Kidneys Inc.

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

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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

The nocturnal dip

There is a strong link between kidney disease and BP variations both in normal and hypertensive individuals that leads to the chicken or the egg conundrum of which came first when we manage our hypertensive patients. It is not very often that we stress on when the BP medications had to be taken to be most effective. The focus is on lowering the BP to expected goals hopefully through out the day and night. One of my previous posts was about an article that focused on a circadian clock and rhythm in the kidneys causing diurnal variations in the BP. Given the evidence that early stages of hypertension, there is a loss of the nocturnal dip, the 10-20% drop in the BP at night time, and it’s association with increased cardiovascular risk, it only makes sense to restore this nocturnal dip in order to decrease the risk. Recently saw this article. neat study, although it is open labeled with relatively small sample size, it is a prospective randomized open-label blinded end-point study, larger sample size than in any other trial to study this effect.

It is a general consensus that bringing the blood pressure to normal is more important than how it is done, in terms of what specific medications are used. But now it seems that it is not only important what medications we choose but also when we choose to give them


n = 661 332 awake group & 329 night time group (at least one medication at night time)

48h ambulatory BP monitoring

Follow up 5.4 years

Primary endpoint: adjusted risk for CV events was three times higher in the awake -group. Adjusted hazard ratio 0.31 p < 0.001

secondary endpoint: adjusted risk for composite outcome (MI, CV death, CVA) was three times higher in awake-group Hazard ratio 0.28 p <0.001

The night-time group had

lower asleep systolic BP mean p < 0.003

lesser proportion of patients with non dipping pattern 41% vs 71% p <0.001

higher proportion with controled BP 56 vs 45% p<0.003

awake BP similar in both groups p= 0.41

The difference in the cardiovascular risk was mainly due to restoration of the nocturnal dipping pattern. There was also a decrease in the albuminuria in the night time medication group.

Bilateral hydronephrosis with non-oliguric renal failure

93 y old man with PMH of prostate cancer successfully treated in another state lost to follow up for about 2 years, when he moved out of the state. Found to have elevated creatinine (increased from baseline of 1.5 4 months prior to 3.3 on presentation) on routine blood work with further investigation shooing b/l hydronephrosis on renal ultrasound. This asymptomatic patient with unknown duration of obstructive uropathy was admitted and no other obvious etiology was found for the worsening renal failure. Foley was inserted without difficulty, and patient was nonoliguric. Nephrostomy tubes were considered unnecessary. Patient discharged after initiating anti-androgen therapy for prostate cancer. Treatment started for prostate cancer with PSA trending down but no improvement in creatinine.

What would be the best next step?

1. Repeat US  to re-assess the b/l hydronephrosis

2. Reconsider decision for nephrostomy tubes

3. IV pyelogram to asses for ureteral obstruction and possible stents

4. Check viability and function with MRA

5. Check Viability with DMSA scan

6. None of the above

Mechanism of hypokalemia in magnesium deficiency

I had summarized this article a while ago (before I started blogging) thought it was worthwhile to publish it, both for my benefit as for others.

Hypokalemia is the most common electrolyte disturbance that nephrologists frequently encounter.

Serum potassium (K) depends on intake, excretion & distribution between extra & intracellular spaces

50% of clinically significant hypokalemia has co-existing Mg deficiency and is refractory to treatment unless Mg is corrected. Causes include loop diuretics, thiazide therapy, diarrhea, alcoholism, barter & gitelman’s syndromes, nephrotoxic meds like aminoglycosides, amphotericin, cisplatin


Mg deficiency causes impairment of Na K ATPase. This decreases cellular uptake of K. {my interpretation: Since Na K ATPase is present in virtually all cells, serum K should rise. This in turn may send signals to the kidney to get rid of K}. Thus, increased gastrointestinal or urinary losses causes K wasting leading to a decrease in total body potassium. Since GI loss is negligible, kidneys play a vital role in this.

EVIDENCE supporting this :

Urinary K excretion is decreased and serum K increases when Magnesium(Mg) when given to hypokalemic hypomagnesemic patients (Bartter’s syndrome, patients on thiazide diuretics) and

even in normal pts, urinary excretion is decreased with Mg infusion

In patients with Gitelman’s syndrome (hypokalemia, hypomagnesemia & met alkalosis) Transtubular potassium gradient (TTKG) is decreased with Mg infusion


K is freely filtered at glomerulus. Most of it is reabsorbed in the proximal tubule and loop of henle. Some K is then secreted in the late distal convoluted tubule (DCT) & cortical collecting duct (CCD)


In late DCT & CCD cells K uptake is at the basolateral membrane (Na K ATPase present only there) then secretion is at the apical side where two types of channels are present. Renal Outer Medullary Potassium (ROMK) & Maxi K channels.

ROMK is inward rectifying K channel responsible for basal K secretion Inward rectifying means “K ions flow into the cells through ion channels more readily than out” I did not understand what this means. I think it may mean that the ROMK channel allows two-way traffic for K but cell-bound direction has two lanes!! That makes it easy for K to move in than move out.

The apical side also has Epithelial Sodium channel (ENaC) that reabsorbs Na & causes depolarization of the apical membrane- this is the driving force for K secretion. This implies whatever increases ENaC activity will also increase K secretion. ( ^ aldosterone)

Inward rectification happens when intracellular Mg binds to & blocks the intracellular end of the ROMK channel

This process in turn is dependent on membrane voltage (depends on Na influx as mentioned before), extra cellular K concentration.

At physiological conditions Mg concentration needed for this is 0.1 -10 mmoles (median 1 mol). Since only 2% of total body Mg is in extracellular fluid, intracellular conc is 10-20 mmols, mainly bound to ATP. Only 5% is free

In kidneys & heart 100% of Mg can equilibrate with the plasma in 3-4 hrs, but for brain it is 10%, muscle 25% Moreover it occurs over 16 hrs.

What this means is that when plasma Mg falls for any reason, the intracellular levels drop first in kidneys & heart. This damages the inward rectifying nature of the ROMK channel

In patients with isolated Mg deficiency, hypokalemia not seen why? Two reasons

1. Because the Na K ATPase is also impaired, this causes less Na uptake by muscle & kidney that will cause K to rise again & become normal..?

{ Doesn’t this also stimulate aldosterone secretion which in turn activates the ENaC in the DCT & CCD?}

2. Increase in K secretion (caused by Mg deficiency as not enough Mg is around to bind to intracellular side of ROMK) causes hyperpolarization of cells in DCT & CCD driving force for outward K flux is decreased and K secretion is limited.

Hypomagnesemia alone is not enough to cause hypokalemia

Additional factors needed are increased sodium delivery & elevated aldosterone levels.

But these factors can independently cause hypokalemia. So How much does hypomagnesemia contribute? Are we back to square one?

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