the advent of antihypertensive therapy has substantially reduced the occurrence of cardiovascular events . however , antihypertensive therapy failed to achieve blood pressure control in all patients , with hypertension control rates remaining in general disappointingly low . blood pressure goals are not attained in some patients despite the simultaneous use of several antihypertensive medications . several terms have been used to define this condition :  refractory hypertension  ,  difficult - to - treat hypertension  ,  difficult - to - control hypertension  ; however , the term  resistant hypertension  seems to prevail . resistant hypertension is currently defined as uncontrolled blood pressure despite the use of optimal doses of three antihypertensive medications , of which one is a diuretic . poor patient adherence , physician inertia , inadequate doses or inappropriate combinations of antihypertensive drugs , excess alcohol intake , and volume overload are some of the most common causes of resistance [ 210 ] . the list of secondary forms of hypertension is long and covers a large variety of conditions ( table 1 ) . the management of patients with resistant hypertension requires a gratifying combination of clinical acumen and common sense . an extensive workup of all patients with uncontrolled hypertension is scientifically unsound , is very costly and requires immense human and technical resources . therefore , practicing physicians need to implement evidence - based medicine . the effective management of patients with resistant hypertension requires an appropriate combination of physiology and pharmacology , taking into account the unique characteristics of each case in order to tailor the therapeutic approach to the individual patient . this paper will address the most common secondary causes of resistant hypertension ( drug - induced , obstructive sleep apnea , primary aldosteronism , and chronic kidney disease ) , which are frequently encountered in hypertensive patients and are , therefore , the most interesting from the clinical point of view . in addition , this paper will attempt to provide a rational for the workup and treatment of patients with resistant hypertension . data from small observational studies show a wide variation ( from 5% to 50% ) according to the studied populations [ 210 ] . data from large clinical trials point towards a relatively high prevalence of resistant hypertension ( 2035% ) . it has to be noted , however , that atypical drug combinations have been used in most of these studies as required by study protocols . therefore , the evaluation of the prevalence of resistant hypertension requires a large , prospective , population - based study , specially designed for this aim . available evidence addressing the prognosis of resistant hypertension is scarce , since virtually no longitudinal study has addressed this topic . data from small clinical studies point towards an increased cardiovascular risk in patients with resistant hypertension . in addition , patients with resistant hypertension frequently have comorbidities that are known to increase cardiovascular morbidity and mortality , such as chronic kidney disease , diabetes , and obesity . moreover , patients with resistant hypertension have higher rates of target organ damage than the general hypertensive population and are thus at increased cardiovascular risk . excessive dietary salt intake is common in patients with resistant hypertension and contributes to treatment resistance by blunting the blood pressure reduction of most antihypertensive drugs , including diuretics and inhibitors of the renin - angiotensin axis [ 210 ] . it has been shown that blood - pressure control is more difficult to be achieved in obese than lean hypertensive patients . several lines of evidence indicate a graded positive correlation between body mass index and blood pressure levels , while weight loss results in blood pressure reduction . insulin resistance , sympathetic nervous system overactivity , sodium retention , and activation of the renin - angiotensin system have been implicated in the pathogenesis of obesity - induced hypertension . alcohol consumption is another important factor [ 210 ] . large alcohol consumption ( > 3 drinks per day ) has been shown to result in blood pressure elevation . in addition , blood pressure control might be achieved more difficult in heavy drinkers due to poor adherence in antihypertensive therapy . the role of physical inactivity in patients with resistant hypertension has not been adequately studied . a variety of prescription or over the counter medicines as well as other exogenous substances may induce hypertension or contribute to treatment resistance . drug - induced hypertension is among the most common causes of secondary hypertension and is frequently encountered in everyday clinical practice . however , despite the frequent occurrence of drug - induced hypertension , primary care physicians frequently miss the opportunity to detect and appropriately manage this iatrogenic form of secondary hypertension . therefore , a detailed and meticulous medical history is of utmost importance in patients with resistant hypertension , since the identification and subsequent withdrawal of the offending drug may alleviate treatment resistance . however , withdrawal of the responsible agent is not always possible ; in such cases , dose reduction and/or search for alternate treatment may substantially improve or even control blood pressure levels . another very important aspect relates to the great variability of the effects of administered drugs on blood pressure . the administration of offending drugs can result in excessive blood pressure elevation in some individuals , while most individuals will experience little or no increases of blood pressure . therefore , it would be very important to identify predictors of blood pressure elevation , in order to individualize drug treatment . a descriptive list of all exogenous agents capable of inducing or exaggerating hypertension is presented in table 2 . however , this paper will focus on the drugs that are widely used , represent the most common causes of drug - induced hypertension , and are thus of major clinical importance : nonsteroidal anti - inflammatory drugs ( nsaids ) and oral contraceptives . in addition , a brief comment regarding specific antineoplastic agents ( anti - vegf ) that have emerged as inducers of hypertension is presented at the end of this chapter , since many clinicians are not aware of this condition . by far , the most common cause of drug - induced hypertension is the use of nsaids . in 265 patients with resistant hypertension identified during a one - year period , treatment resistance was drug - related in 36% of the cases , with nsaids being responsible in 88% ( personal unpublished data ) . osteoarthritis is highly prevalent in the general population , and its prevalence would be even greater due to population aging and the obesity epidemic [ 11 , 12 ] . although lifestyle modification , exercise , and weight loss are considered as first - line therapeutic measures for patients with osteoarthritis , the vast majority of such patients require the systematic or intermittent use of either acetaminophen or nsaids for pain relief . two large prospective cohort studies in normotensive women reported higher risks of subsequent hypertension among nsaids users than in women without regular nsaids administration [ 14 , 15 ] . in the first study , the risk of developing hypertension was increased about two times in women using acetaminophen or nsaids . acetaminophen consumption for 14 days per month and nsaids consumption for 514 days per month was necessary for the risk to be apparent . in the second study , women with frequent use of nonnarcotic analgesics ( > 22  days / month ) had statistically significant higher risk for developing hypertension ; in particular , the hazard ratios were 1.20 for acetaminophen , 1.21 for aspirin , and 1.35 for nsaids . it has to be noted that although acetaminophen is considered to have a better safety profile than nsaids [ 16 , 17 ] , its use was associated with a moderate increase in the risk for incident hypertension in both males and females [ 18 , 19 ] . another large , case - control study revealed a 66% increased risk for initiating antihypertensive drugs in nsaids users compared to nonusers . these detrimental effects of nsaids on blood pressure have been also observed in two older meta - analyses of randomized trials with nsaids [ 21 , 22 ] . in the first meta - analysis , mean arterial pressure was increased by 3.3  mmhg in hypertensive patients whereas the increase in normotensive subjects was negligible ( 1.1  mmhg ) . in the second meta - analysis , nsaids resulted in a significant mean arterial pressure elevation of 5.0  mmhg ; blood pressure elevation was apparent in hypertensive patients with controlled blood pressure , whereas normotensive individuals did not experience such an effect . on the contrary , data reporting no or little effect of nsaids on blood pressure exist in the literature as well . in two cross - sectional studies , no association between use of nsaids and hypertension was found [ 23 , 24 ] . similar findings were observed in two small randomized studies regarding the effects of acetaminophen on blood pressure [ 25 , 26 ] , as well as in studies evaluating the effects of aspirin on blood pressure in hypertensive patients [ 27 , 28 ] . in addition , in a large prospective cohort of 8,229 male normotensive physicians , analgesic use was not associated with increased risk of developing hypertension ( hazard ratio : 1.12 ; 95% ci : 0.971.31 ) . the corresponding hazard ratios were 1.08 ( 95% ci : 0.871.34 ) for acetaminophen , 1.16 ( 95% ci : 0.921.48 ) for aspirin , and 1.05 ( 95% ci : 0.891.24 ) for nsaids . this apparent heterogeneity of available data on the effects of traditional nsaids on blood pressure becomes even more complicated when recent data with selective cox-2 inhibitors are taken in account . in a meta - analysis of randomized trials , use of cox-2 inhibitors was associated with a significant increase in blood pressure compared to placebo ( 3.85/1.06  mmhg ) and nonselective nsaids ( 2.83/1.34  mmhg ) . however , it was shown that a great part of blood pressure elevation could be attributed to rofecoxib . indeed , rofecoxib use is associated with greater blood pressure elevations than celecoxib in both hypertensive and normotensive individuals . the above - mentioned study highlights another important aspect : the potential differences on blood pressure effects between the various nsaids . in a meta - analysis of randomized trials , conducted mainly in hypertensive patients , naproxen and indomethacin were associated with the largest blood pressure elevations , while piroxicam , sulindac , ibuprofen , and aspirin exhibited little if any effect on blood pressure . on the contrary , a randomized study in patients with controlled hypertension showed that the blood pressure was significantly higher with ibuprofen than with lumiracoxib . moreover , in 34,701 participants at the medal ( multinational etoricoxib and diclofenac arthritis long term ) program , patients assigned to etoricoxib discontinued the study due to hypertension more frequently than patients randomized to diclofenac . finally , the potential differences of the effects of nsaids on blood pressure according to the various antihypertensive agents coadministered are of great clinical importance . in a study of elderly hypertensives with osteoarthritis , indomethacin had no effect on blood pressure in patients taking calcium antagonists whereas significant blood pressure elevations were detected in patients taking ace - inhibitors . on the contrary , celecoxib exerted similar to placebo effects in patients taking ace - inhibitors . another study among hypertensive patients with osteoarthritis , comparing the effects of rofecoxib and celecoxib , revealed no differences on blood pressure between the two drugs in patients taking diuretics or calcium antagonists , whereas larger blood pressure elevations were observed with rofecoxib than with celecoxib in patients taking ace - inhibitors or beta blockers . the above presented information clearly indicates that available data on the effects of nsaids on blood pressure are sometimes contradictory and in total far from conclusive . convincing data coming from carefully designed randomized studies are necessary to : ( a ) detect potential differences between the various nsaids on blood pressure , ( b ) clarify the effects of coadministering each nsaid with each one of the various antihypertensive drug categories , and ( c ) identify predictors of blood pressure response to nsaids use . withdrawal of nsaids is indicated in patients with resistant hypertension , exacerbation of prior hypertension , or incident hypertension . substituting nsaids with acetaminophen pain relief is more likely in patients with osteoarthritis and pain of muscular skeletal origin . however , this is not always possible in everyday clinical practice , since patients with chronic inflammatory arthritic diseases ( rheumatoid arthritis ) respond better to anti - inflammatory agents . in such cases , hydrocodone , tramadol , or nerve blocking might be of help , constituting effective alternatives to nsaids . in   cases , however , where nsaids are still necessary , the lower effective dose should be administered , since existing data point towards dose - related effects of nsaids on blood pressure . nsaids affect blood pressure levels via different mechanisms : activation of the renin - angiotensin - aldosterone system , sodium and water retention , induction of vasoconstriction through endothelin-1 and arachidonic acid metabolites , and mainly inhibition of renal vasodilatory prostaglandins ( e2 and i2 ) [ 3743 ] . these detrimental effects of nsaids may lead to deterioration of renal function and acute kidney injury , especially in patients of older age , preexisting hypertension , chronic kidney disease , or diabetes . in such patients , calcium antagonists seem to be more suitable than drugs inhibiting the renin - angiotensin system , since the concomitant administration of nsaids and calcium antagonists is not accompanied by blood pressure elevation [ 36 , 39 ] . the development of nsaids that apart from cyclo - oxygenase inhibition possess nitric oxide promoting properties might significantly ameliorate current situation and alleviate the effects of nsaids on blood pressure . cinods ( cyclo - oxygenase inhibiting nitric oxide donating drugs ) represent a new class of nsaids ; cinod molecules consist of a traditional nsaid and a nitric oxide - donating chemical group connected by a linker . naproxcinod is the first cinod in clinical trials with very promising preliminary results [ 4447 ] . oral contraceptives represent another class of drugs that are widely used and are capable of inducing hypertension [ 48 , 49 ] . the larger study evaluating the effects of oral contraceptives on blood pressure was the nurses ' health study , in which more than 60,000 normotensive women were prospectively followed for 4 years . women using oral contraceptives had an 80% higher risk of developing hypertension compared to women that were not using such drugs . however , withdrawal of oral contraceptives abolished this increased risk , underlining the need for close monitoring in women taking oral contraceptives . a study in hypertensive women revealed that those taking oral contraceptives had more severe hypertension and lower blood - pressure control rates than women using other contraceptive methods . combined oral contraceptives ( progestin and estradiol ) , which were widely used in the past , were associated with blood pressure elevations more frequently than progestin - only oral contraceptives . on the contrary , therefore , current guidelines recommend the use of progestin - only oral contraceptives in women with established cardiovascular disease , or major cardiovascular risk factors ( such as hypertension ) [ 53 , 54 ] . it can , therefore , be summarized that oral contraceptives may contribute to resistance in hypertensive women , but the type of oral contraceptive is important . close monitoring of women and withdrawal of oral contraceptives may alleviate the effects on blood pressure . another class of agents that emerged as inducers of hypertension are the antineoplastic drugs that target the vegf pathway . a monoclonal antibody ( bevacizumab ) binding to the vegf - a isoform , as well as small molecules inhibiting the intracellular tyrosine kinase domains of all three vegf receptors , is used or is under clinical testing for the treatment of various malignancies [ 5557 ] . hypertension was encountered very frequently in patients receiving treatment with vegf - inhibitors . in particular , 2030% of patients treated with bevacizumab , and 1560% of patients treated with vegf kinase inhibitors developed hypertension . three meta - analyses with drugs inhibiting the vegf pathway uncovered a high relative risk for incident hypertension with these agents : 7.5 ( 95% ci : 4.213.4 ) with bevacizumab , 6.11 ( 95% ci : 2.4415.32 ) with sorafenib , and 21.6 ( 95% ci : 18.724.8 ) with sunitinib [ 6062 ] . interestingly enough , the development of hypertension has been correlated with the efficacy of these drugs [ 6365 ] , suggesting that hypertension could be used as a surrogate marker of anti - vegf efficacy . a phase iii trial evaluates this concept in patients with pancreatic cancer receiving anti - vegf agents . clearly , more data are needed to clarify the blood pressure effects of the various drugs acting on the vegf pathway . experimental studies have shown that vegf upregulates endothelial nitric oxide synthase [ 66 , 67 ] , enhances nitric oxide production , and induces nitric oxide - dependent vasorelaxation . moreover , vegf was shown to result in enhanced prostacyclin production and release [ 70 , 71 ] . it can be therefore anticipated that vegf inhibition may lead to reduction of nitric oxide and prostacyclin bioavailability , a subsequent increase of systemic vascular resistance , and finally blood pressure elevation . in addition , arteriolar rarefaction has been observed in animals treated with vegf kinase inhibitors , proposing another pathogenetic mechanism of hypertension with these drugs [ 7274 ] ; preliminary studies in humans reported similar findings [ 75 , 76 ] . finally , enhanced arterial stiffness has been suggested as another contributing factor in the development of hypertension . the recognition of the pathogenetic mechanisms that contribute to blood pressure elevation with vegf - inhibitors might be helpful in identifying the most appropriate drugs for the management of these patients . reliable data evaluating the efficacy of the various antihypertensive drug categories in anti - vegf - induced hypertension are missing . preliminary reports point towards restricted efficacy of diuretics   and beneficial effects of calcium antagonists ; however , appropriate prospective studies are needed in this topic . a vast amount of evidence demonstrates an association between obstructive sleep apnea ( osa ) and hypertension . such an association has been shown in epidemiological , longitudinal , and cross - sectional studies , as well as in studies from specialized clinics [ 8083 ] . in addition , it has been shown that osa in normotensive subjects predicts future development of hypertension . sympathetic nervous system activation plays a crucial role in the pathogenesis of hypertension in patients with osa . enhanced upper airway resistance and intermittent hypoxia are considered to stimulate the sympathetic system , while the subsequent sympathetic overactivity may result in blood pressure elevation via vasoconstriction and increased systemic vascular resistance , increased cardiac output , and enhanced fluid retention . the exact nature of the association between osa and aldosterone excess remains to be elucidated . whether osa results in aldosterone excess or aldosterone excess contributes to osa , or another underlying factor ( like obesity ) promoting both aldosterone excess and osa has not been clarified . several studies have reported an extremely high prevalence of osa in patients with resistant hypertension . two decades ago , a swedish study of 16 patients with resistant hypertension reported a 56% prevalence of osa in these patients compared to 19% in patients with controlled hypertension . in a study of 41 consecutive resistant hypertensives , an 83% prevalence of unsuspected osa was found ; osa was defined as an apnea / hypopnea index ( ahi ) of more than 10 events per hour . another study of 71 patients with resistant hypertension revealed an 85% prevalence of osa ( ahi  5  events / h ) . a study from spain in 62 resistant hypertensives reported a 90% prevalence of osa ( ahi  5  events / h ) . however , when the diagnosis of osa was based on 30 or more episodes of apnea / hypopnea per hour , the prevalence was reduced to 70% , underlining the importance of accurate and homogeneous definition of osa . moreover , all the above - mentioned recent studies did not have a control group in order to exclude the potential effects of confounding factors . a recent study from brazil evaluated 63 patients with resistant hypertension and an equal number of patients with controlled hypertension , matched for baseline parameters apart from blood pressure . a strong and independent association between osa and resistant hypertension has been described ( odds ratio : 4.8 ; 95% ci : 2.011.7 ) ; osa ( ahi  10  events / h ) in 71% of resistant hypertensives and in 38% of responders . continuous positive airway pressure ( cpap ) represents the treatment of choice for patients with osa . it has been shown that cpap decreases the incidence of cardiovascular events in patients with osa [ 89 , 90].the acute application of cpap attenuates blood pressure elevations during sleep . however , the long - term effects of cpap on blood pressure are controversial , from studies reporting a significant decrease in blood pressure to studies reporting small or no effects [ 92106 ] . three meta - analyses have tried to overcome these discrepancies and revealed that the beneficial effect is modest , with reductions in systolic blood pressure ranging from 1.38  mmhg to 2.46  mmhg [ 107109 ] . it is , therefore , not surprising that in a recent randomized study , valsartan was more effective than cpap in hypertensive patients with osa . it has to be noted , however , that most of the above - mentioned studies have not been performed exclusively in hypertensive patients , usually evaluating both normotensive and hypertensive subjects . in addition , larger blood pressure reductions were observed in osa patients with higher baseline blood pressure levels [ 107 , 111 ] , as expected with any antihypertensive approach ; the motto  the higher the blood pressure , the larger the reduction  has been verified over the years . indeed , two small studies in osa patients with resistant hypertension revealed significant blood pressure reductions ( over 10  mmhg ) [ 112 , 113 ] . on the contrary , a study in 42 patients with resistant hypertension showed a smaller mean arterial pressure reduction ( 5.6  mmhg ; 95% ci : 2.08.7  mmhg ; p < .03 ) . interestingly enough , the benefits of cpap were evident only at 1-year after cpap application , suggesting that longer followup periods might be necessary for the benefits of cpap treatment to become apparent in osa patients with resistant hypertension . another important factor is that cpap treatment allowed de - escalation of antihypertensive treatment in the majority of participating patients ( 71% ) . a recent study in 96 patients with osa and resistant hypertension showed a slight decrease in systolic blood pressure ( 1.3  mmhg ) . however , the reduction was significantly larger in patients with abpm - confirmed resistant hypertension ( 7.6  mmhg ) . in addition , the reduction was even larger in cpap users for more than 5.8 hours per day . the above - mentioned data delineate the complexity in identifying patients with resistant hypertension and osa that will have the greater benefits with cpap treatment . an important issue challenging the efficacy of cpap relates to patient adherence . among patients prescribed cpap therapy up to 50% failed to initiate it or did not use it at 3 years [ 116 , 117 ] . another important aspect of treatment is the choice of antihypertensive drugs in patients with osa . the crucial role of sns activation and the increased levels of aldosterone in patients with osa , point towards potential advantages of drugs inhibiting these pathways on reducing blood pressure . indeed , beta blockers were found to be more effective than other antihypertensive drugs in osa patients ; however , relevant data is still far from conclusive . even more interestingly , however , spironolactone was shown not only to significantly lower blood pressure in 12 patients with osa and resistant hypertension , but to reduce the severity of osa as well . further , larger studies are needed , however , to confirm these beneficial effects of spironolactone in patients with osa . pa is characterized by autonomous production of aldosterone by adrenal glands and the subsequent decrease in renin levels though negative feedback . aldosterone excess leads to hypertension , metabolic alkalosis , hypernatremia , and potassium loss resulting in hypokalemia ; the latter is currently considered a late manifestation of pa . pa can result from an aldosterone producing adenoma , bilateral adrenal hyperplasia , glucocorticoid - remediable aldosteronism , or rare familial syndromes . although the diagnosis of adrenal adenomas prevailed during the older times , recent reports reveal that hyperplasia is more frequent than adrenal adenomas . the prevalence of pa in the general hypertensive population remains an unresolved issue [ 122 , 123 ] . historically , pa has been considered a rare disease , affecting about 1% of hypertensive patients [ 124127 ] . however , several studies performed in the last decade report a much higher prevalence of pa ( > 10% ) , suggesting an  epidemic  of this condition [ 128133 ] . these studies , however , were carried out in specialized referral centers , raising concerns of selection bias . indeed , a study of more than 600 unselected patients with hypertension conducted in chile , revealed a 6.1% prevalence of pa , suggesting that the true prevalence is somewhere in the middle . however , irrespective of its exact prevalence , pa has become fashionable again , with leading specialized centers appearing all over the world , from alabama ( d. calhoun ) to italy ( g. rossi ) and from australia ( m. stowasser ) to united kingdom ( m. brown ) . the prevalence of hypertension relates to the severity of hypertension . in the study from chile , pa was found in 1.99% of patients with stage i hypertension and in 13.2% of patients with stage iii hypertension . in another study of more than 400 czech patients with moderate - to - severe hypertension , data from clinical practice indicates that resistant hypertension represents the condition with the highest probability of detecting pa [ 136 , 137 ] . indeed , the prevalence of pa ranged from 1423% in 5 studies conducted in resistant hypertensives [ 138142 ] . a study of 88 patients with resistant hypertension in alabama showed that 18 patients ( 20% ) suffered from pa ; pa prevalence was race independent . the prevalence of pa was quite similar in two other studies , one from seattle ( 17% ) and one from norway ( 23% ) [ 139 , 140 ] . a study from spain reported a 14% prevalence of primary hyperaldosteronism in patients with refractory hypertension ; however , patients with hypokalemia were excluded from the study suggesting that the true prevalence of primary aldosteronism could be up to two times higher than the one reported . finally , a similar prevalence of 14% has been reported in diabetic subjects with resistant hypertension . the above - mentioned studies have reported a pa prevalence of 1423% in patients with resistant hypertension , suggesting that the true prevalence would be around 20% . however , it has to be recognized that all these studies included a small number of patients . in total , only 418 patients participated in these studies , underlining the need for larger studies . a recent study from greece evaluated 2,032 patients with resistant hypertension , with 1,616 of them having  true  resistant hypertension . it was found that about 21% of studied patients had a high aldosterone to renin ratio combined with high aldosterone levels , which were suggestive of primary aldosteronism . however , only half of them ( 11.3% ) were suffering for primary aldosteronism , confirmed by salt suppression tests and response to spironolactone . another very interesting finding is the coexistence of pa and osa in patients with resistant hypertension . in one study of 109 patients with resistant hypertension , osa however , in another study , pa was found in only 34% of patients with osa . . the other forms of endocrine hypertension , presented in table 3 , are less frequently encountered in hypertensive patients and , therefore , represent rare causes of resistant hypertension . in addition , the clinical presentation of these endocrine forms of secondary hypertension is usually so characteristic that is really hard to be missed . since this paper addresses the most common secondary causes of resistant hypertension , readers interested in endocrine hypertension may refer to other recently published reviews [ 146 , 147 ] . hypertension is commonly found in patients with chronic kidney disease ( ckd ) , with 75% of ckd patients taking antihypertensive drugs . on the other hand , 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 albuminuria is present [ 149151 ] . 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% . however , ckd is usually underappreciated as a cause of resistant hypertension , mainly because these patients are being followed at specialized nephrology clinics . 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 , vascular 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 .   another significant contributor to treatment resistance in patients with ckd it has been observed that restrictions in diuretic use were the primary cause of resistant hypertension in patients with ckd . 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 . 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 . 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 . renovascular hypertension is of atherosclerotic origin in the vast majority of cases , thus being 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 . older studies suggested that 1 out of 3 patients with secondary hypertension has renovascular 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 noninvasive 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 , the diagnosis of renovascular hypertension represents an unfulfilled challenge for primary care physicians and remains mainly restrained in specialized centers . 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 . balloon angioplasty was not found superior to optimal drug treatment in the recently published astral study ; several drawbacks , however , limit the interpretation of study findings . another ongoing trial , the coral study , will provide hard - endpoint data with the two different approaches . 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 patients and prevent unnecessary costs and patient discomfort . in summary , ( i ) verification of  true  resistant hypertensionpatients 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 . patient - related problems . adherence to antihypertensive treatment is of utmost importance for the effective management of arterial hypertension . both epidemiological and clinical data strongly indicate that patient adherence to antihypertensive therapy is poor [ 170175 ] . almost half of treated hypertensive patients discontinue drug administration during the first year of treatment whereas long - term adherence rates are even lower . in addition , small studies in patients with resistant hypertension suggest that poor patient adherence represents one of the most common causes of treatment resistance [ 176 , 177 ] . detailed medical history , information by relatives , and use of specific questionnaires might help in identifying patients with poor adherence ; these methods can be easily applied by primary care physicians with obvious benefits . modern technology is used with good results ( electronic pill boxes , internet monitoring ) but is not widely applied yet . special programmes using close contact of health care professionals ( doctors , nurses , and pharmacists ) with patients seem also effective but lack wide application as well . finally , simplification of dosing schedule and use of drugs with superior safety profile may be of benefit . it has been shown that doctors are frequently reluctant to maximize drug therapy , either by adding antihypertensive drugs or by switching drug category , in order to achieve blood pressure goals [ 178181 ] . indeed , a gap between guideline recommendations and their implementation in everyday clinical practice has been recognized and represents a significant obstacle in achieving satisfying blood pressure control rates [ 149 , 150 ] . another contributor to treatment resistance is the use of inappropriate drug combinations or suboptimal doses of antihypertensive drugs . indeed , a study of patients with resistant hypertension revealed that simple measures , such as increasing diuretic dosing or switching to appropriate diuretics , can result in significant blood pressure reductions . in our opinion , however , the most important line of evidence suggesting physician inertia on treatment resistance , comes from recent studies reporting significantly higher control rates of hypertension [ 182185 ] . in these studies , various measures have been used to motivate physicians in achieving blood pressure goals , resulting in improved control rates . therefore , physicians need to be the focus of future efforts for the effective management of resistant hypertension . blood pressure technique - related problems . the requirements for proper blood pressure measurement have been standardized   and incorporated in the guidelines for the management of arterial hypertension [ 149 , 150 ] . however , the measurement of office blood pressure in clinical practice frequently deviates from the recommendations . therefore , falsely elevated blood pressure levels may be recorded due to several reasons : inappropriate cuff size , failure to comply with the recommendations regarding sufficient time before blood - pressure measurement , arm support at the heart level , assessment in a quiet room , triplicate recordings , and coffee intake or smoking before blood pressure measurement [ 187189 ] . the above mentioned factors may contribute to overestimation of blood pressure and  pseudoresistance  . similarly , false elevations may be encountered in older patients , in whom adequate artery compression may not be achieved due to marked arterial calcification . therefore , it is essential to assure proper techniques of blood pressure measurement in order to limit the rates of pseudoresistance . another important aspect of  resistance  is recognition of  white coat  hypertension . it has been noted that in 2030% of patients with resistant hypertension , treatment resistance may be attributed to the  white coat  effect [ 143 , 190192 ] . target organ damage therefore , either ambulatory or home blood - pressure monitoring should be performed in every patient with resistant hypertension , in order to exclude the three main problems require special attention at this step : patient - related problems , physician - related problems , and blood - pressure technique - related problems . patient - related problems . adherence to antihypertensive treatment is of utmost importance for the effective management of arterial hypertension . both epidemiological and clinical data strongly indicate that patient adherence to antihypertensive therapy is poor [ 170175 ] . almost half of treated hypertensive patients discontinue drug administration during the first year of treatment whereas long - term adherence rates are even lower . in addition , small studies in patients with resistant hypertension suggest that poor patient adherence represents one of the most common causes of treatment resistance [ 176 , 177 ] . detailed medical history , information by relatives , and use of specific questionnaires might help in identifying patients with poor adherence ; these methods can be easily applied by primary care physicians with obvious benefits . modern technology is used with good results ( electronic pill boxes , internet monitoring ) but is not widely applied yet . special programmes using close contact of health care professionals ( doctors , nurses , and pharmacists ) with patients seem also effective but lack wide application as well . finally , simplification of dosing schedule and use of drugs with superior safety profile may be of benefit . it has been shown that doctors are frequently reluctant to maximize drug therapy , either by adding antihypertensive drugs or by switching drug category , in order to achieve blood pressure goals [ 178181 ] . indeed , a gap between guideline recommendations and their implementation in everyday clinical practice has been recognized and represents a significant obstacle in achieving satisfying blood pressure control rates [ 149 , 150 ] . another contributor to treatment resistance is the use of inappropriate drug combinations or suboptimal doses of antihypertensive drugs . indeed , a study of patients with resistant hypertension revealed that simple measures , such as increasing diuretic dosing or switching to appropriate diuretics , can result in significant blood pressure reductions . in our opinion , however , the most important line of evidence suggesting physician inertia on treatment resistance , comes from recent studies reporting significantly higher control rates of hypertension [ 182185 ] . in these studies , various measures have been used to motivate physicians in achieving blood pressure goals , resulting in improved control rates . therefore , physicians need to be the focus of future efforts for the effective management of resistant hypertension . blood pressure technique - related problems . the requirements for proper blood pressure measurement have been standardized   and incorporated in the guidelines for the management of arterial hypertension [ 149 , 150 ] . however , the measurement of office blood pressure in clinical practice frequently deviates from the recommendations . therefore , falsely elevated blood pressure levels may be recorded due to several reasons : inappropriate cuff size , failure to comply with the recommendations regarding sufficient time before blood - pressure measurement , arm support at the heart level , assessment in a quiet room , triplicate recordings , and coffee intake or smoking before blood pressure measurement [ 187189 ] . the above mentioned factors may contribute to overestimation of blood pressure and  pseudoresistance  . similarly , false elevations may be encountered in older patients , in whom adequate artery compression may not be achieved due to marked arterial calcification . therefore , it is essential to assure proper techniques of blood pressure measurement in order to limit the rates of pseudoresistance . another important aspect of  resistance  is recognition of  white coat  hypertension . it has been noted that in 2030% of patients with resistant hypertension , treatment resistance may be attributed to the  white coat  effect [ 143 , 190192 ] . target organ damage therefore , either ambulatory or home blood - pressure monitoring should be performed in every patient with resistant hypertension , in order to exclude the patient - related problems . adherence to antihypertensive treatment is of utmost importance for the effective management of arterial hypertension . both epidemiological and clinical data strongly indicate that patient adherence to antihypertensive therapy is poor [ 170175 ] . almost half of treated hypertensive patients discontinue drug administration during the first year of treatment whereas long - term adherence rates are even lower . in addition , small studies in patients with resistant hypertension suggest that poor patient adherence represents one of the most common causes of treatment resistance [ 176 , 177 ] . detailed medical history , information by relatives , and use of specific questionnaires might help in identifying patients with poor adherence ; these methods can be easily applied by primary care physicians with obvious benefits . modern technology is used with good results ( electronic pill boxes , internet monitoring ) but is not widely applied yet . special programmes using close contact of health care professionals ( doctors , nurses , and pharmacists ) with patients seem also effective but lack wide application as well . finally , simplification of dosing schedule and use of drugs with superior safety profile may be of benefit . it has been shown that doctors are frequently reluctant to maximize drug therapy , either by adding antihypertensive drugs or by switching drug category , in order to achieve blood pressure goals [ 178181 ] . indeed , a gap between guideline recommendations and their implementation in everyday clinical practice has been recognized and represents a significant obstacle in achieving satisfying blood pressure control rates [ 149 , 150 ] . another contributor to treatment resistance is the use of inappropriate drug combinations or suboptimal doses of antihypertensive drugs . indeed , a study of patients with resistant hypertension revealed that simple measures , such as increasing diuretic dosing or switching to appropriate diuretics , can result in significant blood pressure reductions .   in our opinion , however , the most important line of evidence suggesting physician inertia on treatment resistance , comes from recent studies reporting significantly higher control rates of hypertension [ 182185 ] . in these studies , various measures have been used to motivate physicians in achieving blood pressure goals , resulting in improved control rates . therefore , physicians need to be the focus of future efforts for the effective management of resistant hypertension .   blood pressure technique - related problems . the requirements for proper blood pressure measurement have been standardized   and incorporated in the guidelines for the management of arterial hypertension [ 149 , 150 ] . however , the measurement of office blood pressure in clinical practice frequently deviates from the recommendations . therefore , falsely elevated blood pressure levels may be recorded due to several reasons : inappropriate cuff size , failure to comply with the recommendations regarding sufficient time before blood - pressure measurement , arm support at the heart level , assessment in a quiet room , triplicate recordings , and coffee intake or smoking before blood pressure measurement [ 187189 ] . the above mentioned factors may contribute to overestimation of blood pressure and  pseudoresistance  . similarly , false elevations may be encountered in older patients , in whom adequate artery compression may not be achieved due to marked arterial calcification . therefore , it is essential to assure proper techniques of blood pressure measurement in order to limit the rates of pseudoresistance . another important aspect of  resistance  is recognition of  white coat  hypertension . it has been noted that in 2030% of patients with resistant hypertension , treatment resistance may be attributed to the  white coat  effect [ 143 , 190192 ] . target organ damage therefore , either ambulatory or home blood - pressure monitoring should be performed in every patient with resistant hypertension , in order to exclude the ( ii ) exclusion of drug - induced hypertensionas discussed in the first section of this paper , several drugs may induce blood pressure elevations , with nsaids and oral contraceptives being the most common . therefore , practicing physicians need to be very meticulous during medical history taking , in order to uncover the use of drugs inducing hypertension . the withdrawal of offended drugs usually results to the return of blood pressure at previous levels . in the case , however , that the drug is considered essential for the treatment of comorbidities , the substitution to another drug with a more friendly profile or the reduction of dose might be beneficial . 
  as discussed in the first section of this paper , several drugs may induce blood pressure elevations , with nsaids and oral contraceptives being the most common . therefore , practicing physicians need to be very meticulous during medical history taking , in order to uncover the use of drugs inducing hypertension . the withdrawal of offended drugs usually results to the return of blood pressure at previous levels . in the case , however , that the drug is considered essential for the treatment of comorbidities , the substitution to another drug with a more friendly profile or the reduction of dose might be beneficial . ( iii ) reduction of dietary sodium intakesodium intake is excessive in the western world , mainly due to the  hidden salt  in processed foods . the average sodium intake is far higher than the recommended 2.4 grams per day , reaching even 10  g / day in patients with resistant hypertension . the important role of sodium restriction in patients with resistant hypertension is highlighted by the findings of a recent study . it was found that reductions in sodium intake are accompanied by significant reductions in blood pressure levels in resistant hypertensives . sodium intake is excessive in the western world , mainly due to the  hidden salt  in processed foods . the average sodium intake is far higher than the recommended 2.4 grams per day , reaching even 10  g / day in patients with resistant hypertension . the important role of sodium restriction in patients with resistant hypertension is highlighted by the findings of a recent study . it was found that reductions in sodium intake are accompanied by significant reductions in blood pressure levels in resistant hypertensives . ( iv ) evaluation for secondary causes of hypertensionas previously discussed , obstructive sleep apnea , primary aldosteronism , and chronic kidney disease represent the most common secondary causes of resistant hypertension whereas several other conditions may be responsible for treatment resistance as well . the diagnostic workup for secondary hypertension is demanding , requires special knowledge and technology , and should be performed in specialized referral centers , which are familiar with secondary hypertension . although a detailed description of the diagnostic workup is beyond the scope of this paper , some signs and/or findings raising the suspicion of secondary hypertension need to be mentioned . in particular : obesity , snoring , daytime sleepiness , and increased neck diameter raise the suspicion of obstructive sleep apnea ; hypokalemia ( either spontaneous or diuretic induced ) is present in about half of cases with primary aldosteronism ; active urine sediment , small kidneys , and impaired renal function point towards chronic kidney disease ; abdominal bruit , difference in renal size raise the suspicion of renal artery stenosis .. 
  as previously discussed , obstructive sleep apnea , primary aldosteronism , and chronic kidney disease represent the most common secondary causes of resistant hypertension whereas several other conditions may be responsible for treatment resistance as well . the diagnostic workup for secondary hypertension is demanding , requires special knowledge and technology , and should be performed in specialized referral centers , which are familiar with secondary hypertension . although a detailed description of the diagnostic workup is beyond the scope of this paper , some signs and/or findings raising the suspicion of secondary hypertension need to be mentioned . in particular : obesity , snoring , daytime sleepiness , and increased neck diameter raise the suspicion of obstructive sleep apnea ; hypokalemia ( either spontaneous or diuretic induced ) is present in about half of cases with primary aldosteronism ; active urine sediment , small kidneys , and impaired renal function point towards chronic kidney disease ; abdominal bruit , difference in renal size raise the suspicion of renal artery stenosis .. 
 ( v ) pharmacologic management of resistant hypertensionthe pathophysiology of resistant hypertension provides the rational for the effective management of this clinical entity . the combination of increased systemic vascular resistance with marked volume expansion in many cases , renders the triple combination of a drug inhibiting the renin - angiotensin axis ( ace - inhibitors or angiotensin receptor blockers ) with a calcium antagonist and a diuretic a very attractive combination for the majority of patients ( unless these drugs are contraindicated or not tolerated , or other drugs are indicated due to comorbidities ) . however , reliable data verifying the superiority of this combination over other combinations is not available . special attention has to be drawn in maximizing the dose of diuretics or switching to loop diuretics in patients with low gfr . the overactivation of the sympathetic nervous system renders beta blockers , alpha blockers , and centrally acting antihypertensive drugs ( clonidine , alpha methyldopa ) of potential benefit in many patients when added in previous therapy . direct vasodilators , such as hydralazine and minoxidil , can be very effective for blood pressure management , especially in african americans and patients with chronic kidney disease . a vast amount of evidence indicates that spironolactone is a drug of choice in the treatment of resistant hypertension . several studies revealed impressive blood pressure reductions in patients with resistant hypertension when spironolactone was added in the therapeutic regime [ 195205 ] . administration of one antihypertensive drug at bedtime has been shown to improve blood pressure control in patients with resistant hypertension [ 206208 ] . the pathophysiology of resistant hypertension provides the rational for the effective management of this clinical entity . the combination of increased systemic vascular resistance with marked volume expansion in many cases , renders the triple combination of a drug inhibiting the renin - angiotensin axis ( ace - inhibitors or angiotensin receptor blockers ) with a calcium antagonist and a diuretic a very attractive combination for the majority of patients ( unless these drugs are contraindicated or not tolerated , or other drugs are indicated due to comorbidities ) . however , reliable data verifying the superiority of this combination over other combinations is not available . special attention has to be drawn in maximizing the dose of diuretics or switching to loop diuretics in patients with low gfr . the overactivation of the sympathetic nervous system renders beta blockers , alpha blockers , and centrally acting antihypertensive drugs ( clonidine , alpha methyldopa ) of potential benefit in many patients when added in previous therapy . direct vasodilators , such as hydralazine and minoxidil , can be very effective for blood pressure management , especially in african americans and patients with chronic kidney disease . a vast amount of evidence indicates that spironolactone is a drug of choice in the treatment of resistant hypertension . several studies revealed impressive blood pressure reductions in patients with resistant hypertension when spironolactone was added in the therapeutic regime [ 195205 ] . administration of one antihypertensive drug at bedtime has been shown to improve blood pressure control in patients with resistant hypertension [ 206208 ] . 
 ( vi ) newer drugs for the management of resistant hypertension endothelin antagonists exhibited promising results in preliminary studies . the future of darusentan remains unclear , however , since in another study in patients with resistant hypertension , darusentan failed to be more effective than placebo regarding office blood pressure reductions . it has to be mentioned , however , that in the latter study , significant differences were detected in ambulatory blood pressure between darusentan and placebo , indicating that further studies are needed with this drug category . another interesting approach for the management of resistant hypertension is the administration of nitric oxide donors . in a recent small clinical study of six patients with resistant hypertension , however , this finding has to be interpreted with caution , since the concomitant use of these medications is contraindicated due to the possibility of severe hypotension . the future of darusentan remains unclear , however , since in another study in patients with resistant hypertension , darusentan failed to be more effective than placebo regarding office blood pressure reductions . it has to be mentioned , however , that in the latter study , significant differences were detected in ambulatory blood pressure between darusentan and placebo , indicating that further studies are needed with this drug category . another interesting approach for the management of resistant hypertension is the administration of nitric oxide donors . in a recent small clinical study of six patients with resistant hypertension , however , this finding has to be interpreted with caution , since the concomitant use of these medications is contraindicated due to the possibility of severe hypotension . ( vii ) interventional management of resistant hypertensiondespite the wide application of antihypertensive therapy , a substantial portion of the hypertensive population remains uncontrolled although taking more than three drugs . this situation calls for testing alternative approaches in patients with resistant hypertension . carotid baroreceptors and renal sympathetic overdrive play a significant role in blood pressure regulation [ 212 , 213 ] . during the last decade , two new approaches have revived the use of interventional techniques for the management of resistant hypertension . carotid baroreceptor stimulation and renal sympathetic denervation have shown promising preliminary results in patients with resistant hypertension [ 214 , 215 ] . however , further studies are needed to establish their role in the management of resistant hypertension . 
  despite the wide application of antihypertensive therapy , a substantial portion of the hypertensive population remains uncontrolled although taking more than three drugs . this situation calls for testing alternative approaches in patients with resistant hypertension . carotid baroreceptors and renal sympathetic overdrive play a significant role in blood pressure regulation [ 212 , 213 ] . during the last decade , two new approaches have revived the use of interventional techniques for the management of resistant hypertension . carotid baroreceptor stimulation and renal sympathetic denervation have shown promising preliminary results in patients with resistant hypertension [ 214 , 215 ] . however , further studies are needed to establish their role in the management of resistant hypertension .
resistant hypertension is defined as uncontrolled blood pressure despite the use of three antihypertensive drugs , including a diuretic , in optimal doses . 
 treatment resistance can be attributed to poor adherence to antihypertensive drugs , excessive salt intake , physician inertia , inappropriate or inadequate medication , and secondary hypertension . 
 drug - induced hypertension , obstructive sleep apnoea , primary aldosteronism , and chronic kidney disease represent the most common secondary causes of resistant hypertension . 
 several drugs can induce or exacerbate pre - existing hypertension , with non - steroidal anti - inflammatory drugs being the most common due to their wide use . 
 obstructive sleep apnoea and primary aldosteronism are frequently encountered in patients with resistant hypertension and require expert management . 
 hypertension is commonly found in patients with chronic kidney disease and is frequently resistant to treatment , while the management of renovascular hypertension remains controversial . 
 a step - by - step approach of patients with resistant hypertension is proposed at the end of this review paper .