The Nephrology Social Media Collective (NSMC) internship was established in 2015 with the goal of training doctors to effectively harness social media in order to be leaders in medicine. NSMC mentors and interns have contributed to our blog from time to time. This month, NSMC intern Dr. Lovy Gaur (@drlovygaur) has summarized an article for us.
1 Keen to screen CAD before transplant? Why it may not be a good idea in asymptomatic patients..
Cardiovascular disease is indeed an important cause of death with a functioning graft and its prevention is therefore of paramount importance since the strategy focuses on saving a precious resource. The fact that predisposition to CV mortality and morbidity is a complex interplay of the traditional and non traditional risk factors, it is difficult to apply the conventional knowledge to this population. Even for general population, the CARP (Coronary Artery Revascularization Prophylaxis) study concluded that the coronary revascularization before an elective vascular surgery does no good to reduce mortality perioperatively.
In a narrative review published in AJKD, Adnan Sharif from University of Birmingham summarizes the evidence available so far and argues that “current cardiac screening algorithms for asymptomatic kidney transplantation candidates are overzealous, counterproductive, and not in the best interests of the majority of people living with kidney failure and should be abolished“.
The first of the very few RCTs done in pre-transplant population include the one published by Manske et al in 1992. The study enrolled insulin dependent diabetes mellitus patients with chronic kidney disease and significant coronary artery disease with patients randomized to receive either revascularization therapy or the medical treatment alone . The trial was prematurely terminated in view of excess mortality in the arm receiving medical treatment alone. But this is to be taken with a pinch of salt since the “optimal” medical therapy comprised calcium channel blockers and aspirin; only one-third received beta-blockers as per the standard medical treatment recommended in that era.
The newer studies recognize that while dobutamine stress ECHO may be effective in identifying coronary artery disease in high risk patients, but coronary interventions are not associated with improved survival. The ongoing CARSK study is an ambitious trial designed to recruit 3200 prospective transplant recipients. It aims to explore if initial screening on entry to transplantation wait list is sufficient, or if multiple periodic screening till transplant offers some benefit.
But the question remains – why screen the asymptomatic individuals if intervention does not offer any benefit. And more so, should an asymptomatic ESRD patient be denied transplant based on a positive screening.
Guidelines don’t seem to help either. The recommendations of American Society of Transplantation, ACC/AHA, Renal Association, ERBP et can all be narrowed to a single statement – “there is no common consensus”.
The screening strategy and further intervention appear to soothe the physician anxiety more than affecting the patient outcomes. It’s time that we introspect the perceived advantages versus observed benefits.
Dr. Lovy Gaur, Nephrologist.
2 Patiromer enables continued use of spironolactone in CKD
Fear of hyperkalemia limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with CKD and resistant hypertension. Indeed, in the prior evaluations of MRAs in resistant HTN, compromised kidney function turned out to be the most important determinant of raised potassium. Hyperkalemia can take away the life in sleep, while renoprotection benefit needs years to be realised.
AMBER -a phase 2, randomised, double-blind, placebo-controlled trial, evaluated the use of ‘patiromer+spironolactone versus placebo+spironolactone’ in 295 adult CKD (eGFR 15-45 ml/min) and uncontrolled hypertension. At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0–29·0; p<0·0001). Availability of these newer, safer and more efficacious potassium binders will definitely expand the use of renoprotective therapies like MRAs, ACE inhibitors and ARBs.
Cost of the binders is currently prohibitive and will remain a barrier until its out of patent for most patients paying out of their pockets. Trial duration was short-12 weeks, so the long term efficacy and safety remains to be studied. Also at the end of 12 weeks, BP reduction with spironolactone wasn’t better in patients receiving patiromer than those in placebo raising a question : will MRA be as effective in CKD as in non CKD population?
3 Association Between Dialysis Facility Ownership and Access to Kidney Transplantation
In his amazing work ‘Sapiens: A Brief History of Humankind’, Yuval Noa Harari reviews how the ‘marriage of empire and science’ in the history made possible many amazing scientific discoveries. Not all marriages are happy like this and the wedlock between capitalism and health care can sometimes be especially problematic.
It’s assumed that patients will be put on chronic dialysis only if they don’t have a live donor, are medically unfit for transplant or are simply unwilling to choose the best option inspite of being adequately informed. Yes, thats what is expected to happen but there are concerns that this may not be true for many ‘for profit dialysis centres in US’, and patients receiving treatment there are far less likely to have access to kidney transplantation, according to this retrospective cohort study of 1478564 patients treated at 6511 US dialysis facilities studied from 2000-2016. As compared to ‘not for profit centres’, these patients were less likely to be wait listed for deceased donor transplant (−13.2% [95% CI, −13.4% to −13.0%], less likely to get a live donor (−2.3% [95% CI, −2.4% to −2.3%) or a deceased donor kidney transplant (−4.3% [95% CI, −4.4% to −4.2%]).
Clinician perception of patient’s candidacy, poor medical follow-up, time spent with patients, format of transplant education, resource allocation for staffing to enable transplant education-might have contributed to these findings. While it’s possible that systematic differences (higher hospitalisation rates, and location in areas with low background transplantation rates in for profit units) in the population of patients at for profit and no profit facilities may still remain, similar observations have been reported previously as well and can’t be completely disregarded. As inferred by this editorial , for-profit dialysis organisations might have systematically and disproportionately focused on the delivery of dialysis services while paying less attention to transplants.
Drawing analogy with “fistula first, catheter last” [what worked here was not the catchy slogan but linkage to reimbursement -dialysis clinic did their best to have AVF first after AVF rates were linked to payments], this editorial nicely put the findings of this research in context and rightly suggests us to adopt a policy of “transplant first, dialysis last”.
4 Roxadustat for anemia in CKD
Roxadustat by inhibiting HIF prolyl hydroxylase inhibitor (nice review here) mimics the natural response to hypoxia with resultant increase in HIF transcriptional activity, which induces the expression of erythropoietin, erythropoietin receptors, and proteins that promote intestinal absorption of iron and recycling of iron from the macrophage iron storage system.
In these twin trials of roxadustat in predialysis CKD and dialysis patients , with regards to primary endpoint of mean change in Hb from baseline to average, roxadustat was better than erythropoietin in pre dialysis CKD and was non-inferior in dialysis patients. Moreover, serum hepcidin levels (a marker of functional iron deficiency) and serum cholesterol decreased significantly in roxadustat group. Hyperkalemia and metabolic acidosis were noted as adverse events significantly more often in roxadustat group.
Roxadustat is already approved for use in China, and these studies are likely to get it approval in other parts of the world. Prof Hase always reminded us of the postmortem examinations in kidney transplant recipients, where almost every organ used to be loaded with iron. Indeed, we probably aren’t paying as much attention to the possibility of this iatrogenic harm. Most promising feature of HIF stabilisers in anemia therapy is that apart from being an ESA, it addresses a key problem in the pathophysiology of anemia in our patients i.e. inflammatory blockade of available iron due to up regulation of hepcidin by cytokines: both trials demonstrated an impressive lowering of hepcidin levels following treatment with roxadustat. While we administer iron to most of our dialysis patients long term safety of parenteral iron is unknown, HIF stabilisers can potentially minimise iron overload that is common in dialysis population.
Landmark anemia trials in CKD have taught us an important lesson: total correction of anemia is not only unnecessary but also hazardous and we continue to debate the pathogenesis of this harm. Whether HIF stabilisers will dissociate benefit of full correction from the risks observed with other ESA will be interesting to see. Both trials were of limited duration and long term safety-efficacy is yet not known.
With each new disease definition or its revision, incidence of that disease increases and sometimes can reach epidemic proportions. Can you recall an instance where adopting the new definition of a disease condition, has led to decrease in its incidence?
Apart from rising incidence of diabetes and hypertension, introduction of CKD definition and classification has contributed significantly to the current epidemic of CKD. Large proportion of ‘such CKD’ affects elderly in whom GFR decline is probably no more consequential than wrinkling of skin, graying of hairs etc. In this review, authors discuss the evidence and rationale for relaxing the GFR based cutoffs for CKD in elderly in the absence of albuminuria, based on 3 important observations. First, in large epidemiological studies, there is no increased risk of mortality for elderly with GFR between 45-60ml/min (in the absence of albuminuria), second, there is important structural difference between pathological GFR decline and an age associated decline: there is no compensatory increase in the single nephron GFR in the former setting, and finally, older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors.
This is an important and must read review, but will this call be responded appropriately by guideline developers?
6 Straight Versus Coiled Peritoneal Dialysis Catheters: A Randomized Controlled Trial.
ISPD guideline acknowledge the clinical equipoise with regards to the PD catheter design straight vs coiled and recommends the use of catheters with either a straight or coiled tip. This is largely due to small numbers and methodological issues with the available studies.
In a Chinese multicenter, open-label, randomized, controlled trial evaluating use of straight vs coiled double-cuffed peritoneal dialysis catheters in 308 patients (153 straight catheters; and 155 coiled catheters), during a mean follow-up of 21 months, the primary outcome of catheter dysfunction or drainage failure occurred in 9 (5.8%) patients who received a coiled catheter and 1 (0.7%) patient who received a straight catheter. Straight catheters had 5.1% lower risk for catheter dysfunction (95% CI, 1.2%-9.1%; P=0.02). The HR of the primary outcome for coiled versus straight catheters was 8.69 (95% CI, 1.10-68.6; P=0.04).
Patients who received a coiled catheter had similar risk for peritonitis but had higher infusion pain scores than those who received straight catheters. Authors concluded that use of straight Tenckhoff catheters compared with coiled catheters reduced the rate of catheter dysfunction requiring surgical intervention. While this is the largest RCT so far examining the issue of catheter design, clinical equipoise probably persist, given the important limitations. Apart from the open label design, and possibility of ascertainment bias, trial was limited by the low event rates and consequent under-powering.