When to Pee in the Cup

Sep 11 2014 Published by under Kidney Function

Screening urinalysis (UA), usually performed by dipstick in a physician's office, ultimately results in a lot of referrals for nephrologists. I am reviewing this topic, and I will have a series of posts about UAs over the coming weeks. First, I want to start with a poll about what is really recommended for healthy, asymptomatic children:

Next week I will reveal the answers from the crowd, as well as what the real answer is.

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Forty-Six

Sep 06 2014 Published by under Kidney Function, Life of a Physician

It's been a dry week.

Zer0. Zip. Nada.

Today, the urine output box shows 46 mL overnight.

Less than an ounce, but an important sign of the return of kidney function.

Keep it up, kid.

Urine is golden.

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Is the Answer at the RIVUR? #NephJC

Jul 16 2014 Published by under Evidence Based Medicine, Journal Club

This study will be discussed as part of the online, twitter-based Nephrology Journal Club on July 22,2014. More information about the workings of #NephJC can be found here.

The Problem of Reflux

Vesicoureteroreflux (VUR) occurs in approximately 10% of children overall, but about one-third of those with a febrile or otherwise symptomatic urinary tract infection (UTI). VUR is associated with an increased risk of renal "scars." Since it was first described in the 1960's, treatment of this backflow of urine from the bladder to the ureter has been recommended for all affected children. Surgery can create a competent valve at the vesicoureteral junction during voiding, but an early randomized trial showed that prophylactic antibiotics to prevent infection were just as effective as surgery in the scarring outcome.

Despite the recommendations for treatment for 50 years, permanent kidney failure attributed to VUR has not declined in the end-stage database of any country. Improved prenatal diagnosis of infant renal anomalies have allowed us to diagnose VUR in the first weeks of life, prior to any UTIs. Some children without UTIs still get renal scarring, leading some to suspect that "scars" may actually be areas of hypoplasia or other abnormal development due to an abnormal ureteric bud.

The original study showed equivalent results from surgery and antibiotic prophylaxis, but it included no untreated control group to assess the strategy of intermittent treatment of  UTIs when they occurred. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial set out to determine if long-term prophylaxis prevented recurrence of UTIs, occurrence of "scars," or contributed to antimicrobial resistance.

The Study

The study was a randomized, double-blind, placebo-controlled trial of prophylaxis with trimethoprim-sulfamethoxazole (TMPS). Children were screened and enrolled after 1 or 2 febrile or otherwise symptomatic UTIs, including positive culture. Bagged urine samples were not allowed. Children in the study ranged in age from 2 months to 6 years and had grades I to IV VUR (severe grade V patients were excluded). Exclusion criteria included other urinary abnormalties, chronic kidney disease, inability to take TMPS, and other selected medical issues.

Studies included dimercaptosuccinic acid (DMSA) scans at baseline and 1 and 2 years later. These scans (the gold standard for kidney scars) were read and scored centrally by two pediatric nuclear medicine radiologists.

Treatment failure was defined as:

  • 2 febrile UTIs
  • 1 febrile and 3 symptomatic UTIs
  • 4 symptomatic UTIs
  • New or worsening "scars" at 1 year

The Results

Baseline characteristics of the children enrolled can be seen here. No significant differences on any parameter existed between the treatment and control groups. Time to first febrile or symptomatic UTI after trial enrollment is shown below:

Figure2

As shown in the paper’s figure 2 above, the two groups separated significantly within the first 6 months of treatment, with TMPS prophylaxis clearly preventing UTIs. By the end of 2 years, approximately one quarter of the placebo group had experienced an infection, while only half that many in the prophylaxis group had fallen ill.

A number of potential modifying factors were assessed for impact on the results, shown in the figure below:

Figure 3

As shown prophylaxis was more valuable for children who presented with febrile, as opposed to symptomatic but afebrile, UTI. Bowel and bladder dysfunction, determined via a standardized survey, also favored the use of TMPS.

Renal “scars” showed no difference throughout the study. Rectal swabs showed no significant difference in the rate of resistance of E. coli to TMPS between the prophylaxis and control groups.

Remaining Questions

Clearly antibiotic prophylaxis reduces the risk of recurrence of UTIs in children with VUR. However, about 75% of children receiving placebo had not suffered a recurrence after 2 years of study. UTIs cause discomfort, school absence, and lost work for parents; even after this trial we have no evidence of long-term damage prevention through the use of TMPS. Antibiotic resistance does not seem to be a big problem in this patient population.

So the question remains: what should we do about VUR?

In my mind, the question is still open. Many families today have qualms about long-term exposure to these medications. Other families dread missing a UTI and would far prefer to take the antibiotic. The tolerance of the family for illness vs the small risks of prophylaxis often prove to be a big factor driving therapy.

That leaves us each a lot of flexibility in our approach to VUR. My personal preference is to watch most cases without prophylaxis initially. Those who have further UTIs in the first few months after diagnosis are encouraged to start prophylaxis and consider surgical treatment. Those without significant recurrences receive follow-up on a regular basis. All of this requires ongoing discussion with the parents and input regarding their tolerance for urinary symptoms.

The pediatric nephrology community hoped that RIVUR would answer our managment questions about VUR. It would appear that we still have more we need to know.

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Fair Warning

Jun 11 2014 Published by under Blog Maintenance

Tomorrow I am off into the friendly skies again, headed for that city on the bay for the 74th Scientific Sessions of the American Diabetes Association. That means my posts for the next week or so will involve diabetes and its complications, especially kidney disease.

Other random shiny objects sometimes catch my attention when I travel, so get ready for those as well.

 

 

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Messy, Complex? Math To Make It Simple: #xBio

Apr 30 2014 Published by under EB2014

A number of renal physiology presentations dealt with modeling of kidney functions. They featured Departments of Mathematics, something which I find a bit intimidating:

As usual, XKCD speaks truth

As usual, XKCD speaks truth

Structural organization of the renal medulla has a significant impact on oxygen distribution

Brendan Fry, Anita Layton

Duke University, Durham, NC

 

The first thing that caught my attention with this abstract was its medullary focus. Nephrologists and physiologists often give the medulla little love. It's not the part of the kidney that we biopsy (at least not what we want to get), and while it does a bunch of stuff for water and volume control, most folks only pay attention to their little piece of it.

AJP Renal 287:767, 2004

AJP Renal 287:767, 2004

So what does it take to model the structure of a kidney? Let's look at an example of a medullary reconstruction in the figure on the right. In this study by Pannabecker and Dantzler, segment-specific markers were used to reconstruct the medullary architecture on sections through the kidney. Cross-sectional photos were "assembled" into these tubular models going from corticomedullary junction (a) through the papilla (e). Red structures are descending thin limbs of the loop of Henle, while blue tubes represent collecting ducts.

And these are only two of the tubular structures that course through the medulla and give it a striped appearance.

So these sorts of studies give us a picture of the anatomic relationships within the medulla. Now we need to start adding what we know about functional relationships. For that, we will see the next figure from Lemley and Kriz.

Kidney Int 31:538, 1987

Kidney Int 31:538, 1987

In this cartoon (not as pithy as the XKCD one, huh?), some known transport properties of various segments gets thrown into the mix. This is, of course, one of the simplest diagrams from this paper.

So people have been doing this stuff for many years (that last paper is 26, the same age as my daughter). As time has passed, our understanding of both the structure and function of these areas of the medulla has improved, allowing a mathematical model to be created. The original model by Anita Layton is illustrated in the next figure. I will let you pull the paper if you want the key to the abbreviations.

AJP Renal 300:356, 2011

AJP Renal 300:356, 2011

In this version, certain assumptions were made about the regions in which these segments lie.

The new model adds to this 2011 version, with further refinements about the spatial relationships and how oxygen would traverse the interstitial goo at various levels. They hope to work further functions into their models in the near future, things like the nitric oxide system and acid-base handling.

I have not done this paper justice; I am merely an MD, at best a humble biologist. I can appreciate how an elegant model can direct new hypotheses and future experiments. I'm afraid, though, that when I model a kidney it will be something like my final figure...

Click for original source

Click for original source

 

 

 

 

 

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Kidney Physiology in People: xBio

Apr 29 2014 Published by under EB2014

Scientists do a lot of stuff to cells in culture and rodents in plastic boxes, but ultimately we often want to better understand the human condition. It's always exciting for me, as a medical doctor, to see the sorts of translational studies that bring concepts from bench to bedside, so to speak.

Improved survival at what cost?

Improved survival at what cost?

Prenatal steroid exposure promotes expression of renal injury indices in African American females

TanYa M. Gwathmey1, Mark C. Chappell1, Patricia A. Nixon2, Lisa K. Washburn3

1Hypertension and Vascular Research, Wake Forest School of Medicine, Winston-Salem, NC,2Health and Exercise Science, Wake Forest School of Medicine, Winston-Salem, NC,3Dept of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC

 

 

Peri- and neo-natologists have know for many years that term delivery is preceded by a burst of cortisol from the fetal adrenal glands. This surge of steroid produces an increase in surfactant production by the fetal lungs, making them ready for postnatal life. It may also help drive kidney maturation for the external world.

In the 1980s betamethasone, a pharmacologic glucocorticoid similar to cortisol, became standard treatment for preterm labor. Women who presented advanced in labor might not receive it, because it would not get to the fetus in time. Those who would likely keep the critter in utero for another day or two got the shot.

Full-term is 37-38 weeks of estimated gestational age (EGA), based on the time from the last menstrual cycle (depending on which classification system you use). Nephrogenesis is not complete in the human fetus until 36 weeks EGA, so anything done in pregnancy prior to that time may have a substantial impact on future kidney structure and function.

The present study examined measures of kidney function in 14-year-old African American girls with or without prenatal exposure to betamethasone. First question: why girls? Turns out the sample of boys in this cohort is insufficient for these sorts of comparisons.  The girls were classified in 3 groups: Full term; Preterm without betamethasone; and Preterm with betamethasone. Both preterm groups had similar degrees of prematurity, averaging 28 weeks EGA. All of these kids are fairly similar in many ways, and all have "normal" blood pressure; however, the preterm girls, both with and without betamethasone, trend higher within the normal range (reported at an earlier meeting).

A number of markers of kidney health were presented in the current poster:

  • 8-isoprostane, a marker of oxidative stress
  • Angiotensinogen, the precursor of angiotensin
  • Angiotensin II
  • Microalbuminuria

Premature girls showed higher levels of urinary angiotensinogen, angiotensin II, and microalbuminuria, with trends to higher levels with betamethasone exposure. Betamethasone exposure increased 8-isoprostane in the urine over full-term girls; preterm subjects without betamethasone exposure had levels intermediate to the other groups.

Obviously these results are not the startling, clear-cut, "eureka" differences that we are used to seeing in studies of models. The numbers are fairly low, with only 10-20 subjects per group. People are less enthusiastic about controlling other variables than our animal or cellular subjects. We do not yet have information on physical activity, body habitus, perinatal exposure to other drugs, and a million other variables that may affect renal health.

We also do not have a non-African-American control group. Blacks in this country have a disproportionate risk of prematurity as well as hypertension and chronic kidney disease. While these studies suggest that being born early and getting betamethasone are both bad for African American kidneys, we do not know if these factors are different for the white population.

Now, don't get me wrong. Betamethasone treatment has improved respiratory issues (along with administration of surfactant at birth), and a long-term risk of hypertension and kidney disease beats dying at birth of prematurity and respiratory distress. It is important that we recognize effects of these agents so we can come up with strategies to mitigate their consequences.

As always, further study is in order. And these investigators are on the case.

 

 

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Award-Worthy Renal Abstracts at #xBio

Apr 21 2014 Published by under EB2014

Pre- and post-doctoral researchers run the world of science. Sure, Principal Investigators get the credit, but our students and fellows actually perform the experiments and make the magic happen. At Experimental Biology each year (#xBio is the official hashtag), abstracts from trainees get considered for possible awards, with finalists judged on their presentations at the meeting.

Click to enlarge

Click to enlarge

All of the finalists will present poster versions of their work on Sunday, April 27, at the Renal Section's Posters and Professors Session. This event runs from 5:30 - 7:30 in Marina Ballroom DE of the San Diego Marriott Marquis & Marina (Level 3 of the South Tower; see the map). In addition to viewing some excellence science, you will get a chance to meet up-and-coming physiologists as well as hobnob with us more senior kidney folk.*

What if you can't make it Sunday evening? Below I have collected the information on the other presentations of the award-finalists' endeavors. Now you have no excuse for missing these amazing works of modern science!

 

 

 

Predoctoral Excellence in Renal Research Finalists

Gerasimova

University of California-San Diego & VA
What makes SGLT2 inhibition so effective in lowering blood glucose in diabetes?
Poster Sunday, 4/27:  689.5/A281
Platform Tuesday, 4/29: Room 25B, 9:00

Kasztan

Medical University of Gdansk
Mechanism of purinergic action on glomerular permeability for albumin
Poster Sunday, 4/27:  692.3/A319

Pollow

University of Arizona
T cell-dependent hypertension is attenuated in female mice during angiotensin II infusion
Poster Tuesday, 4/29: 1136.10/A751

Richards

University of Florida
Regulation of NCC and the WNK cascade by the circadian clock protein Per1 in murine distal convoluted tubule cells
Poster Tuesday, 4/29: 1109.5/A544
Platform Tuesday, 4/29: Room 22, 8:45

Rudemiller

Medical College of Wisconsin
Mutation of SH2B3 attenuates Dahl SS hypertension via inflammatory signaling
Poster Tuesday, 4/29: 1136.15/A756
Platform Tuesday, 4/29: Room 25B, 9:30

Postdoctoral Excellence in Renal Research Finalists

Ares

Henry Ford Health System
Fructose stimulates phosphorylation and trafficking of the Na/K/2Cl cotransporter in rat thick ascending limbs
Poster Tuesday, 4/29: 1109.2/A541
Platform Tuesday, 4/29: Room 22, 9:45

Collier

University of Iowa
Acid activates ENaC and enhances salt taste in human subjects
Poster Wednesday, 4/30: 1181.10/W354
Platform Wednesday, 4/30: Room 22, 12:15

Itani

Vanderbilt University
A potential role of memory T cells in hypertension
Poster Tuesday, 4/29: 1074.1/A76

Shepard

Johns Hopkins University School of Medicine
 Elucidating the role of a renal proximal tubule-specific olfactory receptor
Poster Monday, 4/28: 892.42/A456
Platform Monday, 4/28: Room 25B, 8:30

Wen

University of Nebraska Medical Center
Deficiency in NBCe2 causes distal renal tubular acidosis
Poster Monday, 4/28: 891.2/A413
Platform Monday, 4/28: Room 25B, 9:15

Or you can download a Printable File of these presentations in PDF format!

These works look absolutely amazing! All ten of these emerging scientists deserve congratulations, as well as our presence.

-------------------------------------------------------------

*I will provide autographs upon request; no NSFW body parts, please!

 

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Countdown to #xBio 2014

Apr 11 2014 Published by under EB2014, Societies and Meetings

Two weeks from today I leave my home and head to glorious San Diego for Experimental Biology 2014, the annual gathering of the organizations that comprise the Federation of American Societies for Experimental Biology, AKA FASEB. My favorite of these groups, the American Physiological Society, once again asked me to blog the meeting. I have finally gathered scheduling information and abstracts to organize my activities.

I will be attending and summarizing Saturday's session on storytelling for scientists, presented by Randy Olson. He has followed that traditional career trajectory from tenured professor to film school, and he wrote two books about scientists and communication skills (or, more accurately, lack thereof). I heard him speak at a screening of his film, Flock of Dodos, a few years back. His latest book, written with Dorie Barton and Brian Palermo, is Connection: Hollywood Storytelling Meets Critical Thinking. I am looking forward to seeing how his message has morphed over time. Obviously, I love communications, so this session is right up my alley.

Saturday also starts more traditional fare, including the Cannon Memorial Lecture. James M. Anderson of the NIH will present his talk, The Contribution of Paracellular Transport to Epithelial Homeostasis. As someone who teaches renal pathophysiology, this topic will be relevant. Look for some live tweets during this session.

Of course I will also attend and discuss the Gottschalk Award Lecture for the Renal Physiology Section on Monday afternoon. Susan Wall of Emory University will present her work on The Role of Pendrin the the Pressor Response to Aldosterone.

I have selected a number of abstracts that interest me; next week I will contact authors about coverage, either through email interviews, conversations on site, or perhaps even videos of them at their posters. See something in the program you think I should explore? Drop me a line via twitter (@phlane) or email (pascalelane [at] gmail...you know the rest).

Be sure and follow me on twitter as well as @expbio, and track the official meeting hashtag (#xBio) while you're at it. You may not be gazing on San Diego harbor in the sunshine, but you can still get a feel for the science at the meeting.

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My Arch Enemy

Apr 08 2014 Published by under [Medicine&Pharma]

Oklahoma is recovering from an outbreak of Escherichia coli which has kept me away from the blog recently.

E. coli, as we usually call it, lives all around and in us. A good chunk of that microbiome we keep hearing about includes this bacteria. Most strains happily thrive in our guts, living a perfectly benign coexistence with us. At times they may find their way into our urine or other problematic place, but they can usually be rapidly dispatched.

Some strains produce a toxin first noted in the bacteria Shigella, thus named Shiga Toxin. Autocorrect on my iPhone wants to change "shiga" to "shiva." This may not be an error. This toxin causes incredible inflammation within the bowel. When the gut gets inflamed, it lets water and other material flow on through, producing diarrhea. In this case, the inflammation is so intense that the gut bleeds. A bloody gut produces bloody diarrhea. Nausea, vomiting, and intense cramping complete the clinical picture. This is a case of the runs you will never forget.

Click to Enlarge

Click to Enlarge

In a small number of cases of hemorrhagic colitis, the toxin enters the blood stream and produces a systemic response called a thrombotic microangiopathy (TMA for short). In tiny blood vessels throughout the body (capillaries), the toxin damages the inside. Platelets (oblong lavender thingies in the diagram) activate on these areas of damage to begin repairs. These tiny clots get bigger over time and form a mesh or halt blood blow to an organ, impairing or shutting down its function.

Not all organs seem as prone to TMA damage. The kidneys seem to provide a playground for the toxin and platelets; kidney involvement ranges from the trivial to irreversible infarction or scarring of the kidneys. This is why we call this TMA hemolytic uremic syndrome (HUS), uremia being another term for kidney failure. Other organs can be involved, including the brain, pancreas, liver, and heart.

Obviously the kidney provides a major clotting magnet, or I would not be discussing this entity. We do not really know why one child gets colitis and develops HUS while another gets just a horrible case of diarrhea. Using antibiotics and anti-diarrheal drugs during the colitis can increase the risk of HUS, but they do not explain it all.

Since this syndrome was described in the 1950's mortality has fallen from ~50% to <5% just with supportive care. Mortality generally is confined to patients with significant central nervous system involvement. Apparent kidney recovery occurs in 95% of survivors, although most will develop other signs and symptoms of chronic kidney disease over the decades.

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Saturday Night #Thunder

Feb 24 2014 Published by under Uncategorized

Saturday evening I attended a very special event that I was banned from discussing until now.

In a children's hospital, you get used to celebrities doing things. Local personalities hand out goodies, making our patients and themselves a little happier in the process. Most of the time, they seem to target two patient groups. Premature babies get a lot of love, as do the kids with cancer. Other patients with chronic diseases receive less media attention. Kids with cancer might DIE! Children on dialysis will get transplants and be cured, right?

Not always. And a kidney transplant is hardly a cure, given life-long risks of immunosuppression.

I was delighted a few weeks back to hear that a local star wanted to do a party with our dialysis kids. Not only were they (finally) getting some special attention, but the celebrity would be my favorite OKC Thunder player, Serge Ibaka. My excitement was tempered by the fact that at first we nephrologists were not invited to the party.

Click to enlarge

Click to enlarge

I pouted a bit, but accepted my missed opportunity.

A few days later, I got the call that I could come. None of my family could come with me, but I was welcome to watch my patients interact and have some fun. I also was not to bring a phone or camera, although being on call meant I had to bring the phone. This loophole allowed me to take my completely unofficial illicit photo of the shot blocker at right. That's just the kind of rebel I am, folks.

The event took place in the hospital play zone. Each patient and their immediate family spent about 15 minutes alone with Serge (I shook his hand, I can call him that now, right?) and the kids got personalized Thunder jerseys, autographed in most cases. Then we all came together and he answered questions from the patients. After a group photo, he then shot baskets against the kids on an arcade basketball game (one girl even beat him; she is still glowing). Afterwards, he even posed for selfies with some of the teens. I have never seen such big smiles on the faces of these children; dialysis appointments rarely make you happy.

Things I learned or confirmed?

  1. Standing next to a 6'10" guy makes me feel even smaller than usual.
  2. During the games, Serge looks fierce, like he would not mind breaking your nose. In real life he is charming and quite attractive (and roughly the same age as my children; I have already heard all the Mrs. Robinson jokes this weekend, thanks).
  3. He speaks 5 languages, including his Congo tribal tongue, French, Spanish, Catalan, and English. Many of our patients and families have Spanish as their first language, so this was another delight.

Saturday's event left me with such a happy feeling. I am hoping others will take on the fight for kids with less publicly emphasized disorders, including the drive to raise money for research and treatment. All children deserve to have their health struggles acknowledged.

Thanks, Serge. Now go block some shots.

 

 

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