Diff'rent Looks

May 15 2012 Published by under Kidney Function

The first time I thought about pediatric kidney disease occurred my senior year of high school. That fall Diff'rent Strokes debuted, introducing Gary Coleman as Arnold Jackson, a precocious, wise-cracking 7-year-old from Harlem.

Pediatric kidney disease, 1978

Arnold sometimes seemed wise beyond his years. Of course, he was being played by 10-year-old Gary Coleman who looked far younger than his chronological age. Thanks to focal segmental glomerulosclerosis (FSGS), a particularly nasty form of childhood nephrotic syndrome, and attempts to treat it, Gary's growth was stunted. His adult height measured 4 feet 7 inches, so he could play much younger characters...up to a point. He received two kidney transplants, both of which failed due to recurrent kidney disease.

The entire child cast of the show subsequently led troubled lives. Gary Coleman died in 2010 of a brain hemorrhage.

This week the face of pediatric kidney failure changed when Sarah Hyland, the older sister on Modern Family, revealed that she has lived with chronic kidney disease her entire 20 years of life. She recently received a kidney transplant from her father during the show's summer filming hiatus. 

Pediatric kidney disease, 2012

Lucky for Sarah, she had a much different condition called dysplasia. During development, her kidneys failed to form enough normal tissue to support her throughout her life. Doctors diagnosed her slowly-progressive condition at 9 years of age. She never received the high-dose steroids that gave Gary Coleman his round face. She benefited from decades of research that dramatically improved the ways we manage the growth failure and bone disorders that can accompany all kidney diseases. She will likely have excellent function from her father's kidney for many years without the appearance-altering side effects of earlier anti-rejection drugs.

We have made a lot of progress, but we need to make more. FSGS has some new treatments, but many patients still fail to respond and develop permanent kidney failure. FSGS still recurs in the transplant, killing the new kidney as it did the native ones. Dysplasia does not develop in the transplant, but other conditions may shorten the life of the replacement kidney. The side effects of anti-rejection drugs may be less visible, but their risks of infection, diabetes, and cancer still raise problems. We still have a lot of research to do.

But in my lifetime, look at the progress we have made!

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Career Choices

May 01 2012 Published by under [Education&Careers]

It distresses me that few students and trainees wish to follow in my footsteps. I remember hoping that I would be good enough to get a position in an academic medical center when I rounded as a student. The doctors who trained us had the best job on earth, not only seeing interesting patients but also passing on their knowledge at many levels. Sure, you would make more money in most private practice settings, but I felt the intellectual stimulation and collegiality of The Ivory Tower made up for that little deficit.

Today's students, carrying 3 to 4 times my debt, often make different choices.

I remember falling in love with nephrology. Having done carcinogenesis research I thought hematology-oncology would be my path. My rotation on adult nephrology as a student was memorable mostly for its tedium. Our work focused on two things: general internal medicine problems in patients who happened to be on chronic dialysis and intensive care patients with kidney failure who died after a variable amount of time. Only during my pediatrics training did I discover the truly fun side of nephrology, in particular the puzzle of fluid and electrolyte disorders.

My nephrology fellowship finished almost 21 years ago. Very few students or residents want to follow these footsteps either.

Of course, even adult nephrology has trouble attracting students and residents, despite a growing population of permanent kidney failure patients needing care.

The American Society of Nephrology hopes to fix this problem. The video below addresses its new program "INTEREST in Nephrology Careers."

Please comment if you have any suggestions or answers. Pediatric Nephrology has been a great ride for me so far, and I'm still hanging tight to the reigns.

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#EB2012: Renal Section Honors

Apr 24 2012 Published by under EB2012 Meeting, [Biology&Environment]

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Di Feng makes an award-winning presentation

Every year the Renal Section of the American Physiological Society grants awards to undergraduate and post-doctoral trainees for work they submit and present at the meeting. A committee selects 5 finalists based on the abstract submitted, and their presentations are judged during the Posters and Professors Session that was held on Sunday, April 22.

Undergraduate Finalists

  • Justine Abais, Virginia Commonwealth University
  • Di Feng, Medical College of Wisconsin
  • Teresa Kennedy-Lydon, Roya Veterinary College
  • Jacob Richards, University of Floriday
  • Ryan Cornelius, University of Nebraska

The award went to Di Feng for her work :

Genetic regulation and functional relevance of the p67phox gene in salt-sensitive hypertension
Di Feng1, Chun Yang1, Jozef Lazar2, David Mattson1, Paul O'Connor1, Allen W. Cowley, Jr. 1,3. 1Physiology Department, 2Human and Molecular Genetics Center, 3Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI

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Feng receives her plaque while Jacob Richards looks on

A narrow region on rat Chr 13 was identified to harbor salt- sensitive genes. p67phox, a cytosolic subunit of NAD(P)H oxidase, is located in this region. We have previously found that on a high salt diet, the renal outer medulla (OM) of Dahl salt-sensitive (SS) rats exhibited higher levels of p67phox expression and NAD(P)H oxidase activity than salt-resistant congenic rats that contain the p67phox allele from the salt-resistant Brown Norway rat. We generated the first p67phox null mutant (p67phox-/-) SS rat in which we observed significantly reduced salt-sensitive hypertension. In our present study, we sequenced a 1650 bp promoter region and found that the SS allele of p67phox had a 204 bp deletion and four SNPs compared to the BN allele. The activity of the SS p67phox promoter was 1.7 fold higher than that of the BN p67phox promoter. We further characterized p67phox-/- rats and showed that they had a 40% reduction in OM H2O2 levels measured from interstitial fluid collected by microdialysis. Respiratory burst responses of peritoneal macrophages to phorbol 12-myristate 13-acetate were abolished in p67phox-/- rats. p67phox-/- rats also showed reduced renal injury, including reduced OM fibrosis, infiltrated T cells and macrophages, and glomerulosclerosis. These data provide new insights into the genetic regulation and functional relevance of p67phox in salt-sensitive hypertension. (HL-82798; HL-29587)

Postdoctoral finalists included:

  •  Krishna Boini, Virginia Commonwealth University
  • Richard Grimm, University of Mryland
  • Elena Mironova, University of Texas-San Antonio
  • Ann Riquier-Brison, University of Southern California
  • Ankita Roy, University of Pittsburgh
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Dr. Grimm gives me a guided tour of his work

Richard Grimm took home the award for this submission:

SPAK, OSR1 and Cab39/MO25 form an Interdependent Signaling system which Regulates Thiazide-Sensitive Salt- transport, Distal Tubule Mass and Blood Pressure
P Richard Grimm1, Tarvinder Taneja1, Jie Liu1, Richard Coleman1, Yang-Yi Chen1, Eric Delpire2, James B Wade1, Paul A Welling1. 1Physiology, University of Maryland School of Medicine, Baltimore, MD, 2Anesthesiology, Vanderbilt School of Medicine, Nashville, TN

STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) and, Oxidative Stress Related Kinase (OSR1), co-localize at the apical membrane of the Thick ascending Limb (TAL) and Distal Convoluted Tubule (DCT) and both regulate the potassium- dependent sodium-chloride co-transporter, NKCC2, thiazide- sensitive sodium-chloride cotransporter, NCC in vitro. Yet genetic ablation of SPAK in mice causes a salt-wasting nephropathy that is restricted to the DCT, reminiscent of Gitelman’s syndrome. Here, we explore why proper DCT function is especially SPAK- dependent. In the TAL of SPAK-/- mice, OSR1 and Cab39/MO25, a newly described OSR1/SPAK regulatory protein, remain at the apical membrane where they function with a compensatory increase in the AMP-activated kinase (AMPK) to hyper- phosphorylate NKCC2. By contrast, the OSR1/SPAK/M025 signal transduction apparatus is completely disrupted in the DCT. OSR1 and MO25 become largely displaced from the thiazide-sensitive sodium-chloride cotransporter, NCC, and the apical membrane. OSR1 redistributes to dense punctate structures within the cytoplasm. These changes are paralleled by a dramatic decrease in NCC abundance and phosphorylation. Without SPAK and the proper localization of OSR1 and MO25, phosphorylation- dependent regulation of NCC by dietary sodium restriction is lost. SPAK-/- mice also exhibit a decrease in the mass of the distal convoluted tubule, exclusive to DCT1. As a result of the interdependent nature of OSR1 and MO25 on SPAK in the DCT, SPAK-/- mice are highly sensitive to dietary salt-restriction, displaying prolonged negative sodium balance and hypotension.

Untitled

Dr. Grimm wins

 

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#EB2012: A Pendrin for Your Thoughts

Apr 23 2012 Published by under EB2012 Meeting, [Biology&Environment]

Pendrin, also known as SLC26A4, is a luminal anion transporter. Anions, molecules with a negative charge, include chloride, bicarbonate, iodide, and others. The family of similar transporters (see figure) have some functional overlap, although knock-out studies confirm some individual transport specificities.

A child that lacks pendrin has Pendred Syndrome. This usually occurs as a monogenic recessive disorder (both parents have a mutation in the pendrin gene) although a few families have a digenic inheritance where the mutation occurs in a gene that controls the creation or function of pendrin. The major manifestation of the syndrome is progressive hearing loss; this syndrome may produce as much as 10% of congenital familial deafness. The syndrome also causes enlargement of portions of the inner ear and an enlarged thyroid gland (or goiter). The function of the thyroid remains normal, but it accumulates material and grows.

After Richard J. H. Smith reviewed the features and genetics of the syndrome, Philene Wangemann showed the role of pendrin in ear development in mice.

Click to enlarge

Using conditional knock-outs of the gene, her group has established a critical 2-day period in gestation where lack of pendrin results in deafness. The mice also develop enlargement of the cochlea, just like humans. For her review on pendrin in ear development click here (PDF is free!).

So why does the thyroid enlarge in this syndrome? For those of you who are not endocrinologists (I may not be one, but I do sleep with one), thyroid hormone contains iodine.That's why a low iodine diet so profoundly affects growth and development (AKA cretinism). Since this family of transporters helps move iodine about, the thyroid can enlarge, even though its ability to make and release the hormone is intact. This topic was addressed by Peter Kopp.

Finally (saving the best for last?) Vladimir Pech reviewed the role of pendrin in blood pressure regulation. Pendrin resides in the type B intercalated cells of the cortical collecting duct where it exchanges chloride and bicarbonate between the lumen and the cell. Pendrin knock-out mice have normal blood pressures; however, during states where aldosterone would be activated (low sodium and low volume), pendrin mice are unable to conserve sodium as avidly as those with the transporter.

Huh? Most aldosterone-dependent sodium reabsorption occurs via the ENaC channel in the principal cell. How does a lack of pendrin tell another cell to behave differently? It does so by decreasing the activation of ENaC which requires a cleavage step to work. Perhaps this occurs via altered luminal pH or bicarbonate concentration, or some other signal that impairs the milieu for sodium channel activation. More to come; click here for a nice review (unfortunately not available freely online).

Ear and kidney abnormalities often occur together in children. Pendrin may provide one link to explain some of these issues.

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#EB2012 #Navar: Reflections on the Work of a Lifetime

Apr 23 2012 Published by under EB2012 Meeting, [Biology&Environment]

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Dr. Navar and his entourage, pre-lecture

The final official event of Saturday actually provided the official opening of the meeting for the American Physiological Society (APS). Current president Joey Granger walked us through 125 years of the APS, including the founding of the umbrella organization FASEB (Federation of American Societies for Experimental Biology) 100 years ago. He then introduced the speaker, Gabby Navar, who presented his lifetime of work in renal physiology and the role of the kidney in hypertension (click here for more background).

Science takes place in baby-steps. Even a paper in a glamour journal with years of data, like a toddler's first efforts, is just as likely to lead to falling back on a full diaper as a movement forward. Take enough of these steps, and you can eventually get somewhere. You may always risk a trip and a fall, but with time you move forward.

Dr. Navar's contributions to science brought to mind two major observations. First, hypertension is not a disease. A disease has a cause and an effect. While the effect may be a single physiological measurement such as blood pressure, its causes clearly involve multiple genes and environmental factors. We should think of it as a syndrome.

Syndrome generally means a cluster of symptoms; the origins of the word signify concurrence. For example, a microangiopathic hemolytic anemia with kidney damage leads to a diagnosis of hemolytic uremic syndrome. This syndrome may be the result of several known diseases as well as some not yet characterized. I propose that hypertension, while not a cluster of abnormalities, is a syndrome in  a similar sense. Multiple diseases, defined and not, can cause high blood pressure as their sole manifestation.

The other point I considered overnight was how essential animal research has been in our advances in hypertension. We simply would not be able to tease out the complex relationships between neural, renal, and other mechanisms in blood pressure control without the use of animals.

Congratulations to Gabby Navar for a great talk and a good start to a great meeting.

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#EB2012: Physiology in Perspective

Apr 21 2012 Published by under EB2012 Meeting

Dr. L. Gabriel Navar will deliver The Physiology in Perspective: The Walter B. Cannon Award Lectureship of the American Physiological Society (APS) on Saturday, April 21, at 5:45 pm in Ballroom 20A of the San Diego Convention Center.  If you tweet about the lecture, please use #Navar as your hashtag.

Cannon and the Lectureship

The Physiology in Perspective: The Walter B. Cannon Award Lectureship is awarded to an outstanding physiological scientist, domestic or foreign, who is an APS member. The recipient is selected by the President-Elect in recognition of his/her original and outstanding accomplishments in the field of physiology.  The recipient presents a lecture on "Physiology in Perspective" during the plenary session of the Experimental Biology meeting, addressing Cannon's concepts of "The Wisdom of the Body." The lecture is considered for publication in the Society journal of the recipient’s choosing.

Gabriel Navar

Dr. Navar

Dr. Navar completed his undergraduate studies at Texas A&M University and earned the PhD degree in 1966 from the University of Mississippi under the tutelage of Dr. Author C. Guyton. He then accepted an Instructor position at Mississippi, quickly rising through the ranks to the level of Associate Professor by 1971. He spent a year as a Visiting Scientist at Duke University, where he learned micropuncture under the guidance of Drs. Ike Robinson and Jim Clapp. In 1974, he accepted a position as Associate Professor (and was soon promoted to Professor) at the University of Alabama at Birmingham, where he was affiliated with both the Nephrology Research and Training Center and the Department of Physiology and Biophysics. He moved to Tulane University School of Medicine in 1988, where he is Professor and Chairman of the Department of Physiology.

Fueled by his PhD research on renal autoregulation, Dr. Navar’s long-term research efforts have significantly advanced our understanding of pressure-natriuresis, regulation of glomerular filtration dynamics in the dog, arterial pressure regulation, autoregulatory mechanisms, the tubuloglomerular feedback response, angiotensin II influences on renal hemodynamic and excretory function, and mechanisms of angiotensin II-dependent hypertension. He has published 180 peer-reviewed manuscripts and 123 book chapters and review articles. Dr. Navar has garnered numerous awards in recognition of his research accomplishments, including the Lifetime Achievement Award from the Consortium for Southeastern Hypertension Control, the American Society of Hypertension’s Richard Bright Award, and the Arthur C. Corcoran Award from the American Heart Association. In 1997, he was the Carl W. Gottschalk Distinguished Lecturer of the APS Renal Section, and he won the Berliner Award of the same section in 2007.

Dr. Navar’s research efforts have been inexorably linked to training young scientists. He excels in teaching at the advanced graduate student and postdoctoral levels, helping these individuals with complex concepts of renal physiology, as well as the design, execution, and interpretation of experimental studies. Indeed, Dr. Navar’s mentorship has contributed to the success of numerous individuals who have been named Established Investigators of the American Heart Association, who have had long-term National Institutes of Health grant support, and who are now producing another generation of students and fellows pursuing research in the field of renal physiology. In recognition of his mentoring efforts, he was named the 2005 recipient of the Bodil M. Schmidt-Nielsen Distinguished Mentor and Scientist Award of the APS.

In addition to his research and mentorship accomplishments, Dr. Navar is a tireless servant to the scientific community, having held leadership positions in the American Heart Association Council for High Blood Pressure Research, the American Society of Hypertension, the Association of Chairs of the Departments of Physiology, and others. His service and dedication to the APS include his election to the APS Council (1991–1994), his service as President of the Society (1998 –1999), and his most recent position as chair of the Long Range Planning Committee.

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Poison by Any Other Name

Apr 05 2012 Published by under [Medicine&Pharma]

Evil chemicals! Click for source

What image springs to mind when you see the word...

nicotine?

If you smoke, you may have a warm, fuzzy feeling, but for a lot of us, poison comes to mind. Nicotine makes tobacco products addictive, so it cannot be good. See the diagram at right; it's used as an insecticide! It kills bugs! It must be bad!

Of course, nicotine is merely a chemical. But chemicals are bad, right? Even a natural one that comes from a plant (like tobacco)? Even one with a short, pronounceable name?

So nicotine is bad...except when it isn't.

Renoprotective effects of long-term oral nicotine in a rat model of spontaneous proteinuria.
Agarwal et al. Am J Physiol Renal Physiol 302:F895, 2012
DOI:  10.1152/ajprenal.00507.2011

Nicotine has demonstrated beneficial effects in a number of inflammatory disorders, including inflammatory bowel disease, sepsis, and hypersensitivity pneumonitis. In animal models of ischemia-reperfusion kidney injury results are more variable, depending on the model and route of nicotine administration. It seems that macrophages (immune white blood cells) and capillaries in the kidney have alpha-7 nicotinic acetylcholine receptors which modulate these anti-inflammatory effects.

This study used a rat model of spontaneous proteinuria, Munich-Wistar-Fromter rats. As these rats age, they develop proteinuria. As protein is reabsorbed by the peritubular capillaries in the kidney, filtered agents such as cytokines and growth factors can promote inflammation and further kidney damage. At the time proteinuria begins in this model (24 weeks, a middle-aged rat), animals were begun on one of three doses of nicotine in drinking water along with an untreated control group. Saccharine in the water in all groups masked the taste of nicotine (yes, the control rats were drinking diet soda, circa 1970). Every 4 weeks they measured blood pressure, glomerular filtration rate, and proteinuria. They examined kidney structure in a number of ways after 28 weeks of study, when the rats reached one year of age.

Kidney function (upper panel) & proteinuria (lower panel)

The control rats showed the typical course for the MWF model, with glomerular filtration rates less than half of baseline after 28 weeks of study (see figure at left). This effect on clearance of waste products was blunted by nicotine ingestion. Protein excretion increased in all groups of rats, but, once again, nicotine treatment reduced the level of protein spill.

Nicotine treatment also reduced scarring in the glomeruli, the filtering units of the kidneys. Macrophages, those pesky blood cells that promote inflammation and scarring, were also reduced by nicotine treatment. Production of scar materials by the kidney was also reduced with the nicotine treatment.

So proteinuric patients should smoke? Or at least wear those patches?

Not exactly.

Smoking is a major risk factor for the development and progression of all sorts of kidney diseases. We ABSOLUTELY DO NOT WANT ANYONE SMOKING EVER FOR ANY REASON!

Like most molecules, nicotine has many faces. In this case, we examined its perky, anti-inflammatory side. Nicotine also has other effects that may not be desirable. Short-term ingestion raises blood pressure and heart rate via stimulation of the adrenergic system; these effects were not detected with long-term ingestion in this rat model. Nicotine also affects a number of systems that modulate blood flow (and can therefore affect function) of the kidney. Changes in these systems were not assessed in the present study.

Also, prior studies show that what happens in rats does not necessarily happen in mice when it comes to nicotine. Why? We really do not know. Do these species metabolize nicotine differently? Or is there some other reason for these differences? When it comes to nicotine, are people more like rats or mice or neither?

Nicotine has another danger: addiction. Can we come up with a modified nicotine (with a longer, scarier, more chemically name) that would provide anti-inflammatory effects without producing undesirable vascular or behavioral effects? Anything is possible, but this molecule is still in the future.

The bottom line: nicotine from a natural, plant-based source like tobacco can be a killer. Pure nicotine from the lab may be a healer. Only time and more experiments will tell.

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I Beg to Differ: Diabetes in the US

Mar 20 2012 Published by under [Medicine&Pharma]

Ronald Ricker posted today about upcoming physician shortages and our failure to deal with them. In his writing he considers a number of improvements in health that have increased our lifespans substantially over the past 150 years. His key message, that we are not training enough physicians, is good. I disagree strongly with one of his assertions:

The discovery of insulin by Banting, Best, et. al. largely wiped out the scourge of diabetes.

Before Banting's work, what we now call type 1 diabetes mellitus produced a rapid death by starvation. Some patients could hang on for months on a diet of fat and protein, but without insulin replacement the Reaper came knocking before too long. Insulin allowed these patients to metabolize carbohydrates and survive. In 1921, it seemed the scourge of type 1 diabetes had been wiped out.

Of course, most patients with diabetes mellitus have always had the less dramatic, insidious type 2. This form usually occurs in older individuals, often in association with obesity and insulin resistance. Kimmelstiel and Wilson published the first description of the pathology of diabetic kidney disease in 1936 (PDF here). The discovery of insulin allowed those with type 1 diabetes to live long enough to develop this condition, as well as other complications of the hyperglycemic state. Today, despite improvements in glycemic control, approximately 40% of patients with diabetes of any type will develop kidney complications. Diabetes has become the leading cause of permanent kidney failure in the US, producing 154 new cases per million population per year. Nearly 1,800 people out of every million in the US have permanent kidney failure; of these, over 1/3 suffered this fate from diabetes (see figure from US Renal Data Service).

From USRDS

Insulin seemed miraculous to the children and young adults who developed type 1 disease; however, its discovery did not cure this condition, nor did it "wipe out the scourge." Instead an acute fatal illness became a chronic disease, much like the type 2 form. We ended up with more people living with diabetes.

We still need more research on diabetes and its complications. Better metabolic control, via an artificial pancreas or islet transplants, could potentially cure type 1 diabetes. Type 2 disease, where the initial issue is usually insulin resistance, will not be cured through these endeavors. We need to understand more about how the complications of diabetes, including kidney failure, blindness, nerve damage, gastrointestinal dysfunction, and cardiovascular disease, develop and progress. Why do only 40% of patients get kidney damage from diabetes? What makes one person vulnerable while another patient remains protected?

It has been more than 3 decades since microalbuminuria, the first clinical marker of diabetic kidney disease was reported. Over that time, we have discovered important flaws in its specificity and sensitivity - so we really don't have a marker of early kidney disease! We have not developed an effective new treatment in more than 20 years. I would say we are overdue.

Recent reports in the Journal of the American Society of Nephrology suggest that circulating receptors for TNF alpha may provide a more useful biomarker of risk. It would be a big step forward for research (and patient care in the future), but it is not enough. Unfortunately, recent hits to the NIH budget mean fewer physicians and scientists will be studying these diseases (and a multitude of others).

In short, insulin saved lives, but the scourge of diabetes is still going strong.

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Happy World Kidney Day!

Mar 08 2012 Published by under [Medicine&Pharma]

What a gift!

Today is World Kidney Day, a time to remember that it is great to urinate! This year's official theme focuses on kidney donation.

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Shhh! I Hear a Paradigm Shifting!

Feb 14 2012 Published by under Acid-Base Disorders, Journal Club, [Medicine&Pharma]

The February issue of the Journal of the American Society of Nephrology includes a science in renal medicine article that caught my eye:

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis. Luke and Galla. J Am Soc Nephrol 23:204-207, 2012. doi:   10.1681/ASN.2011070720

If I ever teach metabolic alkalosis again, I have to revise my lecture!

Ever since loop diuretics became available in the 1960s, they have been a recognized cause of metabolic alkalosis. These drugs cause the kidney to excrete excess volume (Na + Cl + water), which is very useful if you have swelling from heart failure or liver disease or kidney problems. If the volume loss goes too far, the patient could develop alkalosis (too little acid/too much base in the blood). The major base in the blood is bicarbonate (HCO3-). Our "old-school" explanation of the pathophysiology follows. Volume depletion turns on aldosterone which controls a number of transporters in the distal nephron. The net effect of these transporters is retention of Na+ with concurrent excretion of K+ or H+. The latter would help perpetuate the alkalosis, because excreted H+ (acid) does not consume any of the blood's buffering bicarbonate. Restoring the patient's volume turns off aldosterone and allows the alkalosis to resolve.

How simple! How elegant! How wrong!!!!!

A number of human and animal studies are reviewed in the article. The alkalosis formerly known as contraction can be induced with diuretics plus dietary maneuvers. If volume is expanded without chloride, using albumin or other solutes, the alkalosis remains. If chloride is replenished without volume repletion, the alkalosis resolves (even though the subject remains volume depleted).  Thus, this form of alkalosis is better described as chloride dependent (CDA).

Click for original source

The figure from the paper summarizes the new explanation. First note that unlike most tubular cartoons, the peritubular capillary is central in this one. Either side of the cells is a urinary space. The cortical collecting duct contains 3 cell types. Principal cells (middle of cellular column) reabsorb Na+ and excrete K+ to maintain electroneutrality in the luminal fluid. A-type intercalated cells (Acid secreting; top of cellular column) can transport H+ into the lumen. This activity during alkalosis with volume contraction may be driven against the H+ concentration gradient because of Na+ absorption by the principal cell, as in the old-school explanation above. Of more importance to the alkalosis, B-type intercalated cells (bicarbonate secreting; bottom of cellular column) express pendrin (Pn) on their luminal membranes. This protein transports bicarbonate into the luminal fluid while reabsorbing Cl-.

In states of chloride depletion (left side of cartoon), Cl- is not available to exchange with bicarbonate, so the latter cannot be excreted. After Cl- repletion (right side) this exchange can occur. Bicarbonate can be excreted to correct the alkalosis, without any alteration in the functions of the aldosterone-dependent transporters in the other cells.

Medical students have always been frustrated that we classify volume status by urine Na during "pure" volume depletion, but with urine Cl during metabolic alkalosis. Various explanations have been offered along the way, the most reasonable being that in periods of excess bicarbonate filtration (like alkalosis) a cation has to accompany it in the urine. Thus, urine Na may be falsely elevated in this setting. Turns out, the urine chloride concentration really is the critical component.

Will any clinical changes result from this new nomenclature? For the most part, no - when patients lose chloride and become alkalotic, they generally suffer volume depletion. We treat this with Na + Cl + water, repleting volume and chloride together.  The paper summarizes a number of relatively recent studies and provides a great illustration of the shifting nature of established physiology.

There is always something new to discover.

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