Chapter Four: The Loop of Henle and Counter Current Exchange

Chapter Four: The Loop of Henle and Counter Current Exchange. Don’t worry, everyone (that means Bud Rose and Homer Smith) thinks this stuff is hard.

References for Chapter 4:

Homer Smith From fish to philosopher (1959 edition) This classic text from Homer Smith considers the evolution of mammalian kidneys but also considers the role of the kidney in the evolution of man and the ability to move out of the oceans but still maintain our internal milieu. 

Homer Smith. The fate of sodium and water in the renal tubules. The Sixth Harlow Brooks Memorial Lecture Bull NY Acad Med 1959 35(5). 293-316/ The fate of sodium and water in the renal tubules

Homer Smith gave this lecture in 1959 and outlined some of the conundrums encountered in understanding tubular function. Along the way there are a few jokes about “renologists,” his classic “rectilinear nephron,” (drawing the nephron as a straight line rather than the usual 2D architecture  drawn to show the depths of the loop compared to segments in the cortex) and more.

Comparing ammonia to ammonium chemically: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023229/ 

Three papers on uromodulin suggest that uromodulin may play a role in calcium handling in the kidney:

  1. Uromodulin Upregulates TRPV5 by Impairing Caveolin-Mediated Endocytosis

  2. The excretion of uromodulin is modulated by the calcium-sensing receptor

  3. The Urinary Excretion of Uromodulin is Regulated by the Potassium Channel ROMK

The history of loop diuretics can be found at this website:  History of Nephrology 

Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients A classic paper that suggests furosemide action requires sufficient albumin for this normally protein-bound agent to be secreted into the filtrate and then act on the luminal surface of the cells of the thick ascending limb. 

This classic paper suggests that the mechanism of diuretic resistance in nephrotic syndrome is not related to protein binding of furosemide to albumin https://jasn.asnjournals.org/content/jnephrol/11/6/1100.full.pdf?with-ds=yes

 A recent excellent review on diuretic resistance Clinical Pharmacology in Diuretic Use | American Society of Nephrology

Sickle Cell Trait (SCT) References

  1. 1970 case series proposing SCT involved in military recruit death during basic training at Ft. Bliss. https://pubmed.ncbi.nlm.nih.gov/5410817/

  2. 1988 study discounting the case series (ie no medical abnormality in recruits with SCT during basic training at Ft. Bliss), but regardless, Ft. Bliss no longer supports military basic training: https://pubmed.ncbi.nlm.nih.gov/3365081/

  3. Review of renal medullary carcinoma and its association with SCT: https://pubmed.ncbi.nlm.nih.gov/26053587/

  4. Largest cohort study looking at SCT and odds ratio of CKD and ESRD, published in JAMA 2014: https://pubmed.ncbi.nlm.nih.gov/25393378/

  5. Relative degree of eGFR decline for “reference CKD,” SCT, and sickle cell disease patients published in JASN 2020: https://jasn.asnjournals.org/content/31/2/393

  6. These two studies look at the prevalence of SCT in african americans on dialysis compared to african americans not on dialysis

    1. Sickle Cell Trait and the Risk of ESRD in Blacks https://pubmed.ncbi.nlm.nih.gov/28280138/

    2. High prevalence of sickle cell trait in African Americans with ESRD https://pubmed.ncbi.nlm.nih.gov/20056747/

  7. This one last review highlights what we still don’t know about sickle trait and sickle disease such as clinical findings (ie rhabdomyolysis) and outcomes (ie risk of CKD/ESRD, transplant implications, etc): https://pubmed.ncbi.nlm.nih.gov/26637716/ 

We didn’t refer to these papers directly but they might be of interest:

  1. This is an excellent review by Karl Nath in Nature Reviews Nephrology Sickle cell disease: renal manifestations and mechanisms

  2. Here’s a review of concentration mechanisms by Jeff Sands and Harold Layton  The Physiology of Urinary Concentration: an Update

  3. This is a superb and concise review of the calcium-alkali syndrome that reviews the effects of hypercalcemia on both the thick ascending limb cells and the principal cells. Got Calcium? Welcome to the Calcium-Alkali Syndrome | American Society of Nephrology

  4. Here’s a review that extolls the virtues of the Tamm-Horsfall protein Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

  5. Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity

  6. Benjamin Rush, MD: assassin or beloved healer?

Outline: Chapter 4

  • Loop of Henle and the countercurrent mechanism

    • 40-45% of the filtrate that is not reabsorbed in the PT enters the LOH

    • Four segments in LOH

      • Descending limb

      • Thin ascending

      • Medullary thick ascending

      • Cortical thick ascending

    • Ends at the macula densa

    • Reabsorbed 25-35% of filtered NaCl

    • Reabsorbed NaCl in excess of water, essential for dilution and concentration of urine

      • First diluting segment of the nephron

  • Cell Model for Na Cl transport

    • Active transport driven by NaK ATPase

    • Sodium enters the thick limb via the NaK2Cl transporter

      • High affinity for Na and K, maintains maximal activity even with sodium levels as low as 5-10 mEq/L. Same with Potassium

        • Chloride delivery is rate limiting

        • NaCl resorption goes up as chloride delivery is increased

        • Figure 4-3 does a nice job of illustrating this

        • K is not limiting because it is recycled back into the tubular lumen

          • That channel is antagonized by ATP

          • So as Na-K-ATPase increases activity (and increases intracellular K and depletes ATP, the channel opens up further)

        • The back leak of potassium makes the tubule positive driving paracellular reabsorption of Mg, Na, Ca

    • Sodium also enters with Na-H exchanger

      • Takes over reabsorbing bicarb where the proximal tubule failed

      • Stimulated by acidemia

      • Suppressed by alkalemia

  • NH4+ can be reabsorbed by the NaK2Cl channel by substituting for K

  • Calcium reabsorption in the TAL is paracellular down charge gradient

    • CaSR blocks K channel

    • Mediated by arachidonic acid metabolite

    • This blocks the whole NKCC, disrupting lumen + charge

    • PTH acts in the cortical thick segment increasing calcium reabsorption via adenylate cyclase

  • Passive Na reabsorption

    • For every 2 Cl reabsorbed, one Na is actively reabsorbed and one is passively reabsorbed paracellular route and the other actively reabsorbed by the NaK ATPase

  • Concentration and flow dependence of loop reabsorption 

    • Proximal tubule resorption is limited by solutes for sodium to partner with for resorption

      • Glucose

      • Amino acids

      • Phosphate

    • In LOH it is solute concentration of chloride that is the limiter

      • Resorption happens until tubular chloride gets to 50-75 mEq/L, then back leak for the peritubular capillaries matches resorption.

      • ADH stimulates NaCl resorption in medullary thick limb

    • Transport in the cortical thick limb

      • Nephrons with long loops originate from the deep cortex so they have a very short cortical thick loop, but but have longer thick cortical segments

      • These contribute most of the Mg resorption (paracellular)

  • The Countercurrent Mechanism

    • The formation of both concentrated and dilute urine is dependent on the counter current system of the loop

    • The excretion of concentrated urine has two essential steps

      • Creation of a concentrated medullary interstitium by resorption of NaCl without water in the medullary ascending limb.

        • Gets an assist from urea reabsorption in the medullary collecting tubule

      • Water permeable collecting tubules allow the urine to osmotically equilibrate

        • Critical role of ADH here

    • There are two additional steps that allow for the maintenance of medullary hyperosmolality

      • ADH dependent water resorption in the cortical collecting tubule

      • Medullary blood flow in the vasa recta is arraigned in a hairpin configuration to minimize loss of solute.

    • The formation of dilute urine is also achieved by this system

      • NaCl reabsorption without water dilutes the tubular fluid

      • If the absence of ADH this dilute fluid becomes dilute urine

  • Countercurrent multiplication

    • Maximum urine concentration is 900 to 1400

    • The only active step in the generation of the medullary interstitium is the NaKATPase of the thick ascending limb. Otherwise it is all passive.

    • “The exact mechanism of countercurrent multiplication is incompletely understood” (3 refs)

    • Really restricted to the 30-40% of nephrons with long loops

    • The transtubular gradient can be relatively small (Rose uses 200 as an example) but over the length of the tubule that can cause a dramatic range of osmolality

    • ADH allows concentration of urine by increasing permeability in the collecting tubule

      • In the cortical collecting tubule the dilute tubular fluid equilibrates with total body water 50 to 285 removal of 5/6ths of the volume

      • In the medullary collecting tubule it equilibrates with the med int.