Hypertension in CKD: what we know, what we don’t and what’s wrong with KDIGO 2021 BP goal of <120mmHg?

Management of hypertension is one of the most important tasks of nephrologists, which if done well can be highly rewarding. More often than not, blood pressure is either left uncontrolled or is lowered too much, putting patients at risk of the attendant complications. Realising the fallacy and dangers of ‘one size fits all’ approach which has been the part of preexisting guidelines, ACC/AHA  2019 guidelines, were a much needed departure from the ‘target based’ to the ‘risk based’ approach of BP treatment. This is a sensible approach, when one views BP elevation as a risk factor for organ damage/dysfunction and not a disease in itself, with lesser emphasis on moving a BP number from a higher to lower value and greater emphasis on reducing the risk posed by elevated BP to the health. 

However, KDIGO 2021 HTN guidelines seem to be traveling back in time to embrace the target blood pressure, the magical number <120 systolic for the entire CKD population (except those on dialysis).

This recommendation not only lacks sufficient evidence, but if implemented strictly by treating doctors, can be potentially disastrous.  A recent review has summarised the serious limitations of the evidence on which KDIGO 2021 BP target is based, and we will discuss here the basis for more conservative BP targets for most patients with CKD. 

Why is BP elevated in patients with CKD? 

Blood Pressure=Cardiac Output x Systemic Vascular Resistance 

Given the fact that most patients with CKD will have high BP, what factors elevate CO or SVR in these patients?

Disturbance of sodium and volume regulation (not appreciable as edema in early CKD), activation of RAS and sympathetic nervous system, anemia and multiple other factors  determine BP by affecting CO or SVR. This makes hypertension in CKD pathophysiologically complex and different from primary hypertension(figure 1). Therefore, the data guiding treatment of primary hypertension can’t be directly extrapolated to HTN in CKD. Hypertension is not a disease in itself but a risk factor for organ damage/dysfunction and consequent morbidity and mortality. Risk with hypertension in CKD is two folds: cardiac plus renal. One also needs to acknowledge the nature of CV disease in CKD which isn’t all the same as the general population without kidney disease. Uncontrolled BP is one of the most important determinants of CKD progression along with proteinuria, and multiple pivotal trials in diabetic CKD –Captopril trial, RENAAL, IDNT-(although they were not BP target trials) have shown the efficacy of antihypertensive therapy in renoprotection. 

Figure 1. Pathogenesis of hypertension in chronic kidney disease 

Limited generalisability of SPRINT CKD to the real world CKD

Data supporting BP target of <120 systolic comes from SPRINT trial. 

First of all, one needs to understand that SPRINT-CKD, unlike EMPA-KIDNEY or DAPA CKD, isn’t an independent randomised controlled trial, and is a pre-specified subgroup analysis of SPRINT trial. 

If you wish to prepare a checklist of ‘refer to nephrology’ for a primary care doctors clinic, you may rather copy paste SPRINT trial exclusion criteria which go like this: diabetes, proteinuria >1gm/day, ADPKD, glomerulonephritis, eGFR <20 (in addition to age <50). Mean serum creatinine in this elderly population (age 67 yrs), was 1.56mg/dl, and urinary albumin excretion was ~40 mg/gm. This clearly is not a ‘nephrologist’s patient population’, unless the physician is a very good friend of yours or is too scared by serum creatinine of 1.56mg/dl in an elderly non diabetic. Indeed, the rate of eGFR decline in SPRINT trial is similar to the age associated decline in kidney function. Extrapolating findings from SPRINT CKD cohort to CKD clinics is going to be a mistake that can cost (mostly borne by kidney). 

The conclusion of the SPRINT CKD goes like this: 

“among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome” . Even authors themselves (and rightly so) don’t claim to have established a new BP target for CKD. These findings only mean that main SPRINT results are also applicable to the ‘accidental CKD’ like the rest of the population. 

Accidental CKD is detected when an elderly patient with comorbidities gets to know that he has CKD after reading the eGFR value in the bold type which at the bottom of the paper also gives the latest KDIGO CKD classification. Telling them “nothing to worry about” and seeing the wrinkles disappear from their faces is one of the happy moments in our practice. This age associated decrease in GFR without significant albuminuria is of questionable significance and is arguably the medicalisation of aging.  

Limited generalisability of the SPRINT CKD was highlighted by a study performed across 40 Italian nephrology clinics, involving 2847 patients. This population differed significantly from the SPRINT CKD, specifically, they have higher risk of ESRD, CV deaths and all cause mortality.  

Intensive BP lowering may be harmful 

An important concern for the broader application of <120 is the harm, and this is particularly relevant to the CKD. Two trials that dealt with a very similar BP target in diabetics and non diabetics (ACCORD BP and SPRINT) reached discordant primary outcomes, however, they concur upon the harm of intensive BP lowering. 

In the ACCORD BP trial, serious adverse events attributed to BP lowering were more likely in the intensive lowering arm: hypotension, syncope, bradycardia/arrhythmias. Importantly, in a population at very low risk of progressive CKD (mean creat 0.9mg, median UACR 14mg/gm), risk of of eGFR <30ml (as an adverse lab measure) was  doubled with intensive BP lowering [99 (4.2%) vs 52 (2.2%) <0.001]. Alarmingly, renal failure occurred in 5 patients in the intensive control arm versus 1 patient in the less intensive arm. 

In SPRINT trial as well, in addition to increased risk of hypotension, syncope and electrolyte abnormalities, intensive lowering led to higher incidence of AKI [204 (4.4%) vs 120 (2.65) HR 1.71 P<0.001], ≥30% reduction in estimated GFR to <60 ml [ 127 (3.85) vs 37 (1.1%) HR 3.49 P<0.001]. 

A post hoc analysis of SPRINT showed a higher risk of AKI and eGFR based renal outcomes (≥30% decrease in eGFR to a value of <60 mL for participants without CKD; and a composite of ≥50% decrease in eGFR the development of ESRD with CKD) in the intensive control group.  This analysis also showed that the CV protective effect of intensive BP lowering is significantly blunted at reduced GFR and was no longer significant at eGFR<45 ml per min(figure 2,3,4).

Figure 2. Risk of AKI is higher in patients with eGFR <45 ml/min( J Intern Med 2018 Mar 283(3):314-327)

Figure 3. eGFR based renal outcomes (≥30% decrease in eGFR to a value of <60 mL for participants without CKD; and a composite of ≥50% decrease in eGFR the development of ESRD with CKD) is higher in intensive BP control group (J Intern Med 2018 Mar 283(3):314-327) 

Figure 4.  CV protective effect of intensive BP lowering is  blunted at reduced GFR and was no longer significant at eGFR<45 ml per min (J Intern Med 2018 Mar 283(3):314-327)

Many patients in nephrology clinics have severe hypertension, often symptomatic with headache, visual disturbances (This is another dark room in nephrology awaiting to be lit). These patients are younger and don’t have other traditional CV risk factors like dyslipidemia or atherosclerotic CVD. How will this group fare with intensive BP lowering? An interesting analysis using patient-level data from 9361 randomised participants of SPRINT trial evaluated a similar issue. They studied the impact of baseline BP and Framingham risk score on outcomes, and showed that in  participants with a baseline SBP of at least 160 mmHg and a lower Framingham risk score, targeting an SBP of less than 120mmHg compared with less than 140 mmHg resulted in a significantly higher rate of all-cause death [hazard ratio (95% CI) for intensive group: 3.12 (1.00-9.69); P = 0.049]. 

SPRINT trial was terminated early after 3.5 years, and therefore the long term impact of these renal events on CKD outcomes remains a question and there is no reason to believe in long term safety of intensive BP control. Premature termination of RCTs carries the risk of overestimating the benefits and underestimating the harm of the intervention. What will happen to this renal function decline over years of follow up? The correct answer to this question is “we don’t know”. However, KDIGO prefers to dismiss it as a hemodynamic and transient phenomenon. Although ‘nephrotoxicity’ of intensive BP lowering  hasn’t bothered trialists and KDIGO guideline makers, the risk benefit of intensive BP lowering needs to be carefully discussed with our patients before implementation.

Why was there a dissociation between CV and renal benefits in SPRINT?

Figure 5. Spectrum of risk factors for CV events changes with progression of CKD

 Is ‘some renal compromise’ an inevitable consequence if you wish to gain CV benefits? We believe that this apparent ‘cardiorenal paradox’ has to do with the different nature of CV risk profile in CKD. With worsening kidney function, the nature of CV risk changes, with greater contribution from non-traditional CKD specific risk factors (in addition to traditional atherosclerotic CV risk factors)(fig 5). CKD in a nephrologist’s clinic resembles more to the participants in the landmark CKD-BP trials: Captopril study, REIN , RENAAL and IDNT, MDRD and AASK.  Unlike SPRINT or SPRINT-CKD, most of these trials dealt with participants having high risk of CKD progression. In such patients, renoprotection is likely to go hand in hand with cardioprotection, and intervention in addition to kidney disease is likely to offer cardioprotection as well (considering the fact that CV disease in this population is often non-coronary i.e. left ventricular hypertrophy, systolic and diastolic dysfunction, and cerebrovascular disease). 

Is KDIGO recommendation valid if standardised BP measurement is universally adopted? 

One argument put forth in support of intensive BP lowering is that if we measure BP properly (standardised office BP or AOBP) and minimize white coat effect, a target of <120mmHg will make sense. 

We argue that even if one imagines a theoretical scenario where AOBP will be used universally for monitoring BP, intensive BP lowering will still have all the attendant risks that we discussed. In a systematic review and meta analysis, involving 9279 participants, AOBP readings were 7-14 mmHg lower (the difference in the routine office BP and “research settings” was ~7 mmHg and that between routine office and AOBP was 14 mmHg). Even if we adjust for the way BP is recorded, none of the pivotal CKD trials (even post SPRINT) had reached target SBP <120 mmHg(table 1).  

Clinical trial	Blood pressure achieved (intervention vs control)
Captopril	128-134 vs 129-136
IDNT	141/77 vs 144/80
RENAAL	140/74 vs 142/74
CLICK	130/70 vs 140/75
DAPA CKD	??? vs 137/78
EMPA KIDNEY	control arm BP 137/78 (Reduction in SBP was−2.6 mm Hg in intervention)

Table 1. List of randomised control trials on CKD patients. with serum creatinine values at the enrolment and target BP achieved in the  trial. As can be seen, even in the research settings the target BP of 120 mmHg was not achieved in landmark trials involving patients with CKD

What do we already know about BP targets in CKD?

Before SPRINT-CKD, what did we know about intensive BP lowering in non diabetic CKD? Two trials that evaluated the effect of intensive versus less intensive BP targets in real world non-diabetic CKD are MDRD (serum creatinine 2-3 mg/dl) and AASK (serum creatinine 2-2.2mg/dl, >30% participants  had UACR >0.22). Both assessed impact of this intervention primarily on kidney function, as decline in eGFR,  and concluded that lower target (<125 in MDRD, <129 in AASK) doesn’t offer additional renoprotection than usual targets. Subgroup analysis of patients with proteinuria suggested the benefit of lower target on kidney outcomes. Post trial follow up of AASK and MDRD (for 14-15 years) claimed reduced overall mortality (HR 0.87, 95% CI 0.76-0.90), and also reduced the progression to ESRD (HR 0.88, 95% CI 0.78-1.00), but the benefit was confined to those with proteinuric CKD. These findings from post trial follow up should be interpreted with caution: they are discordant with primary outcome of the original trials, observed differences in outcomes are marginal, and importantly, there was no difference in the blood pressure between the groups in the follow up period. Several meta-analyses combining these trials of various designs, interventions, different BP targets, not surprisingly, have reached different conclusions claiming (here and here) and refuting (here and here) the benefit of intensive BP lowering.     

Nephrology dark room

Figure 6. There is a lack of data about BP targets in advanced CKD, X axis depicting serum creatinine concentration of the trial population

Even the landmark BP-CKD trials have involved the patients with mild to moderate decrease in kidney function and evidence guiding BP treatment in more severe CKD (and not on dialysis) is virtually nonexistent (figure 6). Unfortunately, KDIGO doesn’t make any distinction about the advanced CKD (which may be one of the most prevalent patient populations in nephrology OPDs), implying that target <120 is valid across the spectrum of CKD. 

What should clinicians do in the absence of convincing evidence for BP goals in their patients? Patient’s values and preferences should be considered while developing guidelines, KDIGO committee didn’t have patient representation. What would patients with CKD value? Patients and clinicians may believe that intensive BP lowering reduces all cause mortality significantly (relative risk reduction of 28%), however they need to be informed about a much smaller absolute risk reduction of 1.9%. On the basis of SPRINT results, for every 1000 patients treated for 3.2 years with intensive BP lowering compared to the less than 140 systolic, on average, 19 persons will benefit, 26 will experience acute renal failure (ARF),^*955 will not experience benefit or harm. Such clear discussion of the risk-benefit should be done with all those patients in whom intensive BP lowering is considered. In our CKD clinic, after screening 119 patients, 12 met inclusion criteria, of which only 2 agreed to go for the intervention of intensive BP lowering (unpublished data, Tukaram Jamale). 

^*ARF was the terminology by SPRINT trial in adverse event reporting. It’s interesting to know how this trial defined acute kidney injury. ARF was included as an event if the diagnosis was listed in the hospital discharge summary, and considered by the SPRINT Safety Officer, after reviewing medical records to be one of the top three causes of the admission or continued hospitalization. A few patients with ARF were noted in the emergency department records instead of hospitalization records.

In the opinion of the KDIGO committee, if there is uncertainty about the risk/benefit, it seems ok to consider the benefit and ignore risk. See a paragraph from the guideline document below:

Is there a plausible mechanism of harm? 

In patients with long standing hypertension and especially those with comorbidities like CKD, the pressure-flow curve of the blood flow in various organs (e.g. brain) is shifted to the right(figure 7).   

Figure 7. In hypertensive patients, the autoregulation curve is shifted to the right.

In other words, the blood pressure threshold that leads to compromised tissue perfusion in hypertensive patients is different (higher) than the general population. Importance of this phenomenon was highlighted in several studies involving patients with chronic hypertension seen in acute care settings.  For example, SEPSISPAM trial, that evaluated two different MAP targets in patients with sepsis (80-85 vs 65-70 mmHg), primary outcome of 28 day mortality didn’t differ in the two groups, however, among patients with chronic hypertension, those in the high-target group were less likely to experience the doubling of serum creatinine [90/173 (52.0%) vs 65/167 (38.9%) p=0.02] and required less renal-replacement therapy [73/173 (42.2%) 53/167 (31.7%) p=0.046] than those in the low-target group. Another trial involving peri operative patients evaluated individualized versus standard BP management strategy (aimed at achieving a SBP within 10% of the patient’s resting SBP vs treating when it falls below 80 systolic), individualized management was associated with a non significantly reduced risk of AKI and CNS dysfunction post op, although primary outcome of SIRS and organ dysfunction wasn’t different in these groups. In another study evaluating the effect of higher target BP in patients with prior hypertension, sublingual microcirculation (assessed by sidestream dark field imaging) significantly improved in patients with higher MAP. Given these observations, and the existing data from large RCTs, normalizing (rather than controlling) blood pressure in patients with chronic hypertension is not only unnecessary but can be harmful and the brunt of this harm is borne by the kidney.

Mean Perfusion Pressure (MPP) is given by the difference between Mean Arterial Pressure (MAP) and Central Venous Pressure (CVP) i.e. MPP=MAP-CVP. Another factor that can further compromise MPP in patients with CKD is increased CVP as a result of volume overload, diastolic dysfunction, and increased left and right ventricular filling pressures. This factor is likely to become more prominent with progressive GFR decline. Although KDIGO 2021 BP targets don’t apply to patients on dialysis, in this population the safe targets are likely to be further higher as highlighted by this pilot RCT. 

Is the quality of evidence and strength of recommendation  2B or 2C?

 KDIGO has graded the evidence supporting intensive BP lowering in CKD as 2B-a suggestion based on moderate quality evidence. We evaluated the evidence in the framework of GRADE, and reached a conclusion that evidence supporting this target is 2B at the best, a suggestion based upon poor quality evidence. Several features of the trials make the case for this: 

1. Evidence supporting this is indirect (subgroup analysis and not an independent trial, now, someone may argue that it’s largest in terms of number, but it also is farthest from true CKD in terms of patient characteristics!) 

2. There is risk of bias as trials considered are open label 

3. Inconsistency of the observations -previous large trial, ACCORD BP, has refuted the hypothesis that intensive BP lowering helps

After having discussed potential risks of the intensive BP lowering, and lack of adequate evidence, and evidence of harm in patients with diabetes, strangely, guidelines have resorted to follow the intensive BP lowering. They applaud SPRINT’s plan of including CKD (GFR 20-59ML); however forget the fact that they ultimately ended up with a participant group with eGFR >70ml ( serum creatinine ~1 mg/dl). Unlike AASK and MDRD trials who also were set out to include patients with CKD and actually included them, SPRINT couldn’t enroll a real world CKD population. The reasons for selective inclusion of patients with higher GFR in SPRINT are unclear but one of them may be the perceived risk of intensive lowering in patients with lower GFR by the site physicians. 

Summary

In the vast majority of the CKD patients in nephrology OPDs, evidence to lower BP target of <120  is nonexistent, and therefore guideline recommendation of <120 is not supported by the good evidence. With progressive decrease in kidney function, you get to the nephrology dark room where no evidence to guide BP management exists. Nephrologists, therefore shoulder the responsibility of treating one of the most difficult blood pressure challenges with no or little evidence to base their decision upon. 

After careful evaluation of the available evidence, one would rather choose to maintain the equipoise about BP goal and individualize it for different situations after shared decision making with the patients. 

May 2023

Hydrochlorthiazide: the turtle of the race?
“Adalphane Acedrex (a Novartis made combo of Reserpine+Dihydralazine+Hydrochlorothiazide)- was available in the hospital formulary and ‘uncontrolled hypertension’ was a rare condition”, Prof Hase would get nostalgic and remark on his grand rounds discussing evolution of pharmacotherapy for hypertension.

One of the earliest classes of antihypertensives, thiazide diuretics, are also one of the most effective drugs, with latest trial evaluating chlorthalidone showing a BP decline of almost 10mmHg. However, whether chlortalidone should altogether replace hydrochlorothiazide is still a matter of debate. This is an attractive proposition given the higher potency and some pleotropic benefits attributed to chlorthalidone (the term ‘pleotropic effect’ awakens sleeping skeptic in us, as this term is typically invoked to defend something that can’t stand scientific rigor alone). Large observational studies and meta-analyses have differing conclusions waiting for a randomized trial to settle the debate. (see here, here and here)

In a pragmatic randomized controlled trial involving 13,523 patients over 65 years of age, getting treated at Veterans Affairs health system, a switch to chlorthalidone (hydrochlorothiazide was the default thiazide at baseline), 12.5 or 25 mg did not improve the primary composite outcome of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non–cancer-related death. Primary outcome occurred in 702 patients [10.4%] in chlorthalidone and 675 patients [10.0%] in the hydrochlorothiazide group (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P=0.45). The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001).

This trial is long-awaited evidence to understand the difference between two commonly used thiazide diuretics for the treatment of hypertension and reassures those physicians who haven’t yet switched to chlorthalidone. The superior efficacy of chlorthalidone to reduce blood pressure doesn’t translate into effectiveness. This trial is an example of low cost, operational research in the setting of structured heath care systems like VA. Such pragmatic trials are feasible, can be completed quickly (phenomenal recruitment rate of 100 patients per week!), and are possible at a substantially lesser cost.

Many hypertension clinics have already switched to chlorthalidone given the higher potency and 24-hour action of chlorthalidone. Both of these reasons are not good enough to inform practice. First, potency may not necessarily translate into efficacy (which current trial confirms). For example, immediate release nifedipine or hydralazine are potent antihypertensives but not necessarily effective at the ultimate goal of BP control-CV protection. Duration of action as well may not be valid argument as the mechanism of BP reduction with thiazides is unclear and both volume depletion and fall in systemic vascular resistance play a role. Modest vasodilatation observed with these drugs is more pronounced with chlorthalidone but contribution of this to the long-term BP reduction may not be substantial to change hard clinical endpoints.

Baxdrostat: new drug to treat hypertension

Hypertension is ‘the disease of kidney’, hypothesis that is supported by the fact that one of the most effective antihypertensives exert their effect via kidneys. Here is a welcome addition to the antihypertensive armamentarium —baxdrostat-a highly selective aldosterone synthase inhibitor. Prior efforts to inhibit this key enzyme in aldosterone synthesis were thwarted by concomitant and undesirable inhibition of cortisol synthesis catalyzed by 11 beta-hydroxylase (which share 93% sequence similarity with aldosterone synthase).

In this phase 2 trial-BrigHTN, 248 patients with treatment resistant hypertension were randomized to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo.

Treatment resistant HTN was defined as: stable doses of at least three antihypertensive medications (one of which was a diuretic) and had a mean blood pressure of at least 130/80 mm Hg (the average of three measurements obtained with the use of an automated in-office blood-pressure monitor).

Trial was stopped early as criteria for overwhelming efficacy were met-a substantial decrease in blood pressure was noted with treatment: difference between the 1mg group and the placebo group, −8.1 mm Hg, and difference between the 2mg group and the placebo group, −11.0 mmHg, but the difference between the 0.5mg group and placebo was not significant.

Resistant hypertension is associated with high morbidity and mortality; baxdrostat is a welcome addition to our armamentarium to manage this condition. Some caution is needed before we consider it as a breakthrough. First, office BP measurements (primary endpoint) were used to assess the efficacy-why on the earth a Pharma who is able to pioneer a drug development can’t afford to use gold standard 24-hour ABPM to assess efficacy, when it is already used widely in practice? Second, there unexpectedly large placebo effect (9-10mmHg). The reasons for this may be multiple and given the office BP measurements used white coat effect is possible. For the same reason, patients with pseudo resistant HTN might have got enrolled. Factors like adherence to salt restriction, drug adherence, optimization of other antihypertensives might have decreased blood pressure in placebo arm as well as the drug (Hawthorne effect). More elderly patients got randomized to placebo; did it put control arm at disadvantage? This difference will be more relevant in long term, when CV outcomes of these patients will be compared. Phase 3 trials, involving larger sample size, longer follow up, and hard CV outcomes will clarify the pace of this agent in hypertension treatment.

Rise and fall of the sympathetic denervation in the treatment of hypertension

Last few months are of sympathetic overactivity: RADIANCE HTN TRIO trial, with its longer term (6 month) follow up and follow up efficacy data of SIMPLICITY HTN 3 were published back-to-back in JAMA and Lancet.

In patient on triple drug combination of CCB, ARB and thiazide, additional reduction in the BP after renal denervation was modest at 2 months. 136 patients with resistant HTN were randomized to ultrasound guided renal denervation-uRDN-(n=69) or a sham procedure (n=67). Primary outcome of reduction in daytime ambulatory systolic blood pressure was more with intervention than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0]vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022). This difference persisted at six months as documented in this prespecified follow up analysis; however was diminished as compared to that noted at 2 months: mean daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of -2.4 [16.6]vs -7.0 [16.7]mm Hg from month 2, respectively).

Authors, nonetheless, are happy about fewer medication usages (although this difference wasn’t statistically significant at 6 months), and lesser need of aldosterone antagonists in intervention arm (hardly a reason to celebrate).

Renal denervation trials are classic example of the “big bang effect ” of scientific innovations. SIMPLICITY 1 and SIMPLICITY 2 reported a phenomenal reduction in BP over 30mmHg (for a moment elevating blood pressure of hypertension pharma). This was a massive overestimate, confirmed by SIMPLICITY 3 that addressed the key flaw of not having a sham control group in previous studies. We thought of waving a goodbye to renal denervation after these results.

But authors of the simplicity 3 want us to walk back in time and believe that the large reductions in BP reported by previous studies are supported by their 36 months follow up data of simplicity 3 trial published by lancet. The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). 

There are more than one reasons not believe this tall claim: first, after unmasking at 6 months study didn’t remain a blinded trial and all the patient and physician related biases can cloud the conclusions. As highlighted by the editorial and a letter, Hawthorne effect- change in the behaviour of physicians (better monitoring, frequent reassessments) and patient (better compliance to dietary restrictions and medications) in the intervention arm can explain the apparent difference. Second, despite having uncontrolled hypertension, control arm didn’t receive additional medications to optimize control (did they punish participants refusing to cross over?). Several important questions are raised by this interesting letter as well.

Another confusing feature of this post trial follow up data was the choice of the comparator group, and the way BP measurements were done for this group. After 6 months, a large majority (101 of 171) of the patient crossed over to intervention, however as one might have expected, authors didn’t compare those who received denervation with those who didn’t. Instead, they considered cross over patients (along with those not crossed over) with their BP at 6month considered for final assessment (last observation carried forward). This further adds to difficulty in interpreting the effect of intervention versus placebo and makes assessment of true effect size difficult.

Lost and found theme has created a large number of Bollywood blockbusters, where lost brother or sister is brought back by the director after plot starts getting dull to add life to the story. Producer/director of SIMPLICITY 3 (Medtronic) tries this, but this is hardly enough to bring back this intervention in hypertension practice. There is no easy way to know the contribution of sympathetic over activity in an individual patient with hypertension and if such measures become available, we may be able to better define the role of this treatment. Until then, results of 36 months follow up can be taken with a pinch of NaCl.

Na restriction works to lower BP , may take potassium’s help

BP control doesn’t always need more drugs or interventions like denervation, sometimes smart and simple interventions can yield significant benefits. Two recent studies highlight this point clearly. Salt restriction can prevent age associated increase in blood pressure (age is no more a non-modifiable risk factor), controls BP in those who are already hypertensive and has huge potential to save lives. Salt restriction is the default advice that most hypertensive patients in our clinic receive but it easier said than done. With rapidly changing food environments, adhering to salt restriction is more and more challenging, controlling salt intake in clinical trial can be difficult. These group of investigators from China in their DECIDE-Salt trial played a smart trick.

48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted salt intake (You can fool your taste buds and slow reduction in the salt intake can go unnoticed) versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (–7.1 mmHg, 95% confidence interval (CI) –10.5 to –3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure.

This degree of reduction in BP is clinically relevant and is equivalent to adding one antihypertensive. Fewer cardiovascular events were noted in salt substitute group (hazard ratio (HR) 0.60, 95% CI 0.38–0.96), but this had no effect on mortality (HR 0.84, 95% CI 0.63–1.13). As expected, salt substitute increased biochemical hyperkalemia, but this was not associated with adverse clinical outcomes. Results confirm the findings of a previous large SSaSS trial which evaluated effect of this intervention in hypertensive rural Chinese population with past history of stroke. Greater reduction in BP (than SSaSS trial) is attributed to “better modulation” of diet in collective living setting where residents have limited control over the composition of the food they eat.

Important finding of the study was no effect of ‘progressively restricted salt intake’ strategy, which authors attribute to reliance on facility manager and cooks to deliver this (whom residents could influence), and the possibility that residents might have identified the food with restricted salt (buds used to a very high salt intake) and resorted to usual salt intake. Whatever may be the reason, this highlights the difficulty of implementing salt restriction at community level.

Predominantly men and Chinese population, lack of complete follow up data from one particular site, lack of 24-hour urine collection to ascertain the delivery of the intervention are the notable limitations. However, this study is a welcome and important addition to the efficacy and feasibility of sodium restriction as an intervention in hypertension.

STOPACE trial

Medical reversal -where in an established practice/treatment is proved either useless or, sometimes, harmful when subjected to rigorous testing by an RCT- is a regular occurrence in medicine. One classic example of this in nephrology was targeting higher hemoglobin in dialysis patients. This practice was proved harmful after many years when subjected to rigorous scrutiny by well designed RCTs. Stopping ACEi with advancing CKD may be another. This practice was based on hunch of the physicians and observational data . Even clinical practice guidelines are silent on what to do with RASi in advanced CKD. With no guidance and data, it was left to whims and fancies of treating physicians to decide regarding use of RASi in advanced CKD. We now have better evidence that stopping RASI may not be the right thing to do in advanced CKD.

STOP ACEi trial randomized 411 patients with advanced and progressive CKD (GFR<30ml/min) either to discontinue or to continue therapy with RAS inhibitors. The primary end point was the eGFR at 3 years. The difference in eGFR at 3 years was not different in the two groups (difference, −0.7ml/min; 95% CI, −2.5 to 1.0; P=0.42). Other important outcomes like ESKD, initiation of dialysis and CV events were no different in both groups.

The trial results are important in many aspects. It breaks the strongly held dogma that RASi must be withheld in advanced CKD. The trial enrolled real world advanced CKD: median age- 63 years, median serum creatinine-3.4mg/dl, median GFR-18ml/min, 29% patients had GFR<15ml/min, and 37% were diabetics.

The findings of the trial do not support the practice of STOPPING RASi in advanced CKD to improve kidney function. But what about effect of RASi on CV outcomes in advanced CKD? Well, there are no data in advanced CKD patients. Observational data suggests an association between increased CV events after discontinuing RASi.

With this study, it is prudent to continue RASi in advanced CKD and it’s time to move from “hunch” based medicine to evidence-based medicine!

EMPA-CKD trial

After iron and iodine, a day is not far when Flozins will be added to the list of food fortifications. That might be an exaggeration. But after securing a star status in management of DKD and heart failure, flozins are all set to stamp their authority in management of CKD patients.

EMPA CKD randomized 6609 CKD patients to empagliflozin or placebo. Enrolled patients had an eGFR 20 to 45 ml/min/ 1.73 m², or who had an eGFR of 45 – 90 ml/min/ 1.73 m² with a urinary ACR >200(mg/gm). After median 2 years of follow up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001).

Of the patients enrolled mean age was 63.8 years, non-diabetics were 54% and 35% had eGFR<3oml/min. Serious adverse events were not different in the groups. The patient population is more like what we see in CKD clinics. EMPA CKD trial in addition to DAPA CKD trial defines the role of flozins in CKD. Benefits were not significant in those without albuminuria (was it due to premature termination of the trial?) and in this patient subgroup further evaluation of these agents is needed.

Heterogeneity of response to treatment of hypertensive

One of my patients with CKD is a tailor and his chief complaint in the last clinic visit was his shrinking business in the era of ‘readymade’. Now a days, it is far more convenient to order online or buy readymade trousers from showrooms. I was wearing such a ‘readymade trouser’ in my cousin’s wedding, and everyone was staring at me instead of the newlyweds on the dais. I had just started feeling elated at my youthfulness, when my smarter half (wife) revealed to me that I was appearing a clown. ‘One size fits all’ approach is disastrous whether its clothing or medicine.

Everyone has experienced this phenomenon in our patients with hypertension; some people respond better to some medication than other. In this interesting and intelligently designed study, authors explored this question in a randomized double blind multiple cross over trial.

280 patients (median age 64 yrs, grade 1 hypertension) were randomized: Each participant was scheduled for treatment in random order with 4 different drugs (from 4 different classes): lisinopril, candesartan, hydrochlorothiazide, and amlodipine with repeated treatments for 2 classes. Each treatment period consisted of one week placebo washout, 2 weeks of dose escalation period, and at least 4 weeks of target dose period. 1468 completed treatment periods were evaluated and significant difference in BP responses were observed: Specifically for choices of lisinopril versus HCTZ, lisinopril versus amlodipine, candesartan versus HCTZ and candesartan versus amlodipine. Personalized approach can achieve BP reduction equivalent to half of that expected from single agent in monotherapy, and half of that expected after adding second agent. While some clinical characteristics are often used practically to decide which drug to start with, they are crude at the best. Laragh has proposed individualization based on plasma renin activity and classified drugs acting on renin axis – R drugs (RAS blockers, beta blockers, sympatholytics) or volume axis of hypertension V drugs (duiretics, CCBs, alfa blockers) and proposed to use drug from two difference classes in combination. This study shows that such approach is not only pathophysiologically appropriate but also produce clinically meaningful effect in BP management.

Since that embarrassing incident at my cousin’s marriage, I get all my trousers from my tailor friend, and he is just amazing. Hypertension, makes one of the good cases for personalized medicine-tailoring.