1. Antihypertensive efficacy of clonidine
In ‘difficult CKD hypertensives’, many nephrologists here use clonidine as a preferred 3rd or 4th add-on (with the guilt in mind- ‘what is the evidence?’). After seeing that on one of his patient’s prescription, I was called back by a very senior GP asking my age and then thanking me for making him nostalgic about his early days of practice 40yrs ago in addition to controlling his patients BP.
Spironolactone is preferred 4th drug to add based on the results of PATHWAY 2 trial. Clonidine is probably the “nephrologist’s spironolactone”- the 4th drug to add in patients whose BP remains uncontrolled with RAS blockade, CCBs, and thiazides. Unfortunately, clonidine has almost become an orphan drug (you will find a passing mention at the bottom of the UpToDate chapter on resistant HTN with no accompanying reference), and today is only talked about its role in de-addiction, hot flushes etc. A KOL in the field of hypertension was clueless when asked about the role of Arkamin (clonidine) in the treatment of resistant HTN in a nephrology conference. He just said,”no data… I don’t know”
Results of ReHOT randomized Study will reduce this guilt to some extent. Patients with resistant hypertension (defined as no office and ambulatory BP monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID). Compared to the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary endpoint- BP control by office BP and ABPM- (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55–1.88]; P=1.00). Secondary endpoint relating to the absolute decrease in BP favored spironolactone leading authors to conclude that spironolactone is preferable for the fourth-drug therapy.
Other important findings of the study were prevalence and predictors of resistant HTN among this population (n=1597). 12% of their patients had resistant HTN. A history of stroke, diabetes mellitus, or BP ≥180/100 mm Hg at study entry was independently associated with it.
2. BP control with the help of barbers
My childhood memories of barbershop are painful: our grandfather taking six of us to his barber friend where they use to relentlessly chat while barber literally plucking out (and not cut) hairs- yes, we all used to be teased by schoolmates as ‘bald ghosts’. This left a permanent impression and I continue to think that ‘one hour a month, with your neck tied to a chair, some nonsensical music at the background, and to make the things worse a barber who won’t just stop talking’ is too much to bear in life. So, I go there with a clear intention of postponing next visit as further as possible.
But, if I were a hypertensive non-Hispanic black (uniquely disadvantaged due to genetics and environment, multiplying their risk of hypertension, kidney failure, and CVD), I must visit a barbershop at least 2 times a month, if I am to get my BP controlled. That’s what this interesting cluster-randomized trial of BP Reduction Black Barbershops published in NEJM shows.
Black-owned Barbershops are not just the places for the haircut but are the cultural institutions that draw a large and loyal male clientele and provide an open forum for discussion of numerous topics, including health, with influential peers. Pharmacist (who were specially trained in BP treatment) led intervention at the barbershop in which barbers encouraged meetings in barbershops with specially-trained pharmacists who prescribed drug therapy under a ‘collaborative practice agreement with the participants’ doctors’ OR active control approach in which barbers encouraged lifestyle modification and doctor appointments only. A phenomenal mean 21.6 mm Hg greater reduction in BP was achieved with the intervention (95% confidence interval, 14.7 to 28.4; P<0.001). A blood pressure level of less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% of the participants in the control group (P<0.001).
For those obsessed with ‘intensive control’, this is an excellent example of the much needed novel ways to achieve ‘extensive BP control’. It would be interesting to see the sustainability and replication of this approach and its impact one hard clinical outcomes. Notwithstanding limitations, comments questioning the place of this research in NEJM are really unfortunate. For those who are at unique health disadvantage, solutions outside the framework of conventional healthcare settings are urgently needed and this is one such way out. This is “Universal health coverage: everyone, everywhere” in action. Barefoot doctors in China, CKD prevention programme in India and home-based neonatal care are other similar examples of this approach decentralizing health care. Excellent blog post by here.
3. The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT)
Visual abstract by Dr. Divya Baipai (@divyaa24), Assistant Professor, Dept. of Nephrology, Seth G.S.M.C & K.E.M.Hospital, Mumbai and an NSMC intern.
‘I just took it at a different time’….this generally means ‘missing the dose’ or ‘I missed one dose’ -most likely means ‘discontinued for a couple of days’. Nonadherence is common and often under-recognized. This is a leading cause of acute rejections and graft loss; especially so for children in whom 44% of all graft losses and 23% of late acute rejection episodes are due to nonadherence. Improving adherence, unlike newer drugs, is one of those few interventions in this area which doesn’t carry the cost of side effects and something that every center should seriously work upon. TAKE-IT randomized kidney transplant recipients between 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States. The multicomponent intervention included electronic monitoring of adherence, messages, emails for dose reminders, and 3 monthly meeting with a coach who used “Action-Focused Problem Solving” to address adherence barriers selected as important by the participant.
Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15- 2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls. The trial was small (n=169) and wasn’t powered to assess clinical outcomes of interest like rejections, graft loss etc.
TAKE-IT TOO will look at effectively integrating the TAKE-IT intervention into clinical practice.
4. Antibiotics for asymptomatic bacteriuria in kidney transplant recipients
Asymptomatic bacteriuria develops in almost half of the renal transplant recipients and there is uncertainty about the treatment. Transplant physicians face this dilemma regularly- whether to treat (and possibly reassure yourself and the patient) or to wait and watch. There are at least two reports (here and here) which demonstrated that treating asymptomatic bacteriuria in general populations and also in kidney transplant recipients was not only unnecessary but also possibly counterproductive-leading to a higher incidence of symptomatic pyelonephritis. Moreover, selecting ‘MDR bugs’ and ‘exotic fungi’ remain other dangers of antibiotic treatment. Given the lack of good quality evidence, KDIGO and IDSA (2005) decided not to issue a recommendation on this topic. AST – Infectious Diseases Community of Practice advised avoiding treating asymptomatic bacteriuria that occurs beyond 3 months post-transplant unless there is an associated rise in creatinine.
A recent Cochrane review Antibiotics for asymptomatic bacteriuria in kidney transplant recipients also doesn’t take you any further and highlights the lack of evidence for treatment. Preventing symptomatic UTI (2 studies, 200 participants: RR 0.86, 95% CI 0.51 to 1.45), all-cause mortality (1 study, 112 participants: RR 2.23, 95% CI 0.21 to 23.86), graft loss (1 study, 112 participants: RR 1.11, 95% CI 0.07 to 17.36), acute rejection (1 study, 112 participants: RR 0.93, 95% CI 0.44 to 1.97), hospitalisation for UTI (1 study, 112 participants: RR 0.74, 95% CI 0.13 to 4.27), graft function (2 studies, 200 participants, MD in serum creatinine concentration -0.06 mg/dL, 95% CI -0.19 to 0.08) and adverse reactions (1 study, 112 participants: no severe adverse event attributable to the antibiotic treatment).
The situation may change soon- at least three RCTs are underway examining this issue. In practice, however, most of us can select patients for treatment: past history of pyelonephritis, significant bladder issues, pyuria, SIRS, unexplained graft dysfunction etc. Also, it may be more effective to work on several modifiable factors (urologist being the first and not always easy) preventing its development: early Foley’s catheter and stent removal, avoiding stent placement altogether, avoiding DGF are among a few.
5. Cisplatin-associated Acute Kidney Injury (C-AKI): who is at risk?
Cisplatin-a potent and important anticancer agent-is associated with nephrotoxicity in approximately 30 percent of patients at some point during their treatment. Observational studies have highlighted various risk factors for AKI following its use, however, their application is limited by small sample size and restriction to a particular cancer type. In the largest study evaluating this risk, Motwani et al developed and validated a score-based model to predict the risk of AKI after the first course of cisplatin. C-AKI occurred in 13.6% of 2,118 patients in the DC and in 11.6% of 2,363 patients in the VC. Older age, higher cisplatin dose, hypoalbuminemia and a history of hypertension were associated with C-AKI. An interesting finding was no association of baseline eGFR with the risk of C-AKI (within the range of study-all the participants had baseline creatinine ≤1.5 mg/dL).
A risk prediction score was generated based on the presence of four identified risk factors (age, cisplatin dose, history of hypertension, and hypoalbuminemia).
|Age ≤ 60
|Albumin >3.5 g/dL
|Albumin 1.3- 3.5 g/dL
|Dose ≤ 100 mg
|Dose 101- 150
|Dose > 150 mg
The probability of cisplatin-induced AKI was 10, 24, and 51 percent for scores of 3, 5.5, and 8.5, respectively. The c- statistic showed that the model was a good if not strong, model. [The c-statistics in the DC and the VC were 0.72 (95% CI, 0.69 to 0.75) and 0.70 (95% CI, 0.67 to 0.73), respectively.] Additional studies will be required to determine the utility of this model in clinical practice.
In authors’ words, ‘this model will empower providers and patients with more accurate, patient-specific information regarding the risk of kidney injury.’
6.Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout
Hyperuricemia and gout are associated with higher cardiovascular risk, the causative role of uric acid here, however, remains controversial. Although febuxostat is more effective uric acid lowering agent compared to allopurinol, it was associated with a modestly higher rate of cardiovascular events resulting in an FDA alert.
In a multicenter, randomized, double-blind noninferiority trial, 6190 patients with gout and a history of major cardiovascular disease were randomized to receive febuxostat 40 to 80 mg/d or allopurinol dosed according to estimated creatinine clearance. Febuxostat scored over allopurinol with regards to urate-lowering (higher proportions of patients in the febuxostat group had maintenance of serum urate levels at less than 6.0 mg per deciliter at most time points); however, the rates of gout flares were similar in the two treatment groups (0.68 and 0.63 flares per patient-year in the febuxostat group and allopurinol group, respectively).
Primary end-point event (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina) occurred at similar rates in the febuxostat group and the allopurinol group (10.8% and 10.4% of patients, respectively, at a median period of 32 months; hazard ratio, 1.03; upper bound of the one-sided 98.5% confidence interval [CI], 1.23; P = 0.002 for noninferiority). However, the risk of death from any cause and the risk of cardiovascular death were higher in the febuxostat group than in the allopurinol group. (7.8% vs 6.4%; HR 1.22 (1.01–1.47), p 0.04). The reason for higher mortality with febuxostat is unclear. Preclinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism.
A major limitation of this trial is a large number of participants who discontinued the trial treatment and did not complete the follow-up. 56.6% of patients discontinued trial treatment prematurely, rates of discontinuation being similar in both the groups.
So until we have more data, allopurinol seems to be a safer option for uric acid lowering in patients with gout and high CV risk. Also, this should curb the enthusiasm wider use of urate-lowering (so commonly seen here) with febuxostat outside current recommendation.
7. Cardiac Rhythm Disturbances in Hemodialysis Patients
The primary cause of death in patients on hemodialysis is cardiovascular, with sudden death (SD) constituting a significant proportion. In a multicenter, interventional-observational, prospective cohort study Sacher et al sought to monitor the mechanisms leading to sudden death.
71 patients were implanted subcutaneously with implantable loop recorders (ILRs) with remote monitoring capabilities. During a mean follow-up period of 21.3 ± 6.9 months, 16 patients died, the cause of death being cardiac in 5.
The actual incidence rates of patients with significant conduction disorders, ventricular arrhythmias, and atrial fibrillation were, respectively, 14 (IQR: 7 to 21), 9 (IQR: 4 to 14), and 18 (IQR: 1 to 26) per 100 patient-years in HD patients implanted with ILRs.
In the multivariate analysis, pre-dialysis serum concentrations of K >5 mmol/l, bicarbonate <22 mmol/l, hemoglobin >11.5 g/dl, high-risk period (±24 h around the first HD session of the week after the long interdialytic period), history of coronary artery disease, occurrence of other cardiac arrhythmia during follow-up, and diabetes were associated with a higher risk for significant conduction disorders. Systolic blood pressure ≤ 140 mm Hg after HD was associated with a lower risk for significant conduction disorder. Serum K <4 mmol/l and the occurrence of other cardiac arrhythmias (conduction disorders or AF) during follow-up were associated with a higher risk for ventricular arrhythmias.
Male sex, serum K <4 mmol/l and serum phosphate >1.45 mmol/l (> 4.5 mg/dL) were associated with an increased risk for atrial fibrillation.
8. Urgent: Stop Preventable Infections Now
23% of the deaths in HEMO trial were attributed to infections (this probably is an underestimate if we consider non-research settings)- arguably is the leading cause of morbidity and mortality in patients on dialysis. Last month, CJASN published a timely series of papers discussing the challenge of infections in hemodialysis facilities. The articles systematically review the extent of the problem and discuss the ways to prevent the infections.
Addressing the Problem of Multidrug-Resistant Organisms in Dialysis: This article gives an overview of the transmission dynamics of multidrug-resistant (MDR) organisms and reviews infection prevention strategies in hemodialysis units. Soon we are going to face resistant bacteria with no antibiotic active against them. To avoid this disaster, prevention of transmission of infection is essential, as is antimicrobial stewardship. The author discusses the CDC recommendations to prevent the spread of MDR organisms.
(1) wearing gloves and performing hand hygiene in between patients and stations
(2) following published guidelines for judicious antimicrobial use and appropriate de-escalation
(3) avoiding multiuse medication vials and common medication carts
(4) disinfection and cleaning of equipment, non-disposable items, and the surrounding environment,
(5) separate clean/ contaminated areas and medication preparation in a dedicated room or a clean area away from treatment stations.
(6) using separate gowns for patients colonized/ infected with MDR organisms and have the high risk of transmission, for example, diarrhea, fecal incontinence or draining, uncovered wounds.
Now, all this appear ridiculously simple but ensuring 100% compliance with these recommendations may not be as easy and needs systematic assessment, training, audits, and retraining.
What We Learned from Ebola- Preparing Dialysis Units for the Next Outbreak: In this paper, the authors discuss the Ebola virus disease epidemic that occurred in West Africa in 2014-2015 to highlight the unique issues faced by out-patient hemodialysis units. They discuss how a unit should prepare itself to face such an epidemic. “Ebola Virus Disease outbreak should serve as a stimulus to establish the situations in which patients with highly transmissible infections might be dialyzed in outpatient settings, review emergency preparedness policies and infrastructure needs, and improve access to infection control expertise in outpatient hemodialysis units.”
100% Use of Infection Control Procedures in Hemodialysis Facilities- Call to Action:
In this paper, authors discuss the role of all the stakeholders in adherence to recommended infection control practices and highlight the important leadership role of nephrologists, especially medical directors, in preventing infections in HD facilities. Infection control procedures, immunization and screening for viral infections, and strategies to improve adherence are discussed.