Not so symple: End of the road for renal denervation procedures?

Since the advent of minimally invasive renal denervation procedures about a decade ago, the nephrology community had been eagerly awaiting conclusion of the SYMPLICITY 3 trial. As many of you might already know, Medtronic, the device’s company issued a press release on January 9^th about the procedure failing to meet the primary efficacy endpoint. To a lot of us, this result has been surprising, and disappointing to a certain extent.

1952 paper from Mayo: Renal denervation/sympathectomy is not a new concept and has been around for almost a century. 

To understand the context, let’s review the background of renal denervation’s role in treatment of resistant hypertension briefly. Per NHANES data from the period 2003-2008, the prevalence of resistant hypertension is 8.9 ± 0.6% of the US hypertensive population, and continues to increase.  I am guessing the prevalence could theoretically be a little lower if the new, more relaxed, hypertension treatment goals of JNC 8 are considered. This was discussed by Matt earlier. 

Renal denervation is supposed to work on the premise that the sympathetic nervous system is hyperstimulated in patients with treatment resistant high blood pressure, and the kidneys modulate that to a large extent. Afferent signaling from the kidneys increases central sympathetic drive, while efferent signals to the kidneys increase renin release and sodium retention, while reducing renal blood flow. Hence, if you could cut off this two way traffic between the kidneys and the sympathetic nervous system, you should be able to bring the blood pressure down. Here is a picture that explains this. And below is a video of how the procedure is performed: 

Renal sympathetic afferent and efferent fibers run circumferentialy in the wall of the renal artery, and ablation reduces both pathways  

We have seen a succession of studies done to validate this hypothesis. Earlier, Matt had talked about the SYMPLICITY-1 trial, which was a non-randomized pilot study. Then we had SYMPLICITY-2 trial in 2010 which was a larger randomized study with 106 patients. This was conducted in Europe, Australia, and New Zealand. This showed significant reduction in office based blood pressures at 6 months, with no serious side effects. And so, with much fanfare and hype, the SYMPLICITY-3 trial was initiated in August 2011. While the study has not been published, the authors chose to communicate the procedure’s lack of efficacy (in meeting the primary end point) via a press release. There was no mention about the status of secondary end points (which included ambulatory BP changes) in the statement.

WHICH BRINGS US TO THE QUESTION…

Why did the trial fail to meet the primary efficacy end point, in spite of the prior data that looked promising? It appears to be the best designed trial till date to study this issue. SYMPLICITY-3 was bigger (535 patients) and better designed (control patients underwent a sham procedure) than its predecessors. I wonder if that itself could have been the reason for us seeing the lack of any benefit. That in fact, the prior trials were outliers given smaller size of the studies, or lack of randomization. Or, could it have something to do with anatomical and functional regrowth of sympathetic nerves that can happen after they are ablated (as can happen post transplant)?  Let us know your thoughts about what you think could have been the reasons!  

IMPLICATIONS FOR CKD PATIENTS

Something that I have always wondered about (and which has nothing to do with this press release) is the safety and efficacy of this procedure in CKD patients. It is plausible that if you are tinkering with the renin angiotensin system, you could adversely affect renal function. Just like you could be leery of giving ACE inhibitors to an advanced CKD-4 patient with hypertension, would you consider not doing this procedure as well? Could we see hyperkalemia develop? In the absence of adequate data, I would say that I don’t know, but we did see a study that tried to answer this question. However, it was a small study (15 patients, and even those didn’t complete follow up), and a short follow up period.   

  

IF ALL YOU HAVE IS A HAMMER, EVERYTHING LOOKS LIKE A NAIL?

So is this development the beginning of the end of renal denervation procedure? Maybe; or maybe not. Medtronic has already suspended further enrollment in other renal denervation trials in the US (SYMPLICITY-4), Japan, and India. However, the device will still remain available for “discretionary use” by physicians (good luck convincing insurance companies to pay for a procedure that is about as good as sham!). But, we still have other potential indications under the sun which could be a breath of life for the device/procedure. These include heart failure, metabolic syndrome, and obstructive sleep apnea.   

Finally, we also have another device that works on the principle of baroreceptor activation that is being actively studied for treatment of resistant hypertension.

Veeraish Chauhan, MD

Does octreotide hold promise for treatment of polycystic kidney disease?

One of the most frustrating things in clinical nephrology is to give a diagnosis of polycystic kidney disease (PKD) to a young patient, and follow that up by saying that they could progress to end stage renal disease requiring dialysis, and “there is not much I can offer to change that”.

Autosomal dominant PKD is the most prevalent monogenic disorder, and the average rate of GFR decline could be as much as 4.4 to 5.9 ml/min. Recently, the well-publicized TEMPO trial has shown a potential clinical application for tolvaptan in stemming the progression of PKD by slowing the growth of the total kidney volume and eGFR decline over a 3-year period.

Another agent that is being studied for a few years for a potential role in inhibiting cyst growth in PKD is octreotide, a long acting somatostatin analogue. This is an agent we in the nephrology universe have been using for some time for the treatment of hepatorenal syndrome. A randomized placebo controlled trial had first reported in 2005 that a 6-month treatment with somatostatin could slow cyst growth. Although we know that decline in kidney function in PKD follows cyst growth, the study stopped short of saying that slowing the cyst growth in this case would translate in to clinically meaningful renoprotection. A similar effect on liver volume has been reported as well.

A few months ago, we saw the results of the ALADIN trial published in the Lancet. This study had a longer follow-up period than the previous studies, and indicated a significantly lower kidney volume in patients treated with octreotide at 1-year follow-up, but not at 3-years.

Given the data we have so far, it appears that octreotide could have a potential role in the treatment of PKD. For some reason, it appears that octreotide slows growth in kidney volume over one year, but the effects become insignificant over the long term. Obviously, more comprehensive studies looking at long-term hard outcome data are needed. Another interesting thing would be to compare the data for octreotide vs. tolvaptan. Although both these agents have shown promise so far (in addition to other contenders like mTOR inhibitors), a major concern is cost. All other things being equal, octreotide could me a cheaper alternative than tolvaptan for what essentially could be a lifelong treatment. At my time of writing this, a ten-day course of 15 mg tolvaptan pills was priced at $3440.00, while a 100 mcg octreotide injection was priced at $11.93!

I can’t wait for the day when we will be able to offer our patients something more definitive for treatment of PKD, rather than the current bandaid regimen of ACE inhibitors, increased water intake, hand-holding, etc.

Posted by Veeraish Chauhan

Diuretics vs. Ultrafiltration: Isn’t the debate settled yet?

We have all been called in to see patients who have developed AKI after receiving mechanical ultrafiltration (UF) for acute decompensated heart failure (ADHF). In almost all situations I have experienced, UF was started early, perhaps without optimization of diuretic therapy. The UF program at our institution is run by the Cardiology service. In spite of the weight of the current evidence, I have seen a distinct specialty specific bias towards UF (Cardiology), and against UF (Nephrology).

After I received the nth consult for AKI in the above setting, I decided to review some evidence for a cardiologist friend. I thought it’ll make for a review of a pertinent situation that we all will continue to face.

In brief, three major randomized trials have compared UF against diuretics in ADHF, over the last eight years. The first one was the RAPID-CHF trial.  The primary end point was weight loss at 24 hours. A larger trial was published in 2007, the UNLOAD trial. Both these trials showed a greater rate of fluid loss with UF than diuretic use. The UNLOAD trial also showed fewer rehospitalizations at 90 days, for the UF group. From a renal perspective, there was no significant increase in creatinine with UF reported in either trial.

The results from the above two trials really made UF almost a “first line” treatment for ADHF. On top of it all, I saw data from a study in Italy increasingly (and perhaps, erroneously) getting extrapolated to UF use for treatment of ADHF. Essentially, the Italian study had shown that intermittent hemodiafiltration could increase diuretic responsiveness and reduce the level of inflammatory cytokines.  Equating hemodiafiltration to ultrafiltration would make me cringe as I struggled to explain the difference to my cardiology colleagues!

Finally, we had the CARRESS-HF trial late last year which tried to answer the same question in a slightly different way (stepped algorithm for dosing diuretics vs UF). At 96 hours, there was no significant difference in weight loss between the two groups. The primary end point of increase in serum creatinine was significantly worse in the UF group.  The UF group also showed a significantly higher rate of other serious adverse events (eg, bleeding, anemia, thrombocytopenia, dyselectrolytemia, sepsis, heart failure). There also was a trend towards higher mortality for patients who received UF.

Given the relatively recent nature of the evidence against UF, it might be some time before we see a universal change in clinical practice. So I guess we nephrologists will continue to see patients of refractory ADHF with AKI, where perhaps diuretics weren’t used in a stepped fashion, or UF was used early. At this time, the American College of Cardiology recommends that UF be used only as a second line treatment for patients who do not respond to diuretic optimization.   

I am curious to know what your experience has been in this setting? Have you experienced a difference of opinion between nephrologists and cardiologists?  

Posted by Veeraish Chauhan

Thromboembolic Prophylaxis in Patients with AFib and CKD: Caught between the Devil and the Deep Blue Sea

I often get curb-sided by cardiologists and internists for my opinion on using warfarin or other anticoagulants for thromboembolic risk prophylaxis in CKD +/- Afib patients. A similar conundrum of using anticoagulation for stroke prophylaxis in dialysis patients was discussed about three years ago on this blog by Conall. Like many other issues in patients with CKD, things are not always black-and-white, and a lot could depend on patient and physician preference.  This often makes the “right answer” a confusing exercise, since CKD patients are also at a higher bleeding risk. Most randomized trials addressing this issue have excluded patients with a GFR below 30. Furthermore, newer direct thrombin inhibitors (dabigatran), or Factor Xa inhibitors (apixaban, rivaroxaban) are available, which might be better than warfarin, at least in the early-CKD patient (although the lack of a reversing antidote is a potential pitfall). Finally, warfarin has a well-established link with vascular calcification (a mortality risk) in dialysis patients. As nephrologists, it is imperative that we are knowledgeable about the best-available data that can help us make an evidence-based recommendation, and so I put together a concise decision-table with links to primary literature sources.

In addition to the “traditional” risk factors for stroke in patients with AFib (as exemplified by the acronym CHADS), it is known that CKD itself is an independent risk factor for stroke. Thus CKD patients, both with, and without AFib, are at an increased risk of stroke. This has been demonstrated in CKD as well as dialysis patients, and the risk worsens with decline in GFR. 

Thus, with the above background in mind, the two main variables that determine what, if any, anticoagulation is to be used in this setting, are (1) the stage of CKD, and (2) the CHADS2 score:

CHADS2 Score	CKD STAGE
	Stage 3, eGFR 30-59	Stage 4, eGFR 15-29	Stage 5, eGFR less than 15, or dialysis
0	Either ASA or AC (weak recommendation)	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??
>1	AC (Direct thrombin inhibitors (dabigatran), and Factor Xa inhibitors (rivaroxaban, apixaban) potentially superior to warfarin	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)

 

ASA = Aspirin

AC = Anticoagulation

?? = Expert opinion only, no strong evidence available - weight risks vs. benefits

Remember that no antithrombotic therapy is warranted if bleeding is a concern

Posted by Veeraish Chuahan

(Apologies for any formatting issues)

Hypothermia Protocol and Dialysis

I recently received an inpatient consultation to see a CKD 5D patient. The reason for consult, as is mostly the case with dialysis patients was that he “needs hemodialysis”.

This dialysis patient wasn’t the average bear though. He had had a witnessed cardiac arrest, was treated by EMS, and defibrillated. He had a return of spontaneous circulation after being pulseless for 20 minutes. As soon as he got to the ER, he was initiated on our standard institutional therapeutic hypothermia protocol.  I was called in to dialyze him because (it wasn’t his usual day) the cardiologist wanted to perform a left heart cath on him the following day, and they “did not want dialysis to interfere with that schedule”. My clinical assessment did not reveal a severe degree of volume overload. He wasn’t hyperkalemic, and had only a mild degree of lactic acidosis that was nicely compensated by him being appropriately ventilated. Due to the concerns that I talk about below, I did not see an emergent reason to dialyze him.

I would like to focus on a few teaching points from a nephrologist’s perspective that I took away from this scenario:

1. Therapeutic hypothermia entails cooling post cardiac arrest patients to 32-34 degrees Celsius, ideally within 6 hours of a cardiac arrest.  Both intravascular and surface cooling methods are used. At my institution, the protocol involves administering up to 3 liters of 0.9% saline (which has been cooled to a temperature of 4 degrees Celsius), over an hour. This is complemented by cooling vests. Once target temperature is reached, the cooling phase is continued for 12-24 hours, after which the patient is rewarmed gradually at the rate of 0.5 degrees Celsius/hour.
2. Sub-physiological body temperatures expectedly have adverse effects. Hypothermia can hamper leukocyte function, increasing infection risk later. Cardiac effects include bradycardia and prolonged QT interval (both were present in this patient). Finally, for us nephrologists, here are some adverse effects and pertinent points that we need to keep in mind for such patients:
3. Hypothermia can cause hypokalemia via two different mechanisms. Low temperature causes a transcellular shift of potassium in to the intracellular compartment. This effect is possibly mediated by increased beta adrenergic and sympathetic activity. In fact, hypokalemia in the setting of hypothermia must be repleted extremely cautiously, if at all, given the risk of rebound hyperkalemia as potassium moves back out of the cells when the patient is rewarmed. This rebound hyperkalemia can be frequently fatal due to arrhythmias.
4. The second mechanism by which hypothermia causes hypokalemia is by the induction of polyuria, also known as “cold diuresis”. This hypokalemia is mediated by increased urinary flow, and is seen in conjunction with hypovolemia, hypophosphatemia, and hypomagnesemia. I didn’t observe any of these in my patient, maybe because of his oligo-anuric status at baseline. Nevertheless, close monitoring of volume status and electrolytes is required.
5. Hypothermia interferes with platelet function and with the clotting cascade. In fact, as per this review, 22% of patients had bleeding post-hypothermia induction. That might be a concern when making the decision to dialyze post-hypothermia patients with heparin.
6. The other issue that I ran in to, that was specific to dialysis patients, was the concern about the patient’s temperature. As we know, most HD machines warm blood before returning in to the patient. With most machines, the warmer cannot actually be turned off and only goes as low as 35 degrees Celsius. In other words, dialysis can inadvertently warm the patient up to this temperature (from the target temp of 32 degrees, per the hypothermia protocol)! CRRT machines do have adjustable temp settings that goes down to 32 degrees, so that might be a safer alternative. Given the risk of inadvertently warming the patient, and because I did not see any emergent indication for dialysis, I did not dialyze the patient. I believed that in that situation, his hypothermia protocol took precedence over dialysis.

In my experience, I have observed that referring non-renal physicians often consider inpatient hemodialysis an ancillary service, akin to placing an order for an x-ray or a lab draw. Seasoned fellows have heard this phrase all too often, “I want you to come down and dialyze this patient”. You are then left with the unenviable task of explaining to the non-renal physician that the decision to dialyze would be made by the nephrologist after proper assessment of the patient (isn’t why they consulted you in the first place?). Let’s not allow our familiarity and comfort with dialysis technology lull us in to putting our guard down. Dialysis is an inherently intense and complicated procedure where multiple clinical parameters need to be closely watched. It’s a fact that is often lost in translation.

Posted by Veeraish Chauhan