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Chapter Five: Functions of the Distal Nephron
Sep 5, 2021
01:35:02
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Quick takeaways
- The distal nephron plays a crucial role in regulating urinary sodium levels, as seen in the Yanomamo tribe with low sodium excretion.
- Understanding the tight junctions in the TOAD bladder is essential for grasping renal physiology complexities.
- Gordon's syndrome and Gitelman syndrome provide insights into genetic disorders affecting sodium reabsorption and electrolyte imbalances.
- Thiazide diuretics exhibit clinical versatility despite side effects, offering valuable treatment options for stone disease, diuretic resistance, and hypertension.
Deep dives
Fascinating Insights into Renal Physiology and Distal Nephron Function
Exploring the complexity and logical system of renal physiology governing bodily fluid balance. The two-year mission detailed in the podcast sheds light on understanding the kidney's vital role in maintaining homeostasis. Chapter five delves into the intricacies of the distal nephron, focusing on tasks like urine acidification, concentration, and sodium regulation, attributing key functions and disorders to this segment.
Segmentation of the Distal Nephron and Insights on Cell Diversity
The breakdown of the distal nephron into four segments - distal tubule, connecting segment, cortical collecting tubule, and medullary collecting tube, challenges conventional teaching terminology. Discussions on cell types within these segments reveal a growing understanding via physiological-based approaches and advanced data techniques uncovering previously unknown cell variations.
Final Qualitative Changes in Urine Retention and Sodium Conservation
Identifying the distal nephron as the site for crucial changes in urine retention, with four primary purposes highlighted - urinary concentration, acidification, potassium secretion, and sodium conservation. Emphasis on sodium conservation where the kidney efficiently maintains sodium levels despite significant concentration changes.
Insights on Genetic Disorders and Thiazide Diuretic Effectiveness
Exploring the impact of Gordon and Gitelman syndromes as inherited genetic disorders affecting sodium reabsorption and illustrating contrasting hypercalciuria, hyperglycemia, and hypocalcemia. Delving into thiazide diuretics, acknowledging their effectiveness across multiple conditions despite concerns like hypokalemia, hyperuricemia, and other side effects.
Detailed Examination of Thiazide Diuretics and Clinical Applications
Dive into thiazide diuretics reveals their intricate mechanisms and clinical versatility. While often underestimated due to their side effects, thiazides remain valuable for conditions like stone disease, diuretic resistance, and hypertension. Understanding their prolonged effect, volume-responsive nature, and diuretic benefits offers a comprehensive perspective on their optimal use.
Mechanism of Thiazides and Loop Diuretics
Thiazides and loop diuretics play a crucial role in treating various conditions by altering urate levels in the body. Thiazides, accompanied by loop diuretics, can lead to hyperuricemia due to competition for urate secretion and volume depletion, emphasizing the complex interplay between these diuretics and conditions like gout. Contrary to common belief, loop diuretics can induce gout flares as well, showcasing the importance of understanding the mechanisms behind diuretic-induced hyperuricemia.
Role of Diuretics in Calcium and Magnesium Balance
Diuretics also impact calcium and magnesium balance in the body. Understanding the intricate interactions between these electrolytes is essential for managing conditions such as hypercalcemia and hypomagnesemia. The podcast delves into the physiological mechanisms of diuretic-induced electrolyte imbalances, shedding light on the significance of potassium reabsorption, chloride reabsorption, and hydrogen secretion in maintaining overall mineral balance.
Physiology of Sodium Reabsorption and Acid-Base Regulation
The podcast explores the sodium reabsorption process in the cortical and medullary collecting ducts, highlighting the unique functions of principal and intercalated cells in regulating electrolyte balance. Additionally, it discusses the sodium-independent regulation of acid-base balance, emphasizing the role of hydrogen ATPase pumps and chloride-bicarbonate exchange in acidifying urine. Understanding these intricate processes is crucial for comprehending the kidney's vital role in maintaining homeostasis.
21.
The Dist Cavalu Tubule Tubue Is the Site in the Kidney Where Calcium Resorption Is Increased
2min
References for Chapter 5--the Distal Nephron
Roger pointed out the fact that the distal nephron can achieve very low urinary sodium as evidenced by observations in people from the Yanomamo tribe Blood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population in this report, 84% of the participants had urinary sodium < 1mmol/24 hours.
Information about the Yanomamo Tribe. It looks like they’re starting to make chocolate, now!
The Yanomami are great observers of nature
The Amazon's Yanomami utterly abandoned by Brazilian authorities: Report
Yanomami Amazon reserve invaded by 20,000 miners; Bolsonaro fails to act
I believe this is the original study looking at urine sodium and blood pressure in the Yanomamo Indians, but the INTERSALT trial linked above I believe had more robust urine data
This study mentions the average lipid profile for men and women along with BMI.
I didn’t mention in the “Voice of God” overview, but there is some interest looking at the Yanomamo and rate of cancer as it relates to the correlation with intracellular potassium to sodium ratios
Josh referred back to his notes and realized that the tightest junctions are in the TOAD not FROG bladders Physiology and Function of the Tight Junction
An excellent review from McCormick and Ellison on the Distal convoluted tubule in Comprehensive Physiology.
We flirt with the disorder of Gordon’s syndrome: Familial Hyperkalemic Hypertension | American Society of Nephrology and its alter ego, Gitelman syndrome: Gitelman Syndrome | Hypertension
JC spoke about this beautiful report on how calcineurin inhibitors lead to hyperkalemia (and mimic Gordon’s syndrome). The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension
This superb review of the DCT includes all the highlights of Rose’s chapter 5 with a modern lens including “braking” from DCT hypertrophy Distal Convoluted Tubule | American Society of Nephrology
Echos of the lessons learned in the DCT can be seen in this review: Diuretic Treatment in Heart Failure | NEJM
Anna reminds us of the ALL HAT trial which showed that chlorthalidone was superior to the lisinopril and amlodipine groups (and the alpha blocker dropped out earlier) Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic
Nice review of drug induced Hyperuricemia with a deep dive into the mechanisms of diuretic induced Hyperuricemia. Drug-induced hyperuricaemia and gout
Plus, despite the concerns that thiazides are weaker than loop diuretics and may not work in CKD, this report suggests that it can still be of use. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study
If you love diuretics, you will love this classic paper from Craig Brater on diuretics Diuretic Therapy | NEJM which also includes the t1/2 of various diuretics and points out that chlorthalidone’s half life is 24-55 hours so eliminated after 4-10 days.
The hypercalcemia seen in some patients who take thiazides may be the unmasking of primary hyperparathyroidism Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades
As we discussed the relative importance of DCT vs Proximal tubule for the hypercalcemia seen with thiazides, Amy reminded us of about the TRPV5 knockout mice: JCI - Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5
JC mentioned the defect in TRPM6 that can cause severe hypomagnesemia: Novel TRPM6 Mutations in 21 Families with Primary Hypomagnesemia and Secondary Hypocalcemia
We enjoyed talking about Liddle syndrome Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome
We wondered about the role of pendrin which was discovered after this book was published. Here’s a nice review: The role of pendrin in renal physiology and also a potential therapeutic target for pendrin: Pendrin—A New Target for Diuretic Therapy? | American Society of Nephrology
More Bradykinen Chronic Overexpression of Bradykinin in Kidney Causes Polyuria and Cardiac Hypertrophy
We ended on a high note when we considered the urothelium of the American black bear. These magnificent creatures have aquaporins 1 &3 that allow them to reabsorb their own urine during hibernation. The urothelium of a hibernator: the American black bear
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