International Journal of Hypertension 7. Chronic Kidney Disease Hypertension is commonly found in patients with chronic kidney disease (CKD), with 75% of CKD patients taking antihypertensive drugs [148]. On the other hand, renal disease represents one of the forms of target organ damage induced by hypertension [149]. It seems that the relationship between hypertension and CKD is bidirectional; the kidney is both “the victim and the culprit” in this relationship. All recent guidelines recommend lower blood pressure goals in patients with CKD, especially when frank albumin- uria is present [149–151]. It has been shown, however, that the vast majority (>85%) of patients with CKD fail to achieve these goals; blood pressure control rates in CKD patients are lower than in other hypertensive patients despite the use of 3 antihypertensive drugs in average [152, 153]. It is, therefore, not surprising that the prevalence of resistant hypertension in patients with CKD is over 50% [154]. However, CKD is usually underappreciated as a cause of resistant hypertension, mainly because these patients are being followed at specialized nephrology clinics. Several factors contribute to treatment resistance in patients with CKD. Sodium and ﬂuid retention plays a cardinal role, while the increased activity of both the sympathetic and the renin-angiotensin-aldosterone systems greatly contribute to treatment resistance. Moreover, vascu- lar alterations both at a structural and functional (increased endothelin-1, decreased nitric oxide bioavailability) level, combined with the consequences of renal ischemia play an additional role [155]. Another signiﬁcant contributor to treatment resistance in patients with CKD regards the use of diuretics in these patients. It has been observed that restrictions in diuretic use were the primary cause of resistant hypertension in patients with CKD [156]. Restricted diuretic use includes either lower doses or inappropriate drug selection; thiazides are usually not eﬀective when GFR is lower than 40 and should, therefore, be replaced by loop diuretics in such patients. In the case that furosemide is chosen, it has to be given at least twice daily due to its limited half-life. Finally, dietary salt reduction may eﬀectively attenuate volume expansion and oﬀer signiﬁcant beneﬁts in these patients. Another important key aspect in patients with CKD is the assessment of urinary albumin excretion. Microalbu- minuria and especially macroalbuminuria are related with marked increments in cardiovascular risk. Drugs inhibiting the rennin-angiotensin axis (ACE-inhibitors, angiotensin receptor blockers, and direct rennin inhibitors) should be included in the therapeutic regime, since their use is associated with reduction of albuminuria and end-stage renal disease [157]. The combination of ACE-inhibitors with angiotensin receptor blockers has not proven any beneﬁts in high-risk patients at the ONTARGET study and was even associated with more adverse eﬀects [158, 159]. However, this combination might still be beneﬁcial in patients with CKD and overt albuminuria [160]. Renovascular hypertension is another common form of secondary hypertension. Renovascular hypertension is of atherosclerotic origin in the vast majority of cases, thus being 7 more frequent in older individuals, diabetics, smokers, and in patients with atherosclerotic lesions at other vascular beds [161, 162]. Indeed, about 25% of patients undergoing cardiac catheterization are found to have renal artery stenosis (RAS) higher than 70%, which could be of clinical signiﬁcance [163, 164]. On the other hand, ﬁbromuscular dysplasia is a much less frequent cause of RAS (approximately 10%) than atherosclerosis, and is more frequently encountered in younger females. Renovascular hypertension is common among patients with resistant hypertension. Older studies suggested that 1 out of 3 patients with secondary hypertension has renovas- cular hypertension [165, 166]. Unfortunately, recent studies in patients with resistant hypertension usually focus on OSA and PA and do not even mention RAS. It seems that RAS came out of fashion, mainly because its diagnosis with non- invasive methods remains tricky. Although several methods are used for the detection of RAS (duplex ultrasound, renal scintigraphy, ands CT and MR angiography) with rather good sensitivity and speciﬁcity [167], the diagnosis of reno- vascular hypertension represents an unfulﬁlled challenge for primary care physicians and remains mainly restrained in specialized centers. Another important aspect regards the management of patients with RAS. Three choices are available nowadays: surgical treatment, balloon angioplasty (with or without stenting), and conservative drug treatment. The surgical approach has subsided during the last decades and is now reserved for speciﬁc indications. Available data regarding the remaining two methods are inconclusive. Balloon angio- plasty was not found superior to optimal drug treatment in the recently published ASTRAL study; several drawbacks, however, limit the interpretation of study ﬁndings [168]. Another ongoing trial, the CORAL study, will provide hard- endpoint data with the two diﬀerent approaches [169]. 8. Rational for the Management of Resistant Hypertension The management of resistant hypertension represents a challenge for the astute clinician. Although it seems rational for patients with resistant hypertension to be referred to specialized hypertension clinics, the initial evaluation can be performed by primary care physicians. We will, therefore, attempt to provide a step-by-step approach for the evaluation and treatment of patients with resistant hypertension. The ﬁrst steps may take place at the primary care level, in the attempt to substantially reduce the number of referred pa- tients and prevent unnecessary costs and patient discomfort. In summary, the following steps need to be followed in the management of resistant hypertension. (i) Veriﬁcation of “true” Resistant Hypertension. Patients with “pseudoresistance” should be identiﬁed and excluded from further evaluation. Three main problems require special attention at this step: patient-related problems, physician-related problems, and blood-pressure technique- related problems.