Treating Resistant Hypertension in CKD patients- A Double challenge for physicians

Recent research has affirmed that hypertension and CKD are closely intertwined, exhibiting a cause-effect relationship. (2) As kidney function diminishes, blood pressure typically rises, whereas a chronic elevation in BP aggravates the course of an already existing kidney disease. A study aimed at evaluating any direct relationship between the relative risk of developing end-stage kidney disease (ESKD) and BP severity revealed that individuals with a baseline BP close to 180/100 mm Hg were approximately 15 times more likely to develop ESKD than individuals with a baseline BP close to 110/70 mm Hg. (3) Research has documented RH in CKD patients to be a major risk factor for cardiovascular disease(4), further highlighting that the successfully managing RH is associated with improved cardiovascular outcomes, in both CKD and ESKD.(5,6)

Prevalence of RH in CKD patients

Data from the National Health and Nutrition Examination Survey (NHANES), from 2003 to 2008, suggests that 12.8% of the anti-hypertensive-treated population meets the criteria for resistant hypertension; further elaborating that this number may rise to>50% in nephrology clinics. (4,5) In the CRIC study,(7) researchers noted that as high as 42% of patients with established chronic kidney disease suffered from treatment-resistant hypertension. In an Italian cohort study analyzing the actual burden of true-resistant hypertension among 436 hypertensive CKD patients under nephrology care, researchers noted a high prevalence of 22.9%. (8)

Several factors like impaired sodium handling, increased activity of the renin-angiotensin-aldosterone (RAAS) and sympathetic systems, impaired nitric oxide synthesis and endothelium-mediated vasodilation, and increased arterial stiffness have been identified as major contributors in the pathogenesis of resistant hypertension in CKD(9,10,11). Such interlinking warrants for optimum control of both RH and CKD simultaneously, to achieve the best results.

Resistant Hypertension and CKD: A dangerous liaison

With a growing number of studies reporting on the increased adverse health outcomes in CKD patients with RH, a summary of the most relevant ones has been summarized below.

• A large cohort study (12) with RH patients on three or more antihypertensive agents observed that the risk of a composite endpoint including death, cardiovascular events, and chronic kidney disease over 3·8 years of follow-up was 18·0% vs 13·5% in those without RH.
• Another study noted that hypertensive nephropathy patients with true resistant hypertension had a higher risk of fatal and non-fatal cardiovascular events and end-stage renal disease or death when compared to patients with hypertensive nephropathy with a controlled BP.(8)
• Notable studies like the REGARDS study and ALLHAT trial concluded that treatment-resistant hypertension increased the risk of progression towards end-stage renal disease in patients with already existing kidney diseases. (7,13) Among the REGARDS study participants, the risk of developing end-stage kidney disease (ESKD) over a median follow-up of 6.4 years was 6.32 times higher in those with than in those without RH. The study further reported that the prevalence of Apparent Treatment-Resistant Hypertension (a TRH) was 15.8% in the eGFR stratum of ≥ 60 ml/min/1.73m2 and 24.9% in the eGFR stratum of 45–59 ml/min/1.73m2, whereas it was 34.9% in those with eGFR< 45 ml/min/1.73m2, suggesting that resistant hypertension goes hand in hand with a gradual decline in estimated glomerular filtrate rate and severity of albuminuria.
• In the notable CRIC study, those with prevalent a TRH had a 48% higher risk for adverse cardiovascular events, 28% higher risk for the composite outcome of > 50% decline in eGFR or incident ESKD, and 24% higher risk for all-cause mortality, when compared with non-hypertensives. (14)

Managing Resistant Hypertension in CKD patients

With updated guidelines put forth by the American Heart Association and American College of Cardiology (15) stating a triple-drug combination of Angiotensin-converting enzyme Inhibitor (ACEi) or Angiotensin receptor blockers (ARB) + long-acting Calcium Channel Blockers (CCB) + Diuretic (or loop diuretic), at maximally tolerated doses, as the first line of treatment in resistant hypertension, recent focus has been directed towards exploring the potentiality of the drugs as multidrug therapy in controlling RH in CKD patients.

Choosing an appropriate Diuretic

Diuretics are of utmost importance in managing extracellular volume overload, commonly noted in renal insufficiency, thus achieving strict blood pressure control in these patients. (16)

Chlorthalidone, backed up by evidence from numerous clinical trials and graded as a long-acting thiazide, has twice the potency of hydrochlorothiazide at similar doses, exhibiting superior efficacy in moderate CKD.(17) Documented to have a much longer duration of action (8–15 h for HCTZ compared with >40 h for chlorthalidone) (17), in clinical studies using 24-h ABPM, chlorthalidone 25 mg/day results in greater reductions in 24-h mean SBP compared with HCTZ 50 mg/day, primarily due to its effect on reducing nighttime mean SBP (18). Therefore, strong consideration should be given to using chlorthalidone over HCTZ, especially given the growing importance of nocturnal blood pressure on cardiovascular outcomes and kidney disease progression in patients with CKD.

Loop diuretics should be prescribed when GFR is less than 30 mL/min as recommended by NICE and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. (19,20) Contrary to furosemide and bumetanide which are required to be dosed at least twice daily given their short duration of action and the potential for intermittent natriuresis leading to a reactive increase in the RAAS, the longer-acting torsemide dosed once daily, is regarded to be better. (21)

Selecting an apt ARB

The panel members appointed to the Eighth Joint National Committee (JNC8) found moderately strong evidence to recommend initial or add-on treatment with ACEis or ARBs for hypertension in all patients with CKD to improve kidney outcomes.(22)

Research has revealed that ARBs extend benefits of renoprotection beyond BP lowering,as has been resonated in notable studies like RENAAL, IRMA II and IDNT trials. (23)

Azilsartan has been backed up by evidence-based trials highlighting that this drug is a suitable option for the treatment of hypertension in patients with any degree of renal impairment (23). Unlike other ARB's dose adjustment is not needed, even in patients with the most severe renal disease.

A growing body of evidence now suggests Fixed-dose combinations of Azilsartan with Chlorthalidone to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. (24)

Adding a CCB

While notably, short-acting CCB formulations may increase sympathetic activity and activate RAAS, due to acute peripheral vasodilation, long-acting CCB agents have been proven to be beneficial in CKD patients.(25)

A notable clinical study, INSIGHT, has demonstrated a significant GFR decline in the diuretic group when compared with nifedipine, establishing the concept of a greater renoprotective effect of nifedipine(26). Resonating with such results, an analysis of Systolic Hypertension in Europe (SYST-EUR) trial for renal outcomes reported that the incidence of mild renal dysfunction decreased by 64% and the incidence of proteinuria decreased by 33% in patients receiving active therapy with nifedipine. (27)

Key pointers

The goals of antihypertensive therapy in patients with CKD should be aimed to concomitantly lower BP, reduce the risk of cardiovascular disease, and slow down the progression of chronic kidney disease.

• Multidrug regimens are advocated to achieve BP goals by interfering with the different pathways involved in the pathogenesis of hypertension in patients with chronic kidney disease.
• Individualized tailoring of treatment should be considered according to the stage of kidney disease, cardiovascular risk or other comorbidities, age, sex, ethnicity, the presence of proteinuria, and risk of drug-drug interactions.
• Keeping in mind the impaired kidney functioning, the routes of drug excretion should be considered and doses adjusted according to GFR levels.
• A triple-drug therapy comprising of 3 antihypertensive drugs of different classes at the maximum tolerated doses including an ARB, a CCB, and a diuretic has shown exceptional success rates in this high-risk group.

Conclusion

Timely diagnosis and optimal pharmacological management, coupled with necessary lifestyle modifications, can go a long way in reversing the poor cardiovascular and kidney-related complications in CKD patients with RH. Choosing an appropriate multidrug therapy is the key to successfully managing such high-risk populations. With triple-drug therapy gaining ground based on elaborate researches, clinicians are placed to rationalize the use of the most potent drugs, depending on the individualistic kidney functioning.

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