Kidneys Inc.

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

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

STEPS to improve the experience of being a doctor

I was watching the episode 4 of Satyamaev Jayate (The truth prevails) (for those of you who do not know about it, it is a recently started much publicized talk show conducted by the celebrity actor Aamir Khan in India, addressing various issues that face today’s India). This episode really got the debate going because obviously though it had some truth to it, it was not the complete picture.

As I was thinking through this, I was struck by the fact that doctors are the most vulnerable group in the health care industry, be it in the United States or India. Doctors are at the disposal of everyone else in the ‘hierarchy’ of healthcare industry. Patients can sue them for bad outcomes or even without justifiable bad outcomes, employers can fire them for no reason what so ever, and if they own their own practice, they can get drowned in their own debts with all the ever-increasing overhead costs, and the public can criminalize, ridicule and metaphorically crucify them. It is true there are corrupt doctors, there are greedy doctors, and unfortunately so for the rest of them that are not. I am all for an outspoken criticism when the situation calls for it (like  the criticism of health care that I think is well deserved and long overdue), and recognize that passionately fighting back at the critique is only going to protect the rotten and corrupt parts of the healthcare system. So we should let the spark grow because that is the beginning of the road to a fairer system. However, we should be mindful of what we could do to amend the broken parts on our side.

It is important for us doctors speak up in this is the age of connectedness, age of social media, where every one ought to have a voice. This is a thought process to address the issues that might prove potentially problematic, not just from the legal standpoint, but also from patients’ perspective. Here are some issues that I thought were important ways to address them. This is mostly what we learned during training, but so often forget to practice

Speak up, Team up, Educate, Protect yourself, Support – STEPS

1. Media misrepresentation of doctor-pharmaceutical relationships – This may be different in different countries. My experience says, it is probably a worse problem in India. There have been many regulations to disconnect the big pharma companies from doctors. However, we are missing the elephant in the room, the real and bigger problem, that lies in the high-end ties and relations between corporate lobbyists & ruling powers. Whenever and wherever you see this kind of content, debate the issue, draw the attention to where the real problem is. ‘Mounam sammati lakshanam’. (silence is a sign of agreement) If you keep quiet, it is not considered polite, but counted as guilt. And if you think you are in a slippery slope with a pharmaceutical company, seek help and get out! You will not regret it. Someday, we will have to use the same medications & treatments and we should be able to do so without worries.

2. Doctors are overworked – Bring up such issues in meetings and devise a plan for work hours and schedules. when you cannot work anymore, please stand up and say, “I am done for the day, I cannot work anymore” and leave. It is better for everyone. Although easier said than done, I have to admit. An alternative would be taking at least an hour break, either for some quiet time or a slow lunch which should revive you enough to keep you going for the rest of the day.

3. Doctors have lost trust – Again, bad events, bad outcomes get more publicity and taint the image of doctors in the public eye. Gain trust of your patients. Inform, educate, communicate, obtain consents  — can’t be said enough. Show them their lab values, normal ranges, abnormal ones, graphs of trends, images and point to where the pathology is. Ask them to get an independent second opinion from another doctor of their choice. If it is different, discuss with the other doctor. It is ok if your first opinion was wrong on second thoughts. Do not forget to inform patients about risks, of everything that you do with their bodies. They have a right to know. Tell them what you are going to do, before palpating their breasts, or pressing on their bellies, or even listening to their lungs. Tell them what you find (sounds ok or looks fine) because they will be anxious about what you are going to find. Give them the assurance that you know what you are doing and if you do not know something you will find out. At the end of a visit, always ask if there is any other question you can answer for them. Do not leave them wondering what you are thinking. This may seem too trivial but very important contributors to what patients think of their doctors and how much they trust them, Convey to them that you are only as perfect as them and definitely care a big deal about their health. Remind yourself everyday that you and your patients are in the same team and are not opponents in a game where your win must mean patients’ loss. Work on gaining trust from your patients not by doing what they want, but assisting them with your expertise and help them make the best decisions for themselves. Tell them what they are entitled to know, instead of sugar-coating the talk and giving false hopes for incurable conditions. Keeping them informed of some bitter truths only makes them better prepared to face their struggles.

4. Employers giving you bad feedback based on what they ‘say’ they heard from patients about you. (while in fact it might be a purely administrative decision). It is a more malignant world than you think. An employed doctor does not have any protection against such kind of accusation, even when it is false. Unfortunately employed physicians are also the ones that depend on feedbacks for their future employments and growth in their careers. Do not let this affect you. Regardless of the kind of practice you have, provide patients with a website address (like vitals.com or health grades.com) where they can provide feedback, so you don’t get falsely accused of bad care. And with good feedback, you attract more patients and retain the ones you have.

5. Support your professional community. Do not discuss the perceived medical failures of your colleagues, or any other medical professional in front of patients. Firstly, you might not even have enough information only based on what patients tell you, that the care they received from another doctor was either wrong or unnecessary. Even if you know it is true, your objection has to be brought up with the other doctor and not with the patient. By not doing so, you are setting up a fertile ground that breeds mistrust. This where communication comes in handy, again. Obtain medical records, consult other physicians involved in your patient’s care. The time spent will save you time and even expenses sometimes.

Even after all this, it is not a cake walk being a doctor. It is quite a walk though, and we have to make the most of it!

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

http://jasn.asnjournals.org/content/22/12/2313.full

highlights

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.

An octogenarian perspective

I had picked up Emily’s patient to help her out, since one of mine was a ‘no-show’. The patient, Mr. Martin was in the infusion room getting an IV infusion . Not wanting to waste time waiting for him to finish, I decided to see him in the infusion room. Luckily, there were no other patients in the room and a computer to access his medical records was right on the table next to his chair. The conversation turned out to be one that I would remember for long. Within a few minutes, Mr. Martin had vented enough to give me glimpses of  his toughened mind, tempered thoughts, emotional vulnerabilities.He had pulled me into his world briefly by revealing some of the victories and losses of his life’s battles.

As I logged in to access his records, I introduced myself and hoping to start up a conversation, asked him how old he was.

Mr Martin belonged to the healthy looking octogenarian kind, even though he had dealt with his fair share of health problems. He actually looked younger than his stated age, not only going by his vigour and confidence, but also by physical appearance. He was neatly dressed, had maintained a good physique despite his physical disabilities.

Confidently he said, “Oh yeah, I want live for another 10 years, atleast. Not that I have any major project like building an empire or something but I now have a reason to live which I did not have before. You know, I am a capitalist..” And he looked at me for a reaction as if it was my turn to tell him what I was..

Me: Well, I am not quite sure what I am. I have conflicts in my mind when I see huge discrepancies in wealth. I feel deeply empathetic towards people who struggle for even basic necessities, while others enjoy an exuberant lifestyle

Him: “I am empathetic too, but if I become a socialist all I do is give away everything and nothing will be left for me. And they won’t even be helped. You need to strike a balance while being aware of the discrepancies & maintaining your empathy. You need to cut a path for yourself” I couldn’t tell if he was trying to change my opinion or was trying to defend his..

Me: Yes may be you are right. Because if you don’t have wealth, you can’t hope to get it from other “empathetic” people.

Now his eyes gleamed, happy that I got his point. “Exactly. I am not wealthy or anything but I have worked hard for what I have”

Me: I think you should stop taking the Magnesium tablet

Him: “Well that is good. Are you a doctor?”

I smiled, Why? are you having doubts? (I remembered that just a couple of days prior to this, another patient had mentioned his difficulty in identifying people in hospitals, since doctors, nurses, nurse practitioners, PAs all dress & look the same)

Him: “No, I can tell people easily. I was just checking if you are a pharmacist since you are adjusting my medications”  he then spoke to me in Spanish

Me: I can’t have a conversation in Spanish, I barely know a few words.

Him: “Well, I can talk to you in French then”. he smiled. for me it meant that he was looking for someone he could talk to. (needless to say, he lived alone)

Me: I am sorry I don’t know French either. I can speak hindi if you want to (note to self, my fall project is (has been forever) to learn Spanish or French)

Him: “No I don’t know hindi, I haven’t been that far yet. I have gone up to turkey, I have flown over india, not in a plane but a bomber. He looked at me with pride as he mentioned bomber.

I was busy gathering data to make my assessment and he probably wanted me to stop it & listen to him.

I can take care of Pakistan in a minute for you, if you wanted. Prrp! , (he snapped his fingers) in a second!” with a delightful expression on his face.

by now I had realized this was going to be a long conversation.

Me: oh no, I wouldn’t want that.

He probably noticed I am not freely entering into a dialogue. and sternly said, “I only have thirty minutes because I have to leave for another appointment” implying he doesn’t have time for me either.

Me: Looking at his infusion, told him that it was unlikely he would be able to get out on time, but I would try my best to finish up my part as quickly as possible.

I was being drawn into this converstation already and I did not mind at all, since I had time & also some interest in listening to this man who seemed enterprising

Yes I know that too, he grinned. “I feel better already. I probably take too many of those water pills. (which I found out was true) he was taking it more frequently than prescribed).

He continued, “I once saw an Indian movie in Paris that my wife took me to. She looks more Indian than any of the Indians that I know of. It was a totally new experience. The only other thing remember about that day was that the Egyptian movie was terrible.

Even while I was grazing through his chart, I could notice a sad tone in his voice when he said, “I don’t remember many thing s from the past but this one I remember very well”

I tried to perk him up a bit,

Me: I am glad you enjoyed the Indian movie, do you remember the name of the movie or the actors

Him: No, I only remember the costumes and the intensity of those scenes. He lifted his arms trying to probably describe a scene or something… but he couldn’t. aah yeah, and those actors can’t kiss. It was evident he remembered those moments somewhat vividly, though he did not remember any details of the movie

Me: Has anyone talked about dialysis to you?

Him: Yeah, they were talking about getting me a tube osmosis or something

Me: Sorry could you please repeat that again?

Him: You see, I am not trained in medical field but I am a well educated person, you know. I understand somethings well. If there is a membrane, I guess the exchange has to be osmosis.

I wasn’t sure if he was annoyed or offended by me asking him to repeat.

with a discontent tone, he continued, “We all are stuck here. We should not even be going to places where we are not supposed to be. Do you know our blood boils when we go to 50,000 feet? we have only 40 secs to live if that happens. Now you will think I am a crazy old man”

Me: No not at all. I would be happy if my brain works like yours when (&if) I am your age.

Him: I know. With a brain like mine, I sometimes cannot handle it myself. I get up in the night & start talking to myself. I become restless.  I have been to great heights, there is no sky and it is definitely not blue, it is just dark, black. I have seen the curve of the earth’s horizon. He was showing it with one hand as a plane and with another the curvature of earth’s horizon.

Me: Wow! That must have been a nice experience. I have only seen it on videos.

Him: Not entirely. You have a pressure helmet and you are under stress, but it gives you a different perspective

I was juggling between this conversation and my assessment and documentation. I had managed to squeeze in a physical exam while asking him a few more questions. Everytime, I tried to pull him back into a ‘medical’ conversation, he would pull me back to his side, so to speak…

Me: How long have you been on this medication?

Calculated & told me the duration,..

Him: When I moved here, I got my wife’s ashes and my medications in the front seat of my car. When I checked the next day, the medication was gone. I mean, somebody so slick?! What would they even do with that? Stealing other people’s stuff. Goddamn people. Oh god, I don’t even know what religion means anymore. he was sad again, actually sadder it seemed as his words dissipated into an angry mumble.

Now I had to stop typing and had to take a pause, since I noticed he was getting intensely emotional, remembering his wife

I tried to distract him, after hesitating for a second, since it was a delicate situation

Me: Hmm, are you a non religious person?

He had already rcovered, I thought

Him: yes. I do believe in god but I am too educated to believe in rituals and customs if that is what you mean. And I believe in god only to the extent that I think that is the only way I will ever see my wife again. Oh well, whatever… People can do all sorts of things if that helps them get peace. I don’t have an objection to that. May be it will help their stress & “hypertension”. He raised his eyebrows skeptically.

I asked him about one of his malignant medical condition.

Him: They put me on hormone injections so I don’t have testosterone in my body. Now I am a woman. I have breasts, I have a belly, I shave only once a week. I don’t know what I am anymore. I cannot control my emotions sometimes. you know, I cry like a baby sometimes. You probably have more testosterone than I do.

wanted to say that it is ok to cry and that everyone cries, but I kept it to myself

My colleague Tanya entered, wanting some info. She respectfully nodded her head as he looked at her, trying to make an assessment in his own mind.. he seemed to like her

Him: “You are pretty”.

She giggled “Oh! no one has ever said that to me”

Me: “Oh come on, that can’t be true

Colleague leaves after a brief exchange of some information with me

Him: See how easy it is to connect with someone? Well, She was actually pretty. If you can breathe, you are pretty.

Me: hehe, yeah may be you are right, I nodded as I continued with my work, trying to finish it up.

Me: So you had an infection in your bloodstream in the past? There was too much past medical history for me to browse through

Him: Oh yes. Can you believe I am still living after going through all of that crap? btw Do you know Ms Leena? she works at the regional hospital where I was admitted

Me: No

Him: She was ‘one of a kind’ person. She is a doll. She is young. well, everyone is young to me at 80 y of age. She is gay. She does not have a sex (gender) she is just a good person. You would have loved to meet with her.

Me: I see.

Me: OK I have made some changes to your medications. And ordered some labs before your next visit. Do you have any questions for me?

Him: Thanks for getting rid of some of those medications. So, are you going to help me live another 10 yrs?

Me: Oh sure, I will try my best. why 10? may be 15…

Him: Who knows, I had less than 30 minutes to live about ½ h ago. (pt was hypotensive and had received  some fluids in the clinic)

Me: I enjoyed the conversation with you. Could I please get your permission to post this on my blog?

The nurse had disconnected the IV lines by now.

We shook hands and then as he got up, he said,

“Sure, anything you want to do. You know, I don’t talk with everyone like this. I felt a positive feedback from you. It was a pleasure talking to you. How do I pronounce your name? how do you spell it?

Me: M as in Mary…, A as in apple…

he wrote it in a small book and he walked out with a sluggish & fragile gait with the help of his walker, dragging his tall statured, weathered self. He must have been a robust and handsome man in his prime days, I said to myself

I get to meet with many old lonely people during my day’s work. This one caught my attention today, mainly because of his resilient attitude which was incongruent with his weakened body, cold & random at times, yet wise & thoughtful, all while trying to deal with his loneliness and shortcomings. At 80 he seemed to have almost come to an agreement and had made peace with a disconsecrate view of the world he is living in.

I have written this from what I remember of all the relevant (or should I say irrelevant?) parts of our conversation

Names, patient information have been changed to protect privacy

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

Vitamin D : The sunshine vitamin

Being a nephrologist, I deal with bone disease related to chronic kidney disease on a daily basis and vitamin D is a major player in these patients. Also, I have been frequently asked about this by many people, so I thought it might be a good idea to put some relevant information together for a quick reference.

 

In June 2011, the endocrine society published recommendations for daily intake and optimum levels, based on extensive literature review. However, these are not based on

large randomized controlled trials (which haven’t been conducted, so far)

 

With whatever evidence we have, these are the take home points:

Main source for Vit D is diet, but very little present, except for oily fish. Another important source is UVB radiation, which converts 7 dehydrocholesterol to pre-vitamin D3 and then D3

Plants have vit D2 more like a pre hormone than a vitamin.

 

Vit D (either 2 or 3) gets hydroxylated at the position 25 in the liver (cyp2r1 &  cyp27a1), stable and half life is 2 wks.

Then, hydroxylated at position 1 in the kidney cyp27b1 (also present in other tissues)

This is the active form of vitamin D.

 

Measurement:

When serum levels are measured the 25 hydroxy form is measured since it is more stable, concentration about 1000 times more than the 25 hydroxy form

The hydroxylation at position 1 depends on PTH (parathyroid hormone), FGF-23 (fibroblast growth factor-23), Calcium, Phosphorus

 

Recommended daily doses of Vit D:

 

Age upto one year: At least 400 IU/day

1 year and older:  at least 600 IU/day However, at least 1000 IU/day of vitamin D may be needed to raise the blood level of 25(OH)D consistently above 30 ng/mL

19 to 70 years: at least 600 IU/day

>70 years: at least 800 IU/day of vitamin D.

In adults (>19 yrs) at least 1500 to 2000 IU/day of supplemental vitamin D may be needed to keep 25(OH)D levels above 30 ng/mL.

Pregnant and lactating women need a minimum of 600 IU/day of vitamin D; 1500 IU/day may be needed to maintain blood levels of 25(OH)D higher than 30 ng/mL.

“Obese children and adults and children and adults on anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS need at least 2 to 3 times more vitamin D for their age group to satisfy their body’s vitamin D requirement,”

Tolerable upper limits of vitamin D, which “should not be exceeded without medical supervision,” include the following:

  • 1000 IU/day for infants aged up to 6 months,
  • 1500 IU/day for infants aged 6 months to 1 year old,
  • 2500 IU/day for children aged 1 to 3 years,
  • 3000 IU/day for children aged 4 to 8 years, and
  • 4000 IU/day for everyone older than 8 years.

Of note all recommendations are only for bone health. No recommendations for ‘purported’ benefits of Vit D (for cancer, cardiovascular health) since they are mostly association studies.

 

Exposure to sunlight:

In fair skinned people: 10 minutes in mid day sun with no sunscreen (when UV index is < 3) is enough to produce about 10000 units of Vit D. This holds good provided the clothing is minimal exposing about 50% of the body. which essentially comes down shorts and tank top

In darker skinned individuals: the time required may be more.

Also note: darker individuals have lower risk for than fair skinned for skin cancer, so they probably could expose themselves longer in order to get the benefits of the natural vitamin D

 

Sunscreen recommendations

 

New FDA rules regarding sunscreen:

 

Sunscreens will carry a broad spectrum label- to indicate that it covers both UVA & UVB radiations

The SPF indicates protection against UVB only which is responsible for sunburn, skin cancer, and vitamin d production in the skin with sun exposure

While UVB affects only the outer layer of the skin, UVA enters deeper layers, 30-40 times more prevalent than the UVB, and linked to tanning and skin aging and skin cancer as well

 

Now, the highest SPF products can claim is 50+ since value above that are not meaningful in terms of protection

 

They can carry labels claiming to prevent cancer, only if SPF is higher than 15

 

Water resistant sunscreens will have to undergo testing, and labels have to specify time of protection in minutes for swimming/sweating

Manufacturers have one year to comply with these rules

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

Vitamin C and kidney disease

61 y old man who had hyperaldosteronism requiring adrenalectomy 4 y prior, bariatric surgery for morbid obesity 1.5 y ago, was off medications for both HTN & DM after the surgery, had contrast nephropathy after cardiac cath done during pre op evaluation for adrenalectomy (no CAD found). Baseline creatinine around 2.

Had transferred care to our facility about 2 mths ago. Had been found to be anemic started on iron therapy. worked as a hydraulic engineer and looks very organized with a neatly maintained folder for all his healthcare issues.

asymptomatic.

BP high in clinic. But states it has been good at home.

Creatinine has trended up from 2.2 in oct 2010 to 2.4 on aug 5 2011, 2.6 on aug 26 2011. 2.9 on sep 16 2011. HgbA1C 5.8

No obvious cause. No NSAID use. No evidence of volume depletion. No reports of hypotension. On enquiry has been drinking some supplement that his wife give him- supposed to be a multivitamin.

Also UA – no proteinuria. HCO3 decreasing to ~ 18. anion gap is 7.8 alb 3.7 protein 7.4

Scratched my head- (if only it worked) I discussed it with colleagues. No luck.  Omeprazole started on his first visit to pcp at our facility (replacement for nexium) was discontinued, even though there was no other evidence for AIN (like rash, fever, Wbc in urine). suddenly one of my colleagues who was talking with a pathologist who mentioned oxalises suddenly remembered this pt who was on vitamin C. The primary care provider had prescribed it in order to enhance iron absorption

I immediately called the patient asked him to stop taking his vit C

I am bringing him back next week. will try to spin his urine and look for oxalate crystals

Thanks to my colleague who kept this case in the back of her mind..

Vit C in CKD

Can cause oxalosis. Many patients tend to take it as they see advertisements for Vit C for its anti-oxidant properties, to increase iron absorption to treat iron def anemia  etc. however, in CKD this may be detrimental since it acts as a precursor for oxalate and can cause oxalate nephropathy.

Could his bariatric surgery contribute to increased absorption of vit C. I do not know the type of bariatric surgery he had done. If he had the most common type (Roux en Y) then it is likely that the Calcium chelated with the unabsorbed fatty acids allowing for increased absorption of the Vit C causing hyperoxalosis and AKI.

This is still the suspected diagnosis. will know more when he gets his herbal OTC vitamin supplement with his next visit.

will update this soon

Article in American Journal of Kidney Diseases

This is an article in press in AJKD. Thanks to Dr. Goldwasser again for making me a part of this.

This is about an interesting scenario we came across where the (measured) serum bicarbonate and calculated (blood gas) bicarbonate were consistently discrepant despite excluding all known possible causes. Interestingly enough, the patient also had pseudo elevation of troponins. The cause likely secondary to an interferent in the assay.

Here is the article

http://www.ajkd.org/article/S0272-6386(11)00943-7/abstract

HEPATORENAL SYNDROME

I tried to understand the pathophysiology of hepatorenal syndrome, which was interesting & will help to understand the treatment better. At the end I put some questions to answer. I don’t know the answer to all of them. I used some abbreviations, let me know if you can’t figure out any…

http://cjasn.asnjournals.org/cgi/reprint/1/5/1066

PATHOPHYSIOLOGY
Intense renal vasoconstriction and progresses with liver disease
Type 2 is gradual worsening along with cirrhosis
Type 1 is acute deterioration due to failure of compensatory mechanisms
Four mechanisms (not studied in humans) see fig 1
1. Peripheral arterial vasodilation & renal vasoconstriction
2. Renal sympathetic nervous system stimulation
3. Cardiac dysfunction
4. Cytokines & vasoactive mediators
^ norepinephrine , renin & aldosterone & low BP this indicates these elevations are in response to the initial drop in BP due to peripheral vasodilation which in turn is in response to splanchnic vasodilation is in response to ^ resistance to blood flow in cirrhotic liver ?
Therapy with vasoconstrictors improve /reverse HRS This means the cause of HRS is inadequate /inefficient compensatory mechanism.
But renal arteries are nonsplanchnic arteries why are they not dilated ? May be due to stimulation of the renal sympathetic nervous system. Hepato-renal & spleno-renal reflex may play a role.
Initial stages of HRS both splanchnic & peripheral vasodilation occurs. As cirrhosis progresses, BP continues to drop despite the hyperdynamic circulation, compensatory mechanism kick in & attempt to cause bring the BP back up by peripheral vasoconstriction, but apparently not enough.
Cardiac dysfunction (systolic & diastolic) occurs. This also causes cardiorenal like picture. Cardiac dysfunction reversed by one year after liver transplantation.
Vasomediators (Nitric oxide, TNF alpha, Endothelin, endotoxin, glucagon, intrarenal prostaglandins)
^ eNOs activity caused by shear stress & induced by endotoxin may cause the compensatory ^ in peripheral vasoconstrictors to become ineffective. NO produced in splanchnic bed mainly.
Precipitating factors for HRS & causes of HRS self explanatory {Fig 2 & table 2}  [precipitated due to cytokine induced aggravation of circulatory dysfunction]
-Large volume paracentesis
-GI bleed
-Bacterial infection
-Acute etoh hepatitis

Diagnosis see Table 1
Four major interventions
1. PHARMACOLOGICAL THERAPY
a. Renal vasodilators easily conceivable idea since the immediate cause is renal vasoconstriction, but none of the studies have shown improvement in GFR despite improvement in renal blood flow. Endothelin A antagonist BQ123 has been studied in 3 pts. Not very useful.
Bottomline Renal vasodilator therapy has been abandoned.
systemic vasoconstrictors, reverses splanchnic vasodilation & indirectly increases renal blood flow
b. vasopressin analogues
Ornipressin given + volume expansion or low dose dopamine ^ RPF ^ GFR ^ Na excretion in 50% of pts but 30% develop ischemic complications – abandoned
Terlipressin + albumin ^ GFR, ^ BP Serum Cr improved in upto 70% pts. Much better n type 2 HRS.
BUT
studies done are for short term use.
Unclear if the benefit is due to volume expansion only. ( one study showed improved survival & HRS reversal in 55% )
Benefit is short lived 80% succumb to their liver Dz if they do not get a new liver
FDA decided not to approve it
Bottomline- use vasopressin instead if you want
What is left?
c. somatstatin analogue octreotide
d. alpha adrenergic agonists midodrine & norepinephrine,
Combination therapy better than either octreotide or midodrine.
Norepinephrine with albumin & diuretics : pts do very well. Counter intuitive as epinephrine levels are already high in HRS pts
2. TIPS
Reduces portal pressure, suppresses the putative hepatorenal reflex, ^ EABV, better cardiac fxn
30 day survival in 71 % of pts
In pts not candidates for transplantation, 12 mth survival 50%, 18 mth was 35% (which is very good)
It can also increase chances of discontinuing RRT! ()
What are the drawbacks?
Does not correct all the underlying mechanisms? (so what? it is justified if it improves survival)
Delay in response, no improvement in Na excretion
Pts with advanced cirrhosis worsen, hepatic encephalopathy
Sequential Vasoconstrictor therapy followed by TIPS very encouraging results
3. RENAL REPLACEMENT THERAPY
Bridging therapy until pts get new liver. It improves survival after liver transplanttaion
Controversial in pts who are not candidates for new liver- Q is are we prolonging survival or prolonging death?
MARS – cell free modified dialysis technique- removes both albumin bound & water soluble toxins. Used in pts not candidates for TIPS (Advanced stage of HRS?) This is still in clinical trial stage.
4. Liver transplanatation
Liver allocated based on MELD score- for a given MELD score HRS pts do worse. So this is unfair according to authors… ( ?)
After liver transplant, pt & graft survival @ 2 yrs similar in pts who had HRS Vs no HRS but decreased at 5yrs for pts with HRS
Duration of RRT did not have any impact on chance of renal recovery after liver transplantation
Liver Kidney Transplantation is an option for pts who have prolonged RRT prior to liver transplantation
BOTTOMLINE prognosis has changed from terminal to reasonable chance of recovery

Questions:
In HRS peripheral & splanchnic vasodilation occurs decreased SVR (systemic vascular resistance) causing renal vasoconstriction. How are these changes different from a pt who has septic shock. & no liver disease?
If NO alleviates the effect of peripheral vasoconstrictors, why it doesn’t affect renal vessels?
Does HRS reverse if the precipitating factor is treated?
How do you diagnose HRS in pts with pre existing CKD?

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