective drug. In the study by Magvanjav et al, physicians were likely to prescribe a drug combination consisting of a beta blocker (BB) and a diuretic as a two-drug combination alternative or as an add-on a renin-angiotensin system blocker. The above is a remarkable choice that has to be underlined, considering the study was performed between 2013 and 2016, period that correlates with the publication of the Joint National Committee (JNC) 8.11 Unexpectedly, the combination of both a diuretic +a BB was associated with a better BP control among CKD patients stage 1-2 receiving 2 or more medications compared to those who were prescribed other combinations. In the recent American guidelines, that is JNC 8, BB were placed as second-line antihypertensive drugs. Also, the combination of a diuretic plus a BB is not recommended appealing to elicit more metabolic disorders. Finally, there is no explicit recommendation in the guidelines for the use of BB in CKD stage 1-4 hypertensive patient.3, 11 Then, how can be explain the superior BP control with a BB-diuretic combination in this CKD cohort? There are same data that support the theory of sympathetic overactivity in patients with CKD, however these observations had been reported in nephrectomized rats and in patients with moderate to severe renal failure as well in patients undergoing dialysis.12 In other words, as there is more kidney damage there is more sympathetic activity. In the present study, the clear benefit was observed in CKD stage 1 and 2, that corresponds to a glomerular filtration rate over 60 mL/min, so these results are inconsistent with the available information so far. Within the limited information of BB in hypertensive patients with CKD, there is evidence of the benefit of cardio-selective metoprolol over amlodipine in African Americans in the reduction of proteinuria and glomerular filtration rate deterioration, but not in achieving better BP control.13, 14 Either way, atenolol is one of the most widely used BB, and more than 50% of the information in meta-analysis derived from studies with this drug. New generation BB such as the ones with vasodilatory characteristics must prove to be more effective, nevertheless until now clinical trials are missing. Unfortunately, the study lacks information regarding which BBs were the most prescribed, however the authors stated that the significant BP control remained after adjusting for type of BB (alpha/beta-blockers vs beta-blockers), suggesting that there was a prescription of carvedilol. Indeed, this better BP control in CKD stage 1-2 with diuretic-BB combination cannot be explained by changes in BB half-lives as could be seen with atenolol in more advanced CKD stages. Another observation is that around 2/3 of CKD patients had a controlled BP, that is <140/90 mm Hg, considering the recommended BP goal at the time of the study. It would have been interesting to know how many hypertensives with proteinuria reached the BP goal of <130/80 mm Hg, recalling that some international societies suggest a lower target in this specific population. But this 65% of patients reaching optimal control is outstanding. This number reflects a very good therapeutic management in a real-world setting, considering that in the PURE study, the proportion of patients with hypertension with BP <140/90 mm Hg among those receiving treatment in North America was 38%.1 However, the results by Magvanjav and colleagues about BP control are quite similar to the published data on BP control in CKD hypertensive patients. In a cross-sectional study with more than 110 000 CKD patients with hypertension from the General Electric Centricity ambulatory healthcare, the overall prevalence of BP control was 24%, but they considered a stricter BP goal corresponding to <130/80 mm Hg as JNC 7 recommended.15 On the other hand, the results from the Chronic Renal Insufficiency Cohort Study-CRIC reported that 67% of the patients had their hypertension controlled to <140/90 mm Hg.5 As Magvanjav et al commented, ¨it is possible that involving specialist-provided care may lead to greater BP control¨; nevertheless, they did not find significant differences between the prescribers' specialties, which demonstrates a transversal capacity of clinical judgment. An important caveat of the results in the study is the methodology of BP recordings. This is today an enormous point of debate after the results of the recent SPRINT trial.16 In the CRIC study, office BP measurements were obtained by certified observers following a standardized protocol.5 In the present study, BP measurements were not taken by a standardized method. Also, as they appointed, there is no information about home BP recordings. New hypertension guidelines strongly recommend home BP recording to improve misclassification given by the presence of white-coat or masked hypertension.2, 3 In CKD patients, the prevalence of masked hypertension has been reported higher, around 40%, so due to this high prevalence, accurate out-office BP measurement is essential in the management of CKD hypertensive patients.17, 18 In spite of the above considerations, the results of the study in regard to socio-demographic and clinical risk factors associated to resistant hypertension in a real-world setting, confirmed that African American race, obesity, diabetes, and obstructive sleep apnea are conditions that the clinician must consider when going to manage the CKD hypertensive patients. Nonetheless, always remember that CDK is the most frequent comorbidity associated with resistant hypertension. The authors have no conflict of interest to disclose.