Chapter Six part 2: The exciting conclusion to the Effects of Hormones on Renal Function
Chapter Six: Effects of Hormones on Renal Function (ANP, other NPs, PTH, Vitamin Ds, Epo)
Please welcome new Channel illustrator, Priti Meena.
References
Josh touts the PARADIGM-HF Trial Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure | NEJM which found this combination was superior to an ARB alone
Joel mentions an early atrial natriuretic peptide trial by Julie Lewis et al. Atrial natriuretic factor in oliguric acute renal failure - American Journal of Kidney Diseases and here’s a metanalysis that put this option to bed: Atrial Natriuretic Peptide for Management of Acute Kidney Injury: A Systematic Review and Meta-analysis
Snack attack? Check out “Snack induced ANP” Snack-Induced Release of Atrial Natriuretic Factor | NEJM
Want more natriuretic peptides than we discussed? Check out this review! Cardiac natriuretic peptides | Nature Reviews Cardiology or this fantastic review: Here’s an excellent review of ANP effect on the kidney: ANP-induced signaling cascade and its implications in renal pathophysiology
Joel mentions the study which probed CRIC cohort regarding NSAIDs. Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study - American Journal of Kidney Diseases and you may like the discussion on NephJC: No Pain for the Kidneys from NSAIDs — NephJC
The KDIGO guidelines can be found here CKD-Mineral and Bone Disorder (CKD-MBD) – KDIGO
Elegant work on the calcium sensing receptor by Martin Pollak https://doi.org/10.1016/0092-8674(93)90617-Ye
Claudin 14, PTH, and calcium absorption in the loop of Henle: Parathyroid hormone controls paracellular Ca 2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14
Carboxymaltose induced hypophosphatemia by increasing FGF-23. Randomized trial of intravenous iron-induced hypophosphatemia
The Dialysis Encephalopathy Syndrome — Possible Aluminum Intoxication | NEJM
NephMadness covered Aluminum binders in 2016.
Roger mentioned the use of ferric citrate as a phosphate binder Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis | American Society of Nephrology
Joel reminded us of the misadventures in efforts to normalize hemoglobin, first in hemodialysis patients The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin | NEJM
Later, in patients with CKD, normalization was also not shown to be better: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease | NEJM , Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia | NEJM
A quick shout out for roxadustat and the Nephmadness Anemia region! Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis | NEJM, #NephMadness 2021: Anemia Region – AJKD Blog
Outline
- ANP
- Natures is after a sodium load is mediated at least partly by ANP
- Cross circulation experiments show humoral cause of natriuresis
- Released from myocardial cells in atria
- 28 amino acid peptide
- Actions
- Direct vasodilator
- Increases water and sodium excretion
- May diminish sodium resorption in proximal tubule
- May increase local dopamine
- Or increase peritubular capillary hydraulic pressure
- Rise in GFR without change in RBF
- So afferent vasodilation
- And efferent vasoconstriction
- Control
- Stretch receptors in the atria stimulate release
- Right > left
- Physiologic role is uncertain
- Infusion studies produce only modest diuresis
- Transgenic mice with 10x the ANP are in Na balance though lower BP
- CHF has high ANP and is sodium avid
- “The physiologic importance of most hormones has been demonstrated in part by the removal of their site of production; unfortunately, the cardiac source of ANP limits the feasibility of this approach.”
- AB to ANP and vaccines against ANP do reduce urine Na, and response to volume expansion
- ANP Mimics
- Urodilatin
- Produced in the kidney, found in the urine
- Not metabolized by endopeptidases
- Changes in urinary sodium track urodilatin better than ANP
- BNP
- Comes from the brain and the ventricals
- Unclear role
- Could it be the cause of CSW? NO
- C-type NP
- From the kidney
- Unclear significance
- Prostglandins
- Produced from metabolism of arachadonic acid
- Production
- Glomerular endothelium
- Vascular endothelium
- Medullary collecting duct
- Cortical collecting duct
- Rapidly metabolized so little systemic effect. It’s all local
- Two important prostaglandins
- PGE2
- Prostacyclin
- Actions
- Vasodilator
- Primarily in situations of vasoconstriction due to Ang2 and nerepi, vasopressin, and endothelin
- Can raise BP in 3-5 points
- Stimulates renin, so NSAIDs can increase K by causing hyporenin hypoaldo
- Antagonize ADH activity
- NSAIDs block this and increased urine Osm
- Unlikely to be clinically significant
- Sodium excretion
- Little role in basal state
- Play a role in hypovolemic state
- NSAIDs can limit responsiveness of diuretics to treat edema
- Hormonal regulation of calcium and Phosphate
- Regulating calcium and phosphate requires changes in intestinal, bone, and renal function
- Unlike Na and K, absorption of calcium and phos is regulated at the intestines
- Vitamin D dependence
- Formation of insoluble solutes
- CaPhos
- CaOxalate
- MgPhosphate
- Calcium circulates as
- Bound to albumin 40%
- Complexed to anions (citrate) 15%
- Ionized 45%
- Phosphorus circulates as phosphate HPO4 2- and H2PO4- at a 4:1 ratio
- Calcium and phosphorus regulated by PTH and vitamin D
- The physiologic roles of other hormones, such as calcitonin and estrogens in the regulation of calcium and phosphate balance are incompletely understood and will not be discussed further. Ref 254
- PTH
- Secreted in response to hypocalcemia
- Sensed by the calcium sensing protein
- Polymorphisms in the gene that codes for CaSR underlie the variability of calcium in normal subjects
- Inactivating mutations lead to hypercalcemia because of an inability to suppress PTH
- Acts to increase serum calcium in three ways
- Stimulates bone resporption releasing Ca and Phosphate
- Requires the presence of “permissive amount” of active vitamin D
- Increases calcium resorption in the gut
- by promoting the formation of 1,25 vitamin D in the kidney
- Increases active Ca resorption in the kidney
- Connecting segment and distal tubule
- PTH also influences Phosphate balance though in contradictory ways to keep phosphate neutral?
- Increases phosphorus resorption from bone
- Increases phosphorus absorption in the GI tract
- Increases renal excretion of phosphorus
- Reduces proximal tubule phos resorbtion
- Specifically type II Na-Phos cotransporter
- With normal kidney function the renal excretion wins out over the first two
- Regulation by acid-base
- Academia stimulate PTH
- This increases urinary phosphate helping increase net acid excretion
- PTH also helps with bone buffering
- Vitamin D
- Fat soluble steroid
- From diet or synthesized in skin and liver
- 25 OH D is activated in the kidney to form 1.25
- 24,25 is an inactive metabolite
- Happens in the proximal tubule in animals and distal nephron in humans.
- Can also happen in lymphocytes and macrophages
- Regulation
- formation is stimulated by PTH and hypophosphatemia
- 1alpha hydroxylase has a vitamin D binding region itself so inhibits its own production
- Low phosphate stimulate 1alpha
- High phosphate inhibits 1alpha
- 24 hydroxylation which inactivated the hormone is stimulated by calcitriol itself
- Actions
- Increases bone resorption (along with PTH)
- Increases intestinal absorption
- Increases renal calcium resorption (along with PTH)
- Binds receptors in PTH to down regulate PTH
- Regulation of calcium and phosphate
- Talks about adjusting total calcium for albumin
- Ca and Phos in renal failure
- Decrease in GFR leads to decreased in phos filtered load and then excretion
- Leads to increased phos retention and concentration
- This leads to increased PTH
- If patients reduce phos intake, no increase in PTH
- Not due to phos binding calcium, lowering ionized calcium
- Alternative is increased Phos suppresses production of 1,25
- Consistent with low 1,25 levels early in CKD not increased as would be expected from low calcium/increased PTH
- Giving calcitriol prevents/reverses hyperparathyroidism, but giving calcium to prevent low calcium does not
- Hypersecretion of PTH normalizes calcium and phos soinitially appropriate
- Long term causes bone disease
- Metastatic calcification
- Prevention of secondary hyperparathyroidism
- Diet
- Binders
- Talks aluminum
- Citrate increases aluminum absorption
- Citrate complex’s with calcium leads to increased permeability of tight junctions allowing passive aluminum absorption
- Citrate binds to aluminum and some of the salt is absorbed
- Catecholamines
- Dopamine
- Kinins
- Erythropoietin
- Epo in renal failure
- Endothelin
- Regulation of vascular tone
- Modulation of fluid and electrolyte transport
- Regulation of cell prolifweration and extracellular matrix accumulation
- Nitric oxide
- Messenger molecule in human organ systems
- Responsible for the bio activity of endothelium derived relaxing factor
- Produced by nitric oxide synthesis
- Three isoforms
- Neuronal (nNOS)
- Macrophage (inducible, iNOS)
- Endothelial (eNOS)
- Short half life
- Nitric Oxide and the kidney