Hydrochlorothiazide—Its time is up

Hydrochlorothiazide (HCTZ) is the most commonly prescribed anti-hypertensive worldwide and the most frequently prescribed diuretic in the United States. More than 95% of prescriptions are for doses of 25mg or less. Despite these unequivocal prescribing patterns, HCTZ has rarely been studied at these low doses, particularly as monotherapy, and has yet to be compared head-to-head with thiazide-like diuretics such as chlorthalidone or indapamide. In contrast, multiple landmark trials have demonstrated consistent reductions in cardiovascular (CV) morbidity and mortality with thiazide-like diuretics as dosed in contemporary practice.

While no trial has directly compared low-dose HCTZ monotherapy with a thiazide-like diuretic, the MRFIT trial offers the closest comparator with the results offering cautionary lessons regarding the benefits of HCTZ at historically prescribed doses (50-100 mg/day). Published in 1982, patients were randomized to placebo or combined lifestyle/drug therapy with HCTZ or chlorthalidone as the initial agent. Not only did HCTZ treated patients have higher all-cause mortality rates compared to those in the chlorthalidone arm but there was a trend towards increased all-cause mortality when HCTZ patients were compared to placebo. Moreover, when those randomized to HCTZ were switched to chlorthalidone, rates of death from coronary artery disease fell below those recorded in the placebo arm.

In contrast, nearly every seminal trial showing improved CV outcomes with diuretics has utilized the thiazide-like diuretics chlorthalidone or indapamide at contemporary daily doses of 25 and 2.5mg, respectively (ADVANCE, HDFP). The SHEP trial was the first large study to address the treatment of isolated systolic hypertension with more aggressive blood pressure goals; compared to placebo, those randomized to chlorthalidone had far fewer CV events. The ALLHAT study, which compared the efficacy of full dose chlorthalidone (25mg/d) with lisinopril (40mg/d), norvasc (10mg/d), and doxazosin (arm terminated prematurely), found that chlorthalidone resulted in the lowest blood pressure among treatment groups. It was not only as effective as the other agents in preventing the primary CV outcome but was superior with respect to the secondary outcome of heart failure (although this may have been related to improved blood pressure control rather than the agent itself). Moreover, truly elderly patients appear to tolerate the more potent thiazide-like diuretics. For example, the HYVET trial was the first study to evaluate the effects of tighter BP control among (relatively healthy) individuals over 80. Those treated with an indapamide-based regimen not only had far fewer fatal strokes but lower rates of adverse events compared to those on placebo.

Small “proof of concept” studies offer possible explanations for these differences in outcome. In a 24-hour ambulatory blood pressure monitoring study comparing equi-potent doses of HCTZ (12.5mg day) and chlorthalidone (6.25mg/day), chlorthalidone distinguished itself by its extended duration of action resulting in blood pressure control throughout the 24-hour period. The pharmacologic property is critical as agents with 24-hour efficacy protect against the morning “surge” in blood pressure, a time when patients are most vulnerable to stroke and myocardial infarction 26821625).

In light of the unequivocal therapeutic efficacy of thiazide-like diuretics and the lack of evidence supporting HCTZ as mono-therapy, the nephrology community should serve as the exception to the aforementioned trend in thiazide prescription patterns. Concern that chlorthalidone/indapamide may be too potent for the elderly are well founded but as the above trials in the aged demonstrate, low-dose therapy (e.g. indapamide 1.25mg/d) can be prescribed, allowing for less volume depletion and metabolic sequelae while providing the extended anti-hypertensive response that may be the key to their superiority over HCTZ.

Conflicts of Interest: None

Hillel Sternlicht, MD
Hypertension Specialist
Author, Concepts in Hypertension Newsletter- Subscribe for free

April Nephrology Web Episode - The Renin Angiotensin Story

This month's video is a 10 minute medical history lesson on the renin-angiotensin story - from Tigerstedt to the Goldblatt kidney.  Hope you find it useful!

Sick of being sick – sickle cell burden and the importance of understanding mechanisms in rare diseases

When we think of the most common causes of kidney failure, usually we think of hypertension and diabetes. The prevalence of hypertension and diabetes in US is approximately 30% and 10%, respectively, and there is no question about the economical and individual burden of these chronic diseases. But what about rare diseases? There have been comments made that because they are rare and thereby by definition affect less people, that we should not focus our efforts on improving diagnostics, treatment options, or  clinical care practice for these diseases. What some people may forget, is that even rare diseases affect our communities, and investing resources into understanding these diseases also informs us about other pathways that may also be dysfunctional in more common diseases.  The classical example is Sickle Cell Disease. The National Organization for Rare Diseases and the NIH put sickle cell disease in the category of rare blood disorder. But if we look at the same disease from a little bit different angle we will see that it is actually the most common genetic blood disorder in US, the prevalence is significantly rising and due to the increased average lifespan in these patients.  The average health care cost reaches almost 1 million dollars per patient (which makes the cost of the health care for sickle cell patients in the US exceeding 1.1 billion dollars annually). Moreover, currently there are only 2 clinically approved drugs for the treatment of sickle cell disease, and neither of them target sickle cell associated renal complications. That really underscores the urgent need for the development of new therapeutic therapies for chronic complications of this “rare” disease. 

Sickle cell disease is caused by single mutation in the hemoglobin gene that results in hemoglobin polymerization, erythrocyte sickling, endothelial activation and vaso-occlusion that subsequently leads to chronic tissue hypoxia and organ damage. Sickle cell nephropathy is the second leading cause of death and at the average age of 23 approximately 20% of sickle cell patients are diagnosed with end-stage renal disease (ESRD).  Sickle cell patients with ESRD have a very high mortality rate, with most surviving less than 3 years after the diagnosis. This level of disease burden occurs due to unknown mechanisms that underlie sickle cell nephropathy. In other words, if we can figure out why and how the pathophysiological processes work within the sickle kidney we will be able to block or prevent it disease progression. So now the question is how can we do that? The answer is very simple; if we want to unravel and better understand the unknown mechanisms we need to start from basics. Basic science gives us this great ability to test potential injury mediated mechanisms in a setting of the disease. 

Lets think about the disease setting for a second from a basic science perspective. We know that central characteristics of the sickle cell disease milieu include hypoxia, oxidative stress, or even thrombosis. These same processes are established inducers of endothelin-1 (ET), a signaling peptide produced by diverse cell types that exerts its physiologic and pathophysiologic actions by binding to two receptor subtypes, ETA and ETB. Elevated endothelin-1 has been demonstrated in sickle cell disease patients. Moreover, in the kidney, endothelin-1 has been widely implicated as a mechanistic contributor to the development of various forms of CKD. Therefore we accepted the challenge to elucidate the mechanisms of sickle cell associated kidney injury and designed the study investigating the renal protective potential of endothelin receptor antagonism in the treatment of sickle nephropathy. We utilized a mouse sickle cell disease model, which is characterized by knocked-out mouse globin genes and knocked-in correct and mutant human globin genes.  This mouse develops full-blown sickle cell nephropathy (by 12 weeks of age). Sickle cell and control mice were treated with selective ETA receptor antagonist or dual ETA and ETB receptor antagonist starting at the time of weaning (when they can live without mom) and continued for 10 months and at the end of the study kidney structure and function were assessed. Our results demonstrated reno-protective effect of selective ETA receptor blockade evidenced by preserved GFR, prevention of proteinuria, and protection of tubular structure and function. Dual ETA and ETB receptor antagonism provided only some of the protection observed with selective ETA receptor antagonist, highlighting the importance of exclusively targeting the ETA receptor in sickle cell disease associated nephropathy. 

Taking into account clinical observations reported in sickle cell patients and rigorously planning and performing basic science studies, we were able to identify selective ETA receptor-mediated signaling pathway underlying the progression of sickle cell nephropathy. Thus, targeting this single receptor we can potentially offer novel and effective reno-protective strategy for sickle cell patients. The significance of this particular approach is supported by the fact that selective ETA receptor antagonist is already approved by FDA and available on the market for pulmonary hypertension, thus the potential kidney-targeted therapy for sickle cell associated nephropathy would be available fairly shortly. There is no doubt that appropriately designed and prospective clinical trials should be preformed to confirm the safety and effectiveness of this novel approach, however the barriers to the next steps of clinical investigation are minimal. This study was recently published (Kasztan et al. JASN 2017)

In conclusion our study is one out of many examples representing the beauty of the translational character of basic research and the great potential that may benefit million of patients with “rare” disease. We should strive to understand the mechanisms of disease and thereby try to prevent disease (or reduced disease progression), improve diagnostic tools, therapeutic interventions, and clinical care for all people, regardless if this is a “rare” or “common” in our society.  

Malgorzata Kasztan PhD

Joseph A. Carlucci Research Fellow of the ASN 

University of Alabama at Birmingham

Birmingham, Alabama

ATTN Nephrology Fellows: Origins of Renal Physiology fellows course now open for applications

Jeff during a trip to MDIBL

As a senior resident at the Beth Israel Deaconess Medical Center, I was fortunate enough to have had the opportunity to attend the Mount Desert Island Biological Laboratories even before I knew there a course for Renal fellows. It was there that I learned of the importance of comparative physiology in our understanding of the Renal physiology we see every day as nephrologists. For anyone who has attended the Renal Fellows course at MDIBL, the Animal House region of this year's NephMadness undoubtedly made you smile. In fact, choosing a winner was like picking your favorite child. How could you decide between how toads and camels solve their osmolality problems?! They didn't even mention why seagulls "spit" (they excrete salty fluid that drips onto their beaks...and it flies off when they shake their heads!). See what you're missing?

5 years after my first trip to MDIBL, I have been back every year since, teaching in the BIDMC and Hospitalist courses. But I will always have a special place in my heart for the Renal Fellows course, where I learned more in 1 week about basic science, renal physiology, and how lucky I was to be a future nephrologist than I ever thought. We worked hard...and we played hard. When not in the lab, we were exploring Acadia National Park on foot and on bicycle, eating obscene amounts of shellfish in Bar Harbor, and getting to know our fellow fellows and some of the most influential physician-scientists in the field.

In fact, I loved the course so much that I decided to study it! Here is our published paper about just how great the Renal Fellows course is So here's the deal,...if you want to go, you have to APPLY. Your course tuition is on the house! (the NIDDK is footing the bill). This year, it's happening from August 18th through 25th.

Visit the website for all the detail. Application Deadline is July 30th (Seats fill fast)

If you have questions, please don't hesitate to e-mail me -

Jeffrey William, MD
Instructor of Medicine, Harvard Medical School
Beth Israel Deaconess Medical Center
jhwillia@bidmc.harvard.edu  


 Check out all of the posts about this course on RFN

CHANNELing basic science to understand renal electrolyte handling

Let me start with a folktale: an old and very senile king wants to know which of his daughters loves him the most. The elder sister says she cherishes him more than the whole kingdom. The younger one, though, loves him “as dear as meat loves salt”. The king gets upset and orders her execution. As most fairy tales, it has a happy ending:  the king is served dinner without salt, learns his lesson, stops the execution and everyone lives happily ever after. In the modern world this story of a salt-loving family might have another sad “end” – end stage kidney disease, and a broke king spending a lot of gold coins on healthcare. It might have ended differently for him though if we had a better understanding of renal electrolyte handing during a high salt diet. This is a million-dollar question (actually, it’s more like hundreds-of-millions-of-dollars-question – I hope someone at NIH reads this blog); we need to know what happens in the kidney at the molecular and cellular level in a disease state. Knowing all the tiny details would be immensely helpful to discover new pharmacological targets. One of the most studied drug targets for renal diseases are ion channels, and electrophysiology is a sophisticated method for measuring ion channel activity.

In my lab at the Medical University of South Carolina among other things we use electrophysiology to uncover the mechanisms that underlie salt-sensitive hypertension.  Since the Nobel Prize in Physiology and Medicine awarded to Erwin Neher and Bert Sakmann for their “discoveries concerning the function of single ion channels in cells" in 1991, electrophysiology has been an immense help to basic and clinical science. Although this technique is very widespread in brain and cardiovascular research, there is only a handful of labs that use it to answer nephrological questions. I have learnt it during my postdoctoral training in the laboratory of Dr. Alexander Staruschenko (Medical College of Wisconsin) where it has been successfully applied to study kidney function for years.

So what exactly is electrophysiology? Basically, it is a technique that allows direct measurement of how ions (Na⁺, K⁺, Cl^-, Ca²⁺ - you name it) move through ion channels in the cell membrane. Using a tiny glass micropipette with an electrode in it, and a micromanipulator, we can press the tip of the pipette to plasma membrane of the cell, and isolate a patch of it that is under the tip (hence the other name of the approach – patch clamp). Since ions have a charge, their movement through the channel to the other side of the membrane generates current that can be sensed by the microelectrode in the pipette. Of course, sensing movement of single ions requires sophisticated amplifiers, filters, digitizers, grounding, knowing Ohm’s law and having a graduate degree in physics (kidding – though I have one, and it does help), and a ton of patience. When performing a patch-clamp experiment we control the environment that the cell is in (we choose the extracellular solution, what we put in the patch micropipette, what voltage we apply to the membrane etc), and this allows us to use different tricks to identify ion channels and then learn how to tweak or test their activity. Using cultured cells, tissues isolated from animal models, or human biopsies, we can directly measure the activity of ion channels and assess what happens in a certain disease condition.

Over the years, scientists have discovered dozens of crucial renal ion channels conducting sodium, calcium, chloride, potassium, magnesium… more are discovered every year. Gain- or loss-of-function mutations that lead to renal diseases have been reported for pretty much each and every one of them. In disease states such as salt-sensitive hypertension a handful of ion channels are known to work improperly, and in order to advance our treatment strategies we need to know how these channels are mediated, what signaling pathways affect them, and what pharmacology can be used to change their activity. As an example, in Dr. Staruschenko’s laboratory it has been shown that epithelial sodium channel (ENaC) in the cortical collecting ducts can be overly active in salt-sensitive hypertension (PMID: 28003189), which meaningfully contributes to an increase in blood pressure. Therefore, specific targeting this ion channel could be a successful means to combat blood pressure in this setting.

One of my good colleagues once compared ion channel electrophysiology to fishing. I have never fished in my life, but since I’ve done a lot of patch-clamp I feel I could easily have an alternative career as a fisherwoman. Nevertheless, although patch clamp electrophysiology is a “long wait – high reward” approach, this unique technique is crucial for our understanding of renal electrolyte handling, and – in skilled and patient hands - it has tremendous potential to push the medical field forward.

Daria Ilatovskaya, MS, PhD, 

Past Ben J. Lipps Research Fellow of the ASN  
Medical University of South Carolina 

Department of Medicine, Division of Nephrology 

Charleston, SC