Kidneys Inc.

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

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.

Lactic acidosis in metformin overdose

Lactic acidosis associated due to metformin is rare and especially so in normal renal function. I had the opportunity to see this. 45 y old woman with major depression who had been prescribed metformin but had not been taking it, ingested about 90 tablets as a suicidal attempt. Seen in the ER within 2-3 hours after ingestion, given charcoal, started on gentle IV hydration, admitted for monitoring. Lactate was elevated to 5.1. Renal function was completely normal with Creatinine of 0.9. Lactate decreased to 0.9 within 24 hours.

Metformin decreases lactate metabolism by suppressing pyruvate carboxylase in the Kreb’s cycle. Glucose utilisation is decreased and lactate production by the hepatocytes is increased.

Bile salts and hypokalemia

Last week, I saw a 53 y old man admitted with end stage liver disease due to chronic alcoholism. He was admitted for altered mental status, acute kidney injury with rise in creatinine from 0.8 about two months ago to 3.4 at the time of admission. However, his serum potassium was 2.4 with transtubular potassium gradient (TTKG ) of 13 (indicates renal wasting). His total bilirubin was 32.

Bile acids are known to cause this low aldosterone and salt retentive states by inhibiting 11 beta hydroxy steroid dehydrogenase enzyme. This enzyme normally converts cortisol into cortisone. When inhibited, as in the above example, it allows normal cortisol to drive sodium absorption and renal potassium wasting in the distal tubules.

Embryology of human kidneys

I intended to post an article on embryology of the kidney. This article just made it easier.

Pronephros draining from the coelom into the pronephric ducts (approximately day 22 of gestation)

Mesonephros draining directly from capillaries into mesonephric (wolffian) ducts: this system is similar to that of aquatic amphibians and fish

Metanephros draining from capillaries into bowman’s capsules and renal tubules (approximatesly by 5th week) and then into metnephric duct that later forms ureters.

While the metanephric ducts travel caudally to join the bladder as ureters, the metanephri rotate and migrate upwards as the torso elongates during development of fetus. this elongates the ureters.

At the end of formation of fully functional kidneys which is by 32- 36 weeks, there are one million nephrons.

http://scienceblogs.com/pharyngula/2011/05/the_basics_of_building_a_kidne.php

Healthcare: The insider edition

Doctors inevitably come into spotlight, being at the front end of health care delivery. Sometimes seen as ‘guardian angels’ restoring health and life, other times, greedy minds sucking resources while they carelessly harm and kill patients to fill their pockets. After experiencing, observing, and hearing from others in this profession, I wonder if doctors are given more responsibility than they can handle, often attributed more aura than they deserve and frequently accused of more corruption than they are liable for. This is my attempt to redeem them from their “divineness” and their “evil” and make expectations, speculations and skepticisms a bit more realistic. When I say doctors, I mean, a typical one in the community, having a clinical job or practice, who doesn’t do research, but reads them, pays dues for being a member of medical societies, attends CME conferences regularly. In short, a doctor who is a consumer within the healthcare industry, which form the majority.

Doctors are trained for their skills and are not magicians. It is a science that has to be delivered artfully. Patients get better not because of anyone’s angelic touch or some celestial mediation, but because of treatments and interventions that are tested, tried and known to work. However, the art of delivering leaves a long lasting impression in patients’ minds. These ‘minor’ details are the major differences between top and mediocre hospitals. This ends my argument about the supernatural powers that doctors are supposed or expected to have.

It is an inescapable fact that healthcare ‘industry’ is more similar to other non-medical fields than it is different. However doctors are expected to play a superior role while everything else in the industry isn’t necessarily so. Healthcare is a business where workers have to be paid, professional relationships have to be maintained, the patients have to be happy, the ‘corporation’ should run successfully. There are lots of limitations that doctors work under, making it extremely difficult if not impossible to meet all of the expectations. Held responsible for the fallacies of the healthcare system, doctors see themselves more as victims of it. There are lot of judgmental attitudes and actions that occur based on isolated events. One patient’s angel may be another’s devil. An awesome doctor for a patient may be a colleagues nightmare and with time, it can all be reversed within no time.

Doctors take different roles making it a recipe where conflicts of interest brew in the same pot. One person becomes doctor +business(wo)man + marketing & sales personnel + scientist + teacher in various combinations. It only gets easier to rationalize decisions that a doctor makes under one umbrella if not another. It becomes an inexcusable rationalization when patients suffer. This may seem inapplicable in a non-medical field, because ‘suffering’ in those contexts may be easily overlooked or more indirect.

Doctors get overworked (sometimes voluntarily when they have independent practices), become victims of abuse and overuse by hospitals, employers and administrators (when employed). As a result they too become irritable, annoyed, annoying, depressed. They walk on the proverbial tight rope on each side of which are the hot oil of litigation and the fire of cost cutting that is flaring up, with the heat almost singeing their hairs. Professional competition, conflicts of interest shake and wiggle the rope, while the balancing stick has to be held on to tightly. The stick consists of professional ethics, competence, compassion and empathy to patients without getting attached to them, business and communication etiquettes, time management, family, personal growth. It is indeed challenging to become a doctor who is loved by everyone around including patients, colleagues, staff, community and family especially all through their career. But if they do make it to the other end of the rope, there is a well deserved applause waiting. Mostly from self as no one else would be watching. It just takes one bad moment to damage the reputation that has been built over years. For a doctor it is devastating, even if the factual consequences for everyone else are hardly so.

Business of healthcare:

Medical profession requires us to empathize but not get attached to patients. It requires us to treat equally, while the insurance companies are allowed to be discriminatory in their payment. In other words, the system rewards you differently for the same treatment delivered. Doctors do not fix the price for their services, the system does. The cost of physician services vary by specialty and by procedures. Physicians cannot sell themselves to drug companies, but the companies have a strong grip on the whole health care system be it through funding research or sponsoring activities of medical societies.

In a typical private practice, overhead costs are prohibitively high (includes space, computers, electronic medical records, staffing, housekeeping, power and water supply), 70% in one place I interviewed! Moreover, the insurance companies & medicare decide the reimbursement. Again doctors are not as powerful as they appear. Taking care of people who are suffering and making them feel better is an extremely rewarding job by itself. But there is just not enough time to do that rewarding job. If you are scheduled to see 30- 40 patients in a clinic, how is it humanly possible to listen to every patient’s complete story? When our job is to care, where and when does it end?

Relationship with drug companies:

Pharmaceutical companies have customers, clients, prescribers and have strategies not only to survive in the market, but also to grow. General public invests in their stocks and shares. It should be a joint effort of doctors and patients  to not lose track of the common goal of greatest good for the greatest number. IMO, a practicing doctor has very little to do with the drug prices. Here is one hypothetical example of how and why: I work in an inpatient setting only. The hospital uses Dalteparin (Fragmin) for DVT prohylaxis. No matter how many enoxaparin (lovenox) representatives provide lunches, every time I try to prescribe it, it will be changed to the former, because that is what is in the formulary. Same with proton pump inhibitors.

On the other hand doctors who are practicing privately, also see representatives and may have some more control on prescriptions. But again, the prescription has to depend on the insurance. If the insurance covers it, all things being equal, the patient sitting in front of a doctor is a priority over the person who can potentially become one in the future and does not have insurance.

Doctors are also frowned upon for eating at pharmaceutical dinners, because it results in increase in drug prices. We probably are guilty of this. More so probably because it operates at a subconscious level and easy to believe there is no effect.  No matter how much I try to deny their effect, the studies have shown otherwise. In fact, these studies are originally published in the same renowned medical journals that also publish other industry sponsored research. The bigger bargains & deals that go on behind the curtains involving corporations, businessmen, government officials go uninvestigated if not unquestioned. Policy makers make it easy for companies to track prescribing patterns of physicians, dislike ban on gifts more than doctors, while condemning and restricting doctors for accepting them. However, doctors’ communities have been listening to these associations. It has resulted in changes to untangle the knot and free this bias. But still there seems to be no difference in the last 10 yrs. In fact, the problem is only getting worse. Here is probably why:

Coverage of a medication under any insurance, who makes the deal? It is between those companies. And they are probably not doctors.

Meals are not the only venue where doctors are ‘exposed’ to new medications. I have found no medical journal without advertisements from drug companies. I still have to come across a conference where pharmaceutical industry has no role. Severing the connections is not easy, because medications are an integral part of medicine. An essential part of the health care machinery, doctors are more like nuts and bolts and not the ‘driver behind the wheel’ status they are given. The people who are behind the wheel are a handful, some of them are doctors some are not. We are culprits to the extent that we let it tide by us, not because it benefits us, but more because it hardly affects us (unless we become patients) and there are always more immediately relevant patient concerns to worry about. Hence, the check point would be probably more efficient if it is at the FDA instead of at the doctor’s office. What is the point of FDA approving a new ‘alternative’ choice medication if a doctor cannot prescribe it due to its cost? A major fraction of high costs are by the sickest patients who are a small fraction. The major flow of money from drug companies is into a handful of people who for the most part have transparent relationships. I would not be using Xigris (drotrecogin alpha) on everyone everyday. But if no one ever used it, we would never learn anything more about it. Not all medications that enter market thrive. (a new drug is approved by FDA every month on average). They stay only if they work. Here is another important article.

The skinny is – doctors should avoid prescribing expensive medications when cheaper alternatives are available. But what about the clinical trials showing an expensive medication as a better choice? Some examples, Carvedilol for beta blocker, Sevelamer for phosphate binding, now the bicarbonate form better than the previous chloride form… . Once FDA approved, there are studies to expand the indications of a medication. And then another study follows through showing how the new medication caused more harm (epogen for anemia in ESRD) The lawyers wait in the waiting room. The vast community of doctors use the results, but a handful of them produce them. How do we maintain quality and transparency in such research? If not published journals (inundated with drug company advertisements) what else do we rely our medical decisions on? For one, I agree that it would be a welcome change (and we should speak up for it) if drug companies were more transparent about the research. The articles published do have to disclose any relation between the authors and pharmaceutical industry.

A slightly different story when it comes to choosing diagnostic studies. Patients have to informed about risks of procedures, benefits, alternatives etc. This article will explain in detail how this operates.

It begins to almost look like a conspiracy against doctors where the professional and personal integrity are put to vigorous testing and the whole system is designed to fail you at every step.

Some numbers to get an idea:

There are currently 1.5 million doctors in US and as per the data available about money flow from doctors to drug companies, about 17,000 got paid. This would be about 1.1%, distributing the amount among themselves with only about 300 or so distributing about half of it. Some of it goes into research, some into consultancies, and a minute fraction into meals. IMO it would be a judgmental error to call a doctor unethical/immoral or greedy because he/she consumes meals offered by a drug company. What is more important is what went on before the drug company had its new drug FDA approved. I wonder if an engineer or an accountant working in a company making medical equipment or soft ware for electronic health records would be equally culpable for accepting & giving freebies in the form of gifts, travels to market and sell their products. Because like everything else, the costs get transferred to the consumer, which in this case are hospitals and practices.

I will be the devil’s advocate for a moment and wonder, why hospitals and cannot get subsidized rates on land, their equipment, transportation and other resources they use. Why are not insurance companies held responsible for making huge profits without doing a penny’s worth of research. Would it be a bad idea to channel a percentage of their profits into the government so medicare can keep its treasury full to help the sick, old and poor?

Why is manufacturing PET scanners, dialysis machines, surgical equipment, performing special blood tests so expensive? Aren’t these companies as responsible (for public health) as pharmaceutical industries? Doctor- drug company relationships- do they deserve this incrimination? Ultimately, most industries connect to and impact health care costs, even if remotely and indirectly.

We cannot deny that unethical, greedy people exist in the field of medicine also and one rotten apple stinks the basket. One mishap and now everyone is required to remove their shoes (and most everything else) at the airport security.

Medical liabilities: Currently doctors are personally* responsible for most lawsuits, isolated again. Liability insurances in some states are prohibitive for even sustaining a practice. While it is not impossible for the doctors mistake alone to cause a bad outcome, more often than not, it is not the case. There are always a series of holes that have to align for something to fall through. It would be a welcome change if doctors can emancipate themselves from the fear of frivolous lawsuits, and this I believe can play a major role in cutting costs of health care. I emphasize *frivolous* because there is always fear of the other extreme where doctors behave recklessly in complete absence of lawsuits.

A good and strong healthcare system is an asset to our society. Since health care industry is weaved intricately into a capitalistic, free market based economy and doctors belong to the work force of this huge industry, isolating only one profession & one industry for the costs at the other end is not only unfair, but biased. Somewhere along the way the major burden and blame of its malfunction seems to be unfairly shifting on to the doctors’ back. Doctors are not as powerful as they are portrayed. This is not to seek permission for unacceptable or reckless behaviors from healthcare professionals, but to seek acknowledgement of how ‘human’ most doctors are, how they are the part of the callous and inflexible system, more as pawns, less as players. And how like most people, they too are constantly battling to eliminate their deficiencies. Doctors are losing the little power they have by remaining silent about all the unfairness and misinformation. It is difficult and impossible to solve these problems by tightening a few screws here and there. What we need is a system wide approach that includes everything that touches healthcare to decrease costs and doctors would be more than willing to become a part of it.

My suggestion for people who are skeptical about their doctors, this website might help to know more and thus help in making informed decisions.

I once had a patient with terminal cancer, with a huge abdominal malignancy, at risk of bleeding, with an extremely poor prognosis if I have to word it optimistically. The family requested air transfer to another facility, due to fear of road travel causing rupture of the mass.

Always explore other options, get second opinions. Ask your doctors if a cheaper alternative is available, be it an investigation or a medication, regardless of whether or not your insurance covers them. What you choose as a patient for yourself will affect other people who can become patients, somewhere else, some other time. It is very difficult for doctors alone to decrease the healthcare costs, when there is no consent from patients, when there is fear of losing license to practice medicine for not using an expensive alternative.

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

Mechanism of hypokalemia in magnesium deficiency

http://jasn.asnjournals.org/cgi/reprint/18/10/2649

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

MECHANISMS

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

PHYSIOLOGY:

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)

CELLULAR MECHANISM:

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?

The morality and rationale behind rationing “the beans”. Egalitarian or utilitarian?

here is a regular periodic meeting in all transplant centers, when doctors, nurse practitioners, transplant coordinators, social workers get together and ‘decide’ which patients in their center are eligible to get a kidney transplant and which ones need have to be removed from the waiting list. This important decision depends on a multitude of factors including but not limited to criteria such as time on waiting list, co-existing co-morbidities, social and family support, financial and employment status of the patients, insurance coverage, mobility and functional status of patients. Although pre-emptive transplantation is the ideal one, we are still far away from its realization, merely due to demand-supply discrepancy. Currently, age is not a factor for denying a kidney transplantation and donor kidneys are allocated on a first come first serve basis. Simply put, having age as a criterion would amount to ‘age discrimination‘. The OPTN/UNOS (Organ procurement and Transplant Network/United Network of Organ Sharing) committee is proposing a change that prioritizes younger patients, allocating younger kidneys to younger recipients. I think this will decrease* the ‘age discrimination’ as well as organ-recipient age discrepancy. Sounds like a paradox?.. Read on.

The number of patients on the kidney transplant waiting list, continues to increase sharply, growing 6 percent in 2008, and reaching more than 77,000 by 2008. Only about 17,000 end up getting transplants every year. The waiting time also continues to rise, varies geographically with a median duration being bat 3-4 yrs and could be as high as 8-9 yrs in areas like new york. Now with aging population and better healthcare technologies, lifespan of people with ESRD (End Stage renal disease) is getting longer and so is the waiting list for donor kidneys. This is mutifactorial:

The median age of the prevalent ESRD population has increased 3.2 percent since 2000, reaching 59.4 in 2008.

The adjusted incident rate of ESRD has grown 9.4 percent for patients age 75 and older, to 1,718 per million population in 2008, while the rates for those age 20–44 have increased by only 5.5 percent,

The adjusted rate of prevalent ESRD for patients age 65–74 has increased 25 percent since 2000, while the rate among those age 75 and older has grown 31 percent, to 5,266. Among those age 20–44 and 45–64, in contrast, growth has been just 11.0 and 17.5 percent, respectively. Meanwhile, the relative scarcity of donor organs is getting worse, despite measures taken to expand the donor pool as the number of organs available is not catching up with the number of waiting eligible recipients.

It is important to note in this context that the pediatric age group has a separate waiting list to avoid long waiting time as the outcomes are maximized both from medical and economical standpoint. These approaches, in my opinion, has apparently created a ‘donut hole’ in the list of patients waiting for a donor kidney. It seems like younger patients, who are neither too young to be in the pediatric group, nor too old enough to have accumulated a long waiting times were being pushed down the long waiting list. They are being denied kidneys that would provide them (and the kidneys) more additional years when compared with a similar older recipient higher on the list. Moreover, older patients have a higher chance of dying with a functioning transplanted kidney. The DWF (death with functioning graft) can be as high as 38% and amounts to about 42% of the kidney transplants. In some ways this situation is similar to the blood group and HLA matching discrepancy that made it harder for the O blood group ESRD patients to get a donor kidney and lengthened their waiting times. Also I can see this as an extension of the ‘pediatric allocation concept’. A 30 y old is relatively a ‘pediatric when compared with a 70 yr old.

Recent proposal to consider age and hence overall ‘predicted life years’ is the most drastic of the changes that have been made, in the last 25 years, to the algorithm of choosing recipients for the available kidneys. The new change is aimed at maximizing the outcomes for both the recipient of the kidney and the kidney itself. This is a good approach because

-The sooner an ESRD Patient gets a kidney, the better the outcomes are

-The longer the graft survives, the longer the patient survives

-The younger the recipient, more likely he/she will outlast the graft, and when that happens, they still have blood vessels and peritoneum in a good shape to last long enough

-It results in more patients with ESRD staying away from dialysis thus decreasing the budget deficit of medicare, which is the main coverage provider for patients with kidney disease

However, being a major and a fairly comprehensive shuffling of criteria by UNOS, major ethical, political, medical debates over the rationale of rationing will soon follow. More interesting would be to know what happens to the existing list where the older patients already predominate the higher parts of ‘the list’. With my quick research, I found out that a separate group will be formed for the youngest of the waiting list, so the younger kidneys are more likely to end up in younger patients. And the rest would follow in real time.

While this change is very appropriate where there organ scarcity and government is spending for the care of recipients, it raises an important question about healthcare that should be, by principle, equally distributed and equally available to everyone. If implemented, the same effect is bound to trickle down other aspects of health care, like end of life care, therapies for malignancies and end stage heart disease. The infamous “death panels” come to mind. But no matter what name they are given, such panels are important for healthcare, where everyone is fighting for a bite.

Some questions arise that cannot be left unaddressed. Medicare only pays for patients for a limited period for post transplant medications and one of the major reasons for failed transplants is non-adherence to those much needed medications, due to prohibitive costs. Should we then prioritize rich recipients over poor ones? Patients that are/were more productive over the unemployed?

While trying to get away from discrimination, do we end up doing just that? Can judgment based on sound scientific evidence and strong statistical data be accused of being discriminatory? Should we stratify both recipients and donor kidneys based on characters to form multiple short waiting lists?

Health policies are made based on population studies and statistical analysis, emphasizing greatest good for the greatest number. Rightfully so, because, when there are way too many people wanting the cake, some one has to decide, who benefits the most by having it, based on available scientific evidence. But more importantly, whoever gets the power to decide will take the blame for playing god.

The policies based on outcomes or consequences are more meaningful than those based on principle without support.

While I am writing this, a random thought flickers and I wonder if there is an end to our dependence on donated organs.  Is there an implantable metallic kidney in the future, ending this rough battle for the ‘beans’?


Idiopathic membranous nephropathy, not idiopathic anymore

Idiopathic membranous nephropathy (IMN) was just that, idiopathic. No causative agent or etiology identified in patients. Like most other things in medicine, idiopathic only means, ‘not yet discovered’. A 2009 NEJM article changed the way we look at IMN and glomerulonephritis in general. Antibodies to M-type phospholipase (A2) receptor was found to be highly specific and sensitive in evaluation of patients with IMN. PLA2R is expressed in podocytes, and IgG4 antibodies co-localized in the glomerular deposits in patients with IMN. Anti-PLA2R Abs found positive in 70-80% of patients with IMN. Serum titers of anti-PLA2R antibodies also correlated with disease activity.  Recently in ‘correspondence’ in NEJM, there was an interesting perspective regarding the limitations of relying only on the circulating anti-PLA2R antibodies for detection.

Now there is more coming up as another genetic locus has been discovered for this unique disease. This in fact may fill the gap from the previous discoveries.

http://www.nejm.org/doi/full/10.1056/NEJMoa1009742

While the PLA2R has been located on 2q24, genome wide studies of single nucleotide polymorphism have shown HLA DQ1 (class2 alpha chain 1) as another focus on 6p21 (long arm of Chromosome 6).. This gene is associated with immune modulation and associated with type 1 diabetes, celiac disease and organ transplant rejection. In case of IMN, it seems to  facilitate the autoimmune response to PLA2R in the glomeruli. Homozygosity for both risk alleles gave an odds ratio of about 78.5. (CI 34.6- 178.2). However, this study included only French, Dutch and British groups, essentially, caucasian population. Looking forward to see more on this.

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