1 ‘Normal BP’ becomes a rare disease now
Half of the globe was fast asleep then [when it was 3:15pm (PST) on 13th November at Anaheim, California]. I had just completed reading Murakami’s ‘Samsa in love’. This is an amazing story of events in the life of a Cockroach who, on one fine morning gets up metamorphosed into a human being. Upon meeting a girl, he neglects basic sexual instincts and prefers to follow the ‘neocortical attribute’ of love. After vivid dreams about ‘metamorphoses’ in early morning hours, I got up and checked my blood pressure and alas! I was no more a proud healthy young adult that went to sleep last night and found myself metamorphosed into someone with ‘elevated blood pressure’. I was one of that majority of the world’s population who was declared having ‘abnormal’ BP at the release of ACC/AHA guidelines on blood pressure. It was 122/81 on 3 consecutive measurements that need lifestyle and diet modifications and 3-6 monthly follow up to see what happens to me as per Guideline 8.1.2…to see if I get another metamorphosis into stage 1 hypertension.
Hypertension is largely treated by primary care doctors, who are not necessarily graduates of modern medicine here whose degree can be various 4 letter permutations and combinations (heard of DEMS?). While one can doubt their qualifications, same can’t be said about their confidence, which, generally is inversely related to the knowledge, which is periodically boosted by pharma food and cocktails. Although guideline claims not advocating drugs for everyone at stage 1 hypertension (>130/80 now), this change of number is likely to lead pharma to a goldmine. Unlike ‘Samsa in love’, basic instincts ‘to prescribe’ and ‘get prescribed’ won’t be easily overcome by doctors and patients. Also, some of the experts think that hypertension is a ‘progressive vascular disease’ and not just the risk factor and therefore needs earlier and more aggressive drug treatment. Exercise, diet and lifestyle modifications were and will continue to be regarded by most doctors and patients as posthumous metaphysical experiences.
Two good points worth putting into practice 1. better measurement of blood pressure with the emphasis on out of office records and 2. assessing CV risk beyond numbers which is a long due change in BP treatment guideline.
Moral of the story is: don’t remain awake late night reading fictions, early morning dreams can come true. Enough of ‘coach’ing, I’m going for a walk now to improve my numbers.
2. Association of BP lowering with mortality and cardiovascular disease across blood pressure levels
Is benefit of BP reduction same at various pretreatment BP thresholds?
Probably not. In this systematic review and meta-analysis involving 74 trials and 306273 participants association of BP-lowering treatment with major cardiovascular events was dependent on baseline systolic BP (SBP). For primary prevention (i.e. in patients without prior heart disease), with baseline SBP 160 or above, treatment was associated with reduced risk for death (RR, 0.93; 95% CI, 0.87-1.00) and a substantial reduction of major cardiovascular events (RR, 0.78; 95% CI, 0.70-0.87). For SBP range 140-159, the association of treatment with mortality was similar (RR, 0.87; 95% CI, 0.75-1.00), but the association with major cardiovascular events was less pronounced (RR, 0.88; 95% CI, 0.80-0.96) and with baseline SBP below 140, treatment was not associated with mortality (RR, 0.98; 95% CI, 0.90-1.06) and major cardiovascular events (RR, 0.97; 95% CI, 0.90-1.04). However, for people with previous CHD and mean baseline SBP of 138 mm Hg, treatment was associated with reduced risk for major cardiovascular events (RR, 0.90; 95% CI, 0.84-0.97), but was not associated with survival (RR, 0.98; 95% CI, 0.89-1.07).
Authors caution about industry bias here, as all the trials involving patients with CHD were industry sponsored. Moreover, limited information on non-BP determinants of outcomes, underrepresentation of women, rather crude division into primary and secondary preventive trials (only 13 trials were truly primary preventive, and 17 trials truly secondary preventive), are limitations to note. Funnel plot asymmetry at highest BP levels (signifying possible publication bias-negative studies remaining unpublished) might suggest an overestimation of benefit here.
BP lowering benefits decrease with decreasing starting BP, and risks of treatment (as a primary prevention measure) below 140 mmHg may outweigh any possible benefit. Sounds contrasting to SPRINT, however, authors feel that cutoff of 140 may not be very different than SPRINT 120, given the different method of measurement in SPRINT.
The goal of BP treatment is not to bring down numbers but to reduce the risk of complications and this risk can be different for different individuals at same BP number. A risk-based approach is likely to be more cost-effective and avoid overtreatment in mild hypertension. This is one thing that’s worth adopting from ACC/AHA.
3. Who develops CKD after recovery from AKI?
A six variable model using commonly used measurements -age, sex, baseline serum creatinine value, albuminuria, acute kidney injury severity, and discharge serum creatinine value was developed in 9973 patients hospitalized in Alberta and was externally validated in with data from a cohort of 2761 patients hospitalized in Ontario, Canada. The main outcome measure was advanced CKD -sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. Authors propose that this will provide an accurate but simple strategy that could be used to identify patients who can be benefited by follow up. Information on albuminuria wasn’t available in all the patients and so was the etiology of AKI, which IMHO can independently affect recovery.
Aren’t most of these factors (baseline CKD, age, sex, proteinuria) independently associated with advanced CKD, even without AKI intervening? The only conclusion from the observational data on ‘AKI-CKD interconnection’ research that can be made for now is: CKD is one of the most important risk factors for AKI and AKI accelerates the progression of CKD. This probably can’t be extrapolated to one of the most common AKI in our practice i.e. the one associated with tropical infections, where baseline kidney function is normal.
4. Sertraline for depression in CKD
About 1 in 4 patients with CKD have depression which is 4 times higher incidence as compared to general population. Antidepressant use is common in this population although placebo-controlled trials are lacking. Here is a double-blind, placebo-controlled, parallel- design, 12-week flexible-dose randomised clinical trial (CAST)conducted at 3 medical centers comparing sertraline with placebo in patients with CKD stage 3-5 (about 50% had CKD 4,5), not on dialysis. This drug was no more effective than placebo and was associated with higher incidence of nausea and diarrhea. Similar findings were reported with use of SSRI in the treatment of depression associated with major medical conditions, which probably is different than depression in general population.
While ‘negative results’ may add to the depression of nephrologists desperate for ‘positive trials’, some important takeaways from this research:
-almost 1/4th of the patients responded to placebo, worth trying option before anything else.
-if one is required to use SSRI for severe depression (trial didn’t include such patients), up to 200mg/day of sertraline was tolerated well except for GI intolerance.
Exclusion of dialysis population and limited duration of follow up are important limitations of the trial.
5. Tolvaptan in ADPKD
After promising results of TEMPO 3:4 trial (only prerequisites to understand this promise are-accept kidney volume as valid surrogate and neglect high discontinuation rate due to adverse effects) in early-stage CKD-ADPKD, here is a phase 3, randomized withdrawal, multi-center, placebo-controlled, double-blind trial of this drug in late-stage CKD. The primary end point-change in the eGFR from baseline to 12 months follow-up-−2.34 ml per minute per 1.73 m2 (95% CI −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml/min 95% CI, 0.86 to 1.68; P<0.001). 5.6% in treated group vs 1.2% in the placebo group developed a significant increase in ALT level.
1.27 ml per minute difference in eGFR is thought to be clinically significant by authors and Otsuka-they postulate that this will translate into postponing CKD stage 5 from 6.2 years to 9.0 years. To understand this, one needs to assume that medicine is mathematics and need to stretch your optimism to assume that drug will continue to make a difference of 1.27ml per year without acceptable side effects over several years of follow up. This trial, in its run in phase, excluded patients who didn’t tolerate tolvaptan. Longer follow-up studies with hard outcome endpoints are desperately needed now and until they are available, freely available ADH suppression i.e. liberal water intake seems enough to me. Considering variable and generally slow disease course of ADPKD, further trials also should target high-risk population where drug’s cost and side-effects will be justified better. Will precision medicine help do this for ADPKD?
6. No need to wait for few minutes to check orthostatic hypotension
Checking for orthostatic BP change in routine clinical visits is a ‘vital sign’, especially in patients on multiple drugs that can affect blood pressure and volume. This becomes all the more relevant if you are serious about SPRINT and ACC/AHA 2017. As a newly joined resident in medicine, I recall doing this exercise for 40-50 patients in the outpatient nephrology department and used to argue with our registrar about the time gap between supine and standing readings. We used to complete the measurement in 2 min and he insisting for a 5min gap.
In this prospective cohort study involving 11,249 middle-aged adults (mean age, 54; many with cardiovascular disease or risk factors, or on medications), orthostatic hypotension (defined as systolic drop of ≥20 mm Hg or diastolic drop of ≥10 mm Hg) was assessed at baseline, with BP readings taken with an automatic cuff every 25 seconds as many as 5 times after a patient rose from a supine to a standing position. During the median follow-up of 23 years, about 12,000 adverse events, that included falls, fractures, syncopal episodes, motor vehicle accidents, and death, were recorded and these were found most consistently and closely associated with measurements made within first 60 seconds upon standing. Waiting for more than 2 minutes may, in fact, miss some of these patients.
7. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine
(See the excellent summary of the article by @hswapnil on NephJC here). This large randomized 2 X 2 factorial trial enrolled 5177 patients (more than any of the previous trials) who were scheduled for angiography to receive 1.26% sodium bicarbonate or 0.9% sodium chloride and oral acetylcysteine or placebo. The primary endpoint was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. The trial was stopped prematurely after a prespecified interim analysis after the primary endpoint occurred in similar proportion (about 4 to 5%) of patients in all the four groups. Contrast-associated acute kidney injury, which was defined as an increase in serum creatinine of either at least 25% or at least 0.5 mg per deciliter from baseline at 3 to 5 days after angiography occurred in about 8-9 % patients and there were no significant between-group differences in these rates.
Does it change what we practice? We have stopped using N-acetylcysteine already. We could use normal saline and sodium bicarbonate interchangeably. But do we need to?
The trial did give a very clear answer to the research question it asked. However, contrast-induced AKI is going through the existential crisis and ~4% incidence of significant renal dysfunction at day 90 in PRESERVE population may be argued as an evidence for its existence. However, as we don’t have a control group here (who didn’t receive contrast), and not all kidney events were adjudicated to contrast use, so, for now, we don’t have any definitive answer to this existential crisis.
8. One-Day Donor Assessment Model in a Living Kidney Donor Transplant Program
Being evaluated as a donor for organ transplantation is an emotionally complex journey. A thorough evaluation is required to make sure the donation doesn’t put the donor at undue risk. However, a lengthy process of donor evaluation would significantly slow the entire program of living donor transplantation. Graham and Courtney in an article published in AJKD describe their experience with a ‘1-day donor assessment pathway’ as quality improvement project that led to a sustained increase in the living donor renal transplantation rate. To decrease the donor fatigue and subsequent dropout, they introduced a pathway where the prospective donor would undergo all the investigations and consultations over one day. Over 5 years, the program assessed 431 potential donors, of which 66% went ahead for actual donation. Of course, the people undergoing the evaluation were happy, most of them rating this process as ‘very good’. There was a sustained increase in the living donation rate from <5 per million population per annum (pmp pa) before 2010 to >32 pmp pa by 2015. This is incredible!
While it is likely that this increase is the result of multiple factors, authors feel that the 1-day assessment process has been the main driving force behind this improvement.
By making appropriate changes according to the local needs, this concept is likely to work in any program.