61

Chapter 8 Managing Hypertension in a Patient with Renal Dysfunction: The Double Jeopardy KEWAL C. GOSWAMI • SHANMUGAM KRISHNAN

India which screened over 5000 individuals re-vealed a prevalence of 17% of CKD in screened population with at least 6% being stage 3 CKD and only 8% of CKD patients were aware of their CKD with hypertension being the most common cause and more common than among those without CKD 6 . Prevalence of resistant hypertension is par-ticularly high in CKD (up to 22%) which contrib-utes to worse outcomes 7 , 8 and drugs are limited further due to CKD. Unlike Western countries where a signifi cant proportion of patients undergo renal transplantation soon after diagnosis, in India ma-jority of patients continue to be on medical follow-up with infrequent dialysis further worsening hy-pertension and associated end-organ damage. Indian registry showed only 35% of stage 5 CKD were on renal replacement therapy in its sixth an-nual report.

BLOOD PRESSURE MEASUREMENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE

In India, BP readings are taken most commonly in hospital and appropriate techniques should be fol-lowed in measuring BP to avoid spuriously high or low readings 9 . Prevalence of both offi ce hyper-tension and masked hypertension is common in patients with CKD. Masked hypertension is wherein hospital BP readings are within normal range spuriously but ambulatory BP measurement (ABPM) or home BP measurement reveals the ele-vated blood pressure. In meta-analysis done on trials involving 980 patients, the overall prevalence of masked hypertension was 8.3% 10 . In particular, masked uncontrolled hypertension detected by home BP readings or ABPM is associated with worse outcomes . White coat hypertension is

INTRODUCTION

Chronic kidney disease (CKD) is common in South Asia and about 20% of adults above 30 years have CKD. Hypertension and diabetes are leading causes of CKD and both of these occur much younger in South Asia compared to Western population with increasing incidence in last two decades 1 . Awareness of hypertension and control of hypertension are both low in India compared to developed coun-tries 2 . Treatment of hypertension in CKD is prob-lematic in that many physicians still prescribe non-angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) as the fi rst line due to fear of worsening renal damage, hyperkalae-mia further contributing to poor control of blood pressure (BP) thus accelerating the progress of CKD and worse outcomes.

EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE AND HYPERTENSION

The prevalence of hypertension varies with the stage of CKD and increases with the stage of CKD. Overall prevalence of hypertension in stages 4 and 5 is more than 90% 3 . CKD is defi ned as glomerular fi ltration rate (GFR) less than 60 mL/min/1.73 m 2 or albuminuria of more than 30 mg/g of creatinine 4 . Hypertension can both be a cause and consequence of kidney disease accelerating the decline in GFR with poor hypertension control. In MRFIT study , the relative risk of developing end-stage renal dis-ease (ESRD) was about 22 times more common in people with BP�210/120 than the optimal BP of �120/80 mm Hg (see ref 5 ). Knowledge of hyper-tension and CKD in general population is low, par-ticularly in developing countries, and control of hypertension is very low. KEEP study done in

62 SECTION II — Preventive Cardiology

elevated BP in hospital but with normal BP read-ings by home BP or ABPM and it is not associated with worse outcomes. Its estimated prevalence is 18%. Home BP monitoring is thus considered supe-rior to offi ce monitoring. In patients undergoing dialysis, this is a major problem as due to volume retention, BP measurement before dialysis may be falsely elevated making it an unreliable marker of overall BP control. Home BP monitoring with auto-mated devices even with its limitations are consid-ered superior to offi ce BP measurement 11 , 12 . Role of ABPM need further large scale studies for future recommendations.

GUIDELINE RECOMMENDATIONS FOR BLOOD PRESSURE CONTROL

Different guidelines advocate various cut-offs for BP control but even the higher values are rarely achieved in clinical practice in Indian settings. Key guideline recommendations are summarized in Table 8-1.

AASK study compared intensive BP control (defi ned as mean arterial pressure [MAP] �92 mm Hg calculated as 2/3 diastolic pressure � 1/3 sys-tolic pressure corresponding to BP �130/80) versus standard BP control (MAP �107 mm Hg corre-sponding to BP 140/90) in hypertensive CKD pa-tients with GFR between 20 and 65 mL/min. There was an initial trial phase followed by a cohort phase with follow-up of 10 years. Although the primary outcome in the overall trial population was not signifi cant, in subgroup analysis there was a statistically 27% signifi cant reduction in the in-cidence of primary outcome (doubling of serum

creatinine, ESRD or death) in patients with base-line proteinuria 18 .

MDRD study compared intensive BP control (MAP �92 mm Hg) versus standard BP control (MAP �107 mm Hg) in 840 patients for a mean follow-up of 2 years and found that there was no signifi cant difference between two groups in rate of decline of GFR 19 . Long-term follow-up of these pa-tients after the trial completion did show a signifi -cant difference for kidney failure and the composite outcome, though ACEI drug usage differed between these two groups 20 .

These initial trials thus showed no signifi cant dif-ferences between intensive versus standard BP con-trol, although there was evidence of benefi t for re-nal outcomes for patients with baseline proteinuria. Patient level meta-analysis done by Jafar et al. re-vealed that treatment with ACEI decreased the risk of progression of CKD and with maximal lowering of systolic blood pressure (SBP) to between 110 and 130 mm Hg (see ref 21 ). Guidelines thus were based mostly on cohort studies and on these randomized control trials (RCTs).

A recent large RCT SPRINT trial showed that intensive SBP lowering of less than 120 mm Hg is associated with improved outcomes compared with SBP of less than 140 mm Hg. It is important to note in this trial that diastolic blood pressure was lowered to less than 70 mm Hg in the inten-sive control group. There was no adverse event with respect to GFR worsening between two groups in CKD patients despite achieving this lower BP in the short-term follow-up of this prematurely ter-minated trial. In patients with CKD subgroup also, there was signifi cant improvement in outcomes (HR 0.73, CI 0.53–1.0). However, there were more events of GFR worsening in patients without CKD (3.8% vs. 1.1%) 22 .

After the publication of this trial, no major guidelines were published and so the next guide-lines may have different BP recommendations de-spite potential drawbacks of this trial in particular method of BP measurement. For patients on dialysis generally advocated pre- and postdialysis BP are 140/90 and 130/80 mm Hg, respectively 23 .

PATHOPHYSIOLOGY OF HYPERTENSION IN CHRONIC KIDNEY DISEASE

Major pathophysiological causes of hypertension in CKD are salt and volume retention, sympathetic ner-vous system activation, activation of renin–angioten-sin–aldosterone system (RAAS) and multitude of other mechanisms.

TABLE 8-1 SUMMARY OF GUIDELINE RECOMMENDATIONS FOR BP CUT-OFFS IN HYPERTENSION CONTROL IN CKD

JNC 8 (2014) (see ref 13 )

140/90

KDIGO (2012) (see ref 14 )

130/80 with microalbuminuria

140/90 without microalbuminuria NICE (2014)

(see ref 15 ) 130/80 with microalbuminuria

ESC (2013) (see ref 16 )

140/90

SBP � 130 with overt proteinuria ISH/ASH (2013)

(see ref 17 ) 130/80

63Chapter 8 — Managing Hypertension in a Patient with Renal Dysfunction: The Double Jeopardy

SALT AND WATER RETENTION

CKD leads to salt and water retention by decreased fi ltration in addition to activating neurohormonal systems and accumulation of metabolites such as di-methyl arginine. In patients with CKD, sodium excre-tion is achieved at the expense of elevated BP mostly by increased peripheral resistance. Calculation of the dry weight is important in patients undergoing dialy-sis, which is defi ned as body weight achieved at the end of dialysis at which patient remains normoten-sive and without symptoms. There is a lag phase for BP reduction after dialysis despite normalization of extracellular volume. It usually takes a month to achieve maximum reduction in BP with dialysis 24 .

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM ACTIVATION

RAAS system can be activated due to multitude of mechanisms including decreased number of func-tional nephrons, renal artery stenosis and endothe-lial damage. Proteinuria and hypertension contrib-ute to worsening renal function as nephron sclerosis occurs. Angiotensin II leads to glomerular hyperfi l-tration thus increasing proteinuria and increases oxidative stress leading to glomerular and tubuloin-terstitial fi brosis. Aldosterone also plays an impor-tant role in increasing proteinuria and sclerosis in-dependent of angiotensin effects 25 . Inhibitors of RAAS in particular as shown in Fig. 8-1 , additive mechanisms such as addition of aldosterone an-tagonists can decrease proteinuria more than other drugs if tolerated well 26 .

OTHER MECHANISMS

Sympathetic nervous system activation, endothe-lial factors such as increased endothelin, decreased nitric oxide and increased asymmetric dimethyl arginine, drugs predominantly erythropoietin and immunosuppressants (steroids and calcineurin in-hibitors) are some of the other contributing mech-anisms.

TREATMENT

General approach to treatment of hypertension in CKD is summarized in Fig. 8-2 .

Angiotensin I

Angiotensinogen

Angiotensin II

AT1 receptor AT2 receptor

Renin

ACE ACE Inhibitors

ARB

Aldosterone

Cardiac, renal and vascular effects (increased sodium and water reabsorption, increased proteinuria, increased BP, sympathetic activation)

Aldosteronereceptor

antagonists

Renin Inhibitors

Figure 8-1. Renin–angiotensin–aldosterone pathway and its inhibitors.

ACEI or ARB

CKD stage 1–3 = Thiazidetype diuretics

CKD stage 4–5 = Loop diuretics

Dietary salt restriction

Diuretics

CCB ± Beta blockers

Other drugs (Spironolactone,Minoxidil, Clonidine, Alpha

blockers, Hydralazine)

Figure 8-2. Management of hypertension in CKD.

64 SECTION II — Preventive Cardiology

DIETARY SALT RESTRICTION AND DIURETIC USE

Dietary salt restriction has been shown to lower BP at the population level and in hypertensive pa-tients. As salt retention plays an important role in patients with advanced stages of CKD, salt restric-tion will augment the effects of antihypertensive drugs 27 .

(a) Thiazide and thiazide-like diuretics: Choice of diuretics in hypertensive patients in general are thiazide and thiazide-like diuretics, which decrease BP in the long term by de-creasing peripheral resistance rather than by decreasing volume. Its effi cacy in advanced kidney disease is limited as net sodium excre-tion is very less due to its action predomi-nantly on distal tubules which contributes to only 5%–10% of total sodium excretion. Its effi cacy in patients with GFR � 30 mL/m 2 is doubtful 28 .

(b) Loop diuretics: Loop diuretics, in particular long-acting diuret-ics, decrease salt and water retention thus being effective even in advanced stages, although higher doses are required in order to achieve the same concentration in tubular fl uid as ex-cretion decreases. Combination of both loop diuretics and thiazide diuretics overcomes the problem of diuretic resistance in early stage CKD patients probably by decreasing rebound sodium absorption. In small pilot trials, combi-nation therapy was found to be benefi cial in increasing sodium excretion and additional decrease in BP 29 , 30 .

ACEI/ARB

ACEI by inhibiting angiotensin converting enzyme decreases production of angiotensin II and ARB acts on the receptor level to inhibit the action of angio-tensin II. However, alternative pathways of genera-tion can still contribute to formation of angiotensin II. ACEI in general have been shown to be favour-able and comparable to diuretics in hypertensive patients 31 . All ACEI/ARB have a class effect on hy-pertension and renoprotective effects by decreasing proteinuria. Some patients do experience important side effects such as worsening of renal function and hyperkalaemia. Risk of hyperkalaemia is more pro-nounced with worsening stages of CKD and in ad-dition with aldosterone antagonists. Despite these risks, they have been shown to be renoprotective

even in ESRD patients. Combinations of ACEI and ARB have not been shown to be benefi cial, but rather with increased adverse risks and should be avoided. In a meta-analysis, there was 3.4% higher rate of hyperkalaemia without signifi cant change in mortality 32 .

AASK study showed that treatment with ACEI resulted in statistically significant 40% re-duction in the outcome of 50% decline in GFR or ESRD compared to calcium channel blockers (CCB) group in stage 3 CKD patients. IDNT trial done in 1715 stage 3 diabetic CKD patients with proteinuria revealed a significant 24% reduction with ARB in composite primary end point of doubling of serum creatinine, ESRD or death compared to CCB which was independent of BP reduction. Composite cardiovascular end points were not significantly decreased in this trial 33 . RENAAL study showed that treatment with losartan had a beneficial effect on renal out-comes 34 . Several other trials also showed the ad-ditional beneficial effects of ACEI/ARB in stages 1–3 CKD patients and these formed the backbone of treatment in these groups of patients. Despite improvement in renal outcomes, none of these trials showed a significant decrease in cardiovas-cular and cerebrovascular outcomes with these drugs.

Hou et al. conducted an RCT in stage 4 CKD with ACEI and showed that the rate of decline of GFR, proteinuria and progression to CKD is signifi cantly less compared to control group. Drug was safely tolerated after a preliminary run in period with around 5% risk of hyperkalaemia which was similar to placebo 35 .

Although RCTs in stage 5 CKD are limited regard-ing safety and effi cacy of ACEI/ARB, a large prospec-tive cohort study done in Taiwan, by Hsu et al., encompassing 28,000 patients found that use of ACEI/ARB was associated with a decreased risk of dialysis or death of around 6% reduction. Of note, the rate of hyperkalaemia was more with the use of these drugs, but mortality was not increased due to hyperkalaemia. They estimated that 5.5% of pa-tients on ACEI could be prevented from need for dialysis per year at the cost of 2.5% absolute in-crease in risk of hyperkalaemia 36 .

Even in patients who develop hyperkalaemia on ACEI/ARB, continuation of these drugs have shown to decrease worsening of CKD and proper manage-ment of hyperkalaemia addressing secondary causes and low-potassium diet did not lead to more epi-sodes of hyperkalaemia than the other group in which it was discontinued 37 .

65Chapter 8 — Managing Hypertension in a Patient with Renal Dysfunction: The Double Jeopardy

OTHER DRUGS

Hypertension control in CKD patients requires mul-tiple drugs and in general CCB and beta blockers are highly effi cacious, well tolerated by these patients and are recommended. If BP is still uncontrolled with these medications, minoxidil, clonidine, alpha blockers, hydralazine and other drugs can be added. Mineralocorticoid receptor antagonists (MRA) such as spironolactone is primarily restricted to use in stages 1–3 CKD patients with resistant hypertension as hyperkalaemia is more common with these group of drugs when added to ACEI/ARB 38 .

FUTURE PERSPECTIVES

Despite the advancements in CKD management and treatment of hypertension, a signifi cant pro-portion of patients still have uncontrolled hyper-tension on multiple drugs. Well-conducted RCTs on MRA and long-term effi cacy and safety of ACEI/ARB in stages 4 and 5 CKD are needed. Longer sessions of haemodialysis for improving BP control need further studies. Advent of renal denervation despite its initial negative results in trials needs better stud-ies and baroreceptor stimulation long-term studies are the need of the hour 39 , 40 . Even application of current therapies to decrease BP with regular home BP monitoring to the current goals will go a long way in decreasing morbidity and mortality.

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