Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Archive for the category “Research”

Research in medicine

I have been intending write this for a while, just did not know how and where to start, for fear of being considered a fox that could not reach the ‘sour’ grapes. Since I entered this country my perception of research has changed over time significantly. And today I saw an article from a former NEJM editor, Marcia Angell, about how unreliable and untrustworthy research has become. I will put down my two cents before I read what that article has to say

From the perspective of a medical student who is seeking a successful career, a scientific endeavor, eager to prove oneself, I realized early on to get into a residency, having publications is an important part of your resume. Of course one has to reach the mark of standard of  many other medical students. Soon after I started working as a “research assistant,” in a basic science research lab, I understood the complexity of a good research, purposes of research not as I imagined it but as I saw and understood it.

I was overwhelmed by the amount of publications that were out there, the number of medical journals, the complicated way of interpreting the study results. This is after the humongous time consuming laborious painstaking dedicated experiments were conducted. Even though, I was listed as an author in a couple of papers, I struggled to understand and almost felt I was cramming the details just before my interviews. What did I know, I was too new to be critical about this. Then came a day when I had to present a paper for an in-house conference. As I read that long paper assuming it is going to be a cram session, i saw the points were relevant, logical, proven. It required a good deal of time to even figure that out. So I came out of my basic science research with utmost respect for people who do real basic science research

As I entered my residency (not sure how much my publications really helped me in that), I again sought research hoping that this time, it will be different since it is clinical research. Unfortunately, I hardy got to work with people who are PASSIONATE about their research. I don’t mean talking passionately but being passionate about what it is they want to find out. Does not matter even if it seems totally irrelevant, but if it is an unknown and it is a well founded research, someday, it will be a dot that could be joined in the puzzle. But instead what I found was, research more or less followed trends. For example, there would be a slew of articles about hormone X or chemical Z and then they become the be all end all panacea for most researchers out there trying to get a publication out. That brings me to the ‘purpose’ of research.

I imagined purpose of research in the real sense should be to find out something that is not known. It could be as trivial as what is the rate at which a candle burns, or as major as ‘what kind of antibody  can possible cause condition A,’ but as long as the very basic methods are strong and founded, the results must be reliable. and it is OK get a negative result or to even not get a result.

But as I understood along the way, there are very few researchers who do this kind of research (and probably they rarely ever publish), But when they do it will be groundbreaking. And then there are others doing run of the mill research, following the trends and fashion of the publication world, adding one more article to the ocean of medical journals. The motivation for research is no longer curiosity but the following:

1. Publish, publish, publish. Conduct one experiment and try and get 3-4 papers out of it, saying the same thing back and forth in several ways

2. Publication is a marker for good research and your academic and scientific skills, so it will help one meet career goals, be it obtaining a position, retaining a position or climbing up the career ladder

3. Publications ensures more funding, more fame. The funding source, if it is the manufacturing company, again dilutes the findings by a some unknown factor. And readers are to read the article with a grain of salt.

There are articles of evidence based medicine, guidelines based on such reliable articles. But if my mailbox is filled with 4 journals each with 15 articles on an average, I read may be 2 from each one. Then 2 months later there is one with opposite conclusions. What should a clinician do? How reliable is the ‘data’ of evidence based medicine? How shaky are the methods used in the trials, how influential was the funding source?

This is enough to steer one away from even reading the articles even from major holy grail journals

This holds good for all the research articles out there medical or not. Since we do not have an alternative an objective scientific research, we are left with no choice but to keep it clean and safe from such alternative motivations and conflicts. If we don’t, we might as well be doing voodoo

now let me read what the former NEJM editor has to say

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Idiopathic(primary) FSGS and suPAR(soluble urokinase Plasminogen Activator Receptor)

Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome that could be idiopathic(primary) or secondary(genetic, infectious like HIV & parvo B19, drug induced IFN-alpha, pamidronate, lithium, Reflux nephropathy, hyperfiltration, HTN, obesity, Sickle cell etc). Clinically, it manifests as proteinuria with patients being asymptomatic to nephrotic. Proteinuria is non selective. Other features are HTN, Hematuria. with normal serological tests & complement levels. FSGS accounts for up to 1/3 of idiopathic nephrotic syndrome in adults and is the most common cause of nephrotic syndrome in african americans. Left untreated it frequently progresses to ESRD (End stage Renal disease.

While the management of secondary FSGS is directed at treating the cause when applicable, treatment of primary or idiopathic FSGS usually is nonspecific and targeted towards decreasing proteinuria, controlling BP, lipid control and low protein diet. In severe cases treatment is with steroids (tapering dose for at least 6 months) and for those who develop complications or are intolerant cytotoxic therapies like cyclosporine, tacrolimus, mycophenolate or cyclophosphamide. There are experimental therapies that include plasmapheresis.

 

It has long been speculated that there is a permeability factor playing a major role in the pathogenesis of idiopathic FSGS.

Recently it has been found out that suPAR (Soluble urokinase plasminogen activator receptor) is elevated in up to 2/3 of patients with primary FSGS. Evidence that higher SuPAR levels correlate with increased risk for recurrent FSGS after transplantation in patients with FSGS further supports the theory of this circulating factor in the pathogenesis of this condition. Importantly, molecular studies have also shown that the molecular size of suPAR is very close to the predicted molecular size of the “permeability factor” that has been considered to play a major role in the pathogenesis of idiopathic FSGS.

 

How does suPARwork?

 

suPar activates the podocyte beta 3 integrin (necessary for anchoring the podocyte foot processes to the glomerular basement membrane & also maintain cellular structure) causing foot process effacement, proteinuria & glomerulopathy.  Since it plays a major role, removing this factor by plasmapheresis or interfering SuPAR- beta 3 integrin interaction through antibodies will abrogate the pathogenesis of this disease

 

This opens up the therapy of plasmapheresis for such patients. It not only potentially keeps patients away from renal replacement therapy, but also may inhibit the progression of the disease at early stages to prevent its complications. However, It has to be noted that plasmapheresis has been shown to be effective in some patients with recurrent FSGS in a renal allograft, but not in patients with FSGS in their native kidneys. Could this be explained by presence of more than one such circulating factors or could it be due to patient selection?

 

For now, it is exciting to know more and more “idiopathic” glomerulopathies have prospects of entering the ‘treatable’ category of kidney diseases

BARD for Diabetic nephropathy

This week in NEJM, there is a major article with results from a new study BEAM, showing efficacy of a medication, Bardoxolone methyl (BARD) an oral antioxidant, in chronic kidney disease due to diabetes. We have always known of medications that decrease renal function. This would be the first medication that improves renal function. It works by inhibiting renal injury by oxidative stress and inflammation in diabetic kidney disease. However, Its role in other conditions with the same pathophysiology has not been tested, yet. Type 2 Diabetes being the most common cause of CKD (chronic Kidney disease) this new drug (if tested safe and effective in long term studies), might give the much needed major turn in management of diabetic kidney disease.

Summary from the NEJM article:

Sponsored by Reata pharmaceuticals, an employee of the sponsor wrote the first draft of the manuscript. study design by first author and representatives of the sponsor.

Glomerular Filtration Rate GFR estimated using the four variable (Modification of diet in Renal disease) MDRD equation

Patient characteristics: similar in all four groups. mean age 67 y, well controlled blood sugars, 98% were receiving ACE, ARB or both. Mean GFR was about 32 +/- 7 ml/min/1.73m2. Albumin to creatinine ratio (ACR) was distributed almost in thirds.

Exclusion criteria: type 1 diabetes, nondiabetic kidney disease, a glycated hemoglobin level of more than 10%, hepatic dysfunction, or a cardiovascular event within the previous 3 months.

Results:

Primary outcome: Change from baseline of estimated GFR Bardoxolone methyl vs placebo at 24 wks –> upto 12ml/min/1.73 m2 difference in eGFR between placebo and the BARD group

Secondary outcome: change in eGFR at 52 weeks–> upto 10 ml/min/1.73 m2 difference in eGFR between placebo and BARD group

Exploratory outcomes:

a) Cumulative changes in estimated GFR from baseline to 52 wks –>54% in placebo group. ~ 20 % in 25 mg group and 75 mg groups, 27% in 150 mg group

b) Time to and percentage of patients with > 25% reduction in eGFR 13% in placebo vs 2% in BARD group

c) Slight but significant increase in ACR in 75 & 150 mg BARD group at 24 & 52 wks.

d) Significant decreases in levels of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo at 24 wks

Adverse events: more in bardoxolone group 18% vs > 50%

1. muscle spasm most common in first 12 wks, resolved spontaneously with continuation of drug

2. Hypomagnesemia (not related temporally to 1.)

3. Alanine amino transferase elevation, mild and transient

4. GI side effects (nausea, vomiting, decreased appetite)

5. Last but not least : The BARD group had slight but significant increases in ACR. Authors explain it by attributing it to increased GFR but decreased tubular reabsorption.

Discussion: Oxidative stress and inflammation is the final common pathway for chronic kidney disease in diabetic nephropathy. Bardoxolone activates the Keap1-nrf 2 (kelch like ECH associated protein1nuclear factor E2 related factor) pathway thus ameliorating damage, hence preventing deterioration the pathogenic agents. It interacts with cysteine residues in keap1, causing translocation of Nrf2 to nucleus and upregulation of several cytoprotective genes. Bardoxolone activates nrf2 expression in glomerular endothelial cells and peritubular capillaries, increased hemoxygenase 1 in tubules and interstitial leucocytes. BARD also exerts inhibitory effect on nuclear factor kB pathway. This leads to decreased inflammation, BUN, and amelioration of both glomerular and tubular injury

Side note: Nrf2 deletion causes inflammation/oxidative stress.

Conclusion:

Treatment with BARD lead to sustained and significant improvement in GFR in patients with CKD due to diabetes. The effect was sustained after 4 weeks after discontinuation of the drug.

Increases in the estimated GFR was independent of changes in albumin excretion

The absence of a significant decline in the estimated GFR among patients receiving placebo may reflect the fact that most patients did not have macroalbuminuria at baseline and their important risk factors (e.g., blood pressure and glycated hemoglobin levels) were well controlled with standard medical care

However, bringing skepticism to the table: we know that proteinuria is a not only a major marker for renal function but also mediates injury. If the glomerulus is in some way protected by BARD, it has to be reflected by decrease in albuminuria. or there might be a possibility that the protection conferred by BARD might be negated by increased proteinuria.

Important questions that pop up:

The GFR was estimated by creatinine based equations. Does BARD have any effect on serum creatinine itself outside of its reported protective effect, either in laboratory measurements or in its production or secretion. In any of such situations, it can lead to a falsely higher GFR on calculations. There is reference (Number 28) that says no.

By excluding patients with poorly controlled diabetes, with higher glycated hemoglobin levels is there a selection bias where only patients with better predicted outcomes were studied. Note that the placebo group

But being optimistic, if it works out, this medication could potentially play a major role in many disease processes that are mediated by the Keap1-Nrf2 pathway.

Green dialysis

Some stats & facts

Average american family 400 gallons of water a day

Dialysis uses tremendous amounts of water — 32 gallons (120L) required during a typical dialysis session. Water purified by reverse osmosis prior to entering dialysis machines & water rejected by reverse osmosis goes down the drain.

7.13 billions gallons of potable grade A water wasted per year, with high salt content being its only problem. After desalination, it meets standards set by WHO & united nations food and agriculture organization for use in irrigation & landscape.

All the water, if saved and used, is enough to supply a city as big as salt lake city

It has already been done in Australia. more details in this link

http://www.renalbusiness.com/articles/2011/03/making-dialysis-green.aspx

Some more facts from the Australian Pilot Project

The RO water, better than drinking water wasted at 1100ml/min. It also fell within all national and international requirements for drinking water.

This otherwise rejected water was stored in tanks. They supplied the central sterilization department, the rest was used for cleaning, gardening, laundry and toilets.

The australian practice also adapted solar power that powered the reverse osmosis machines and also the dialysis machines. The cost of setting all this up turns out to be lesser than conventional expenses (electricity and waterbills) in the long run. It even becomes an income generator, once the cost is paid back.

The clock in the Kidney

One the one hand, there are huge advances being made in medicine, especially in the field of regenerative medicine, while on the other, it seems like we are just beginning to understand how intricate our bodies are. Exploring human body at a molecular level has only revealed how much of it still remains unknown. Hypertension is a chronic medical condition that has economic impact due to cost of care and also in terms of work days lost. Partly because of its ‘asymptomatic’ nature, it is still an unrecognized, underdiagnosed, untreated and undertreated condition. When it does come to attention, despite countless medications that are available and prescribed, they just do not seem to work. An important factor might be non adherence to diet and medications. But there may be some more things we need to know.

This article caught my attention, recently. It is a brief review article about the circadian clock in the kidney and how it might impact the blood pressure variations. It gives clinical and molecular evidence for its presence and effects, highlighting the need for more research in this direction, which may help to tackle this major cause of morbidity and mortality.

http://jasn.asnjournals.org/content/22/4/598.full

Glomerular Filtration Rate, Renal blood flow, urine and electrolyte excretion exhibit diurnal variations (healthy individuals produce more electrolytes and urine during the day), very similar to the one seen in other organ systems like the nervous system and the heart. Although observations in the kidneys have been made about a century ago, the underlying mechanisms are still incompletely understood. (Circadian –> Circa & dies from Latin)

This circadian variation partly depends on the retino-hypothalamic tract which carry light signals from the eyes. The supra-schismatic nucleus of the brain functions as a master clock. It probably is not a coincidence that this nucleus is also extremely important in salt and water balance via the arginine vasopressin pathway.

Cardiovascular events and cerebrovascular events peak in the morning hours, and reflects the blood pressure increases in the morning, which then plateaus during the day then dips at night.

Circadian variation of blood pressure entails a nocturnal dip in BP by 10-20%, the absence of which is associated with an increased risk of cardiovascular events, increased Left Ventricular Hypertrophy, myocardial infarctions, carotid artery wall thickness, cerebrovascular disease, microalbuminuria, Chronic Kidney Disease, dementia.

Circadian variation of blood pressure in turn is also controlled by aldosterone signaling. (hyperaldosteronism causes a non dipping pattern).

Renal transplant has also been shown to restore the pattern, and suggests an intrinsic renal pathology as the cause. Again supported by the classic dog experiment of ‘escape’ from aldosterone escape when renal blood vessels are maintained at normal pressure compared with systemic blood pressure.

Salt handling by the kidneys  is probably more important than the amount of dietary salt as a cause of hypertension (HTN), since it is uncommon in normal renal function. {This brings us back to the chicken and egg of conundrum of Hypertensive Nephropathy}

Joining all the dots available, It is probably a positive feedback loop with renal disease (not evident by normal laboratory parameters) causing anon dipping pattern and then HTN in the first place, which in turn causes further renal damage (and other organ damage) disrupting the salt handling ability of the kidneys. The initiating renal disease could be in inappropriate sodium handling due to disrupted circadian clock, which in turn could be a manifestation of dysfunctional or dysregulated clock genes.

Molecular evidence:

Many genes have been shown to exhibit rhythmic expression in the kidney- clock controlled genes. Some examples

1. expression of E-Cadherin and claudin-4 parallel the circadian changes observed in sodium excretion

2. Period 1 (Per 1) plays a role in aldosterone dependent transcription of Scnn1a which is the rate limiting subunit of epithelial sodium channel.

3. NHE3 (mRNA for) exhibits circadian variation

others include V2R, V1aR (vasopressin receptor) Aqp2, Aqp4 (aquaporins)

More evidence

Per 2 mutations cause a non dipping pattern in rodent models

In cry1/Cry2 null mice, rhythmic expression of NHE3 is blunted, aldosterone levels are elevated. This elevation is due to overexpressed gene for a dehydrogenase isomerase, Hsd3b6.

The critical issue in dealing with BP variation and the disrupted circadian rhythm is in differentiating abnormality in the intrinsic clocks as opposed to the supra-chiasmatic clock.

At bedside,

Chronotherapy is the administration of medications at different times of the day with the goal of restoring the circadian rhythm rather than just relying on day time blood pressure measurements. This approach is more effective and also decreases the risk of cardiovascular morbidity and mortality. (MAPEC Trial). This is further evidence for the important role of the clock.

At bench,

Accumulating molecular evidence offers potential targets for interventional therapy for hypertension

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