Is Thiside Diaretic a Good First Line Agent?

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! 

Yanomami

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

Bradykinen Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting duct

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