The renin-angiotensin-aldosterone system (RAAS)

Kidney has a lot of specialised tissues, with a filtration system of nephrons composed of glomeruli, tubules, connecting ducts etc, plus a blood supply composed of veins, arteries and capillaries, and the peritubular cells around these systems. The process of kidney damage strongly involves fibrosis whereby these specialised tissues turn into non-functional scar tissue. Specialised cells are replaced by fibroblasts.

As a result functional capacity dependent on the specialised systems or cells is diminished. But functional output, at least initially, is maintained because the residual systems are made to work harder, eg by increased angiotensinII, and RAAS activity generally, and increased anoxia in the case of the peritubular cells producing EPO. AngiotensinII and the RAAS and anoxia are all agents that increase fibrosis leading to increased loss of functional capacity, leading to increased need for stimulus, leading to - - - - -.

Eventually the residual capacity is inadequate to respond to the heightened stimuli and overt CKD is recognised. Lowered GFR would appear early. Anemia through lowered capacity for EPO production only much later, because the actions trying to maintain the GFR would be adding to anoxia. Also angiotensin II has the potential for stimulation of EPO production independently of anoxia.

Enter olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. . AngiotensinII is blocked. GFR falls further because the existing reduced capacity is no longer forced to greater output. Blood supply to the peritubular capillaries is increased because it is no longer being choked off to raise glomerular pressure to maintain GFR. The increased peritubular oxygenation removes the anoxia stimulus to production of EPO which falls and anemia results, or is increased.

Note that that the basic level of kidney capacity in the plus olmesartan scenario is really much better than would apply for a similar GFR observed in untreated situations that doctors may have dealt with. Hence their reasonable alarm, particularly when they are taught CKD is a variably, but inevitably, progressive disease: and ultimately incurable.

Elevations in serum creatinine with RAAS blockade: why isn't it a sign of kidney injury? ¹⁾

Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. ²⁾

• Poor kidneys can seem OK because the renin-angiotensin-aldosterone-system (RAAS) adjusts them to maintain their capacity (sub clinical kidney disease).

• This adjustment is achieved at the cost of rising blood pressure, reduced renal blood flow and increased occurrence of kidney damage.

• Blocking the RAAS, particularly with olmesartan, lowers blood pressure, increases renal blood flow and decreases the occurrence of kidney damage.

  These benefits of RAAS blockade are accompanied by a fall in kidney capacity. 
  This can involve:
*     lowered GFR,
*     decreased sodium retention,
*     increased potassium retention,
*     decreased acid excretion,
*     decreased phosphate excretion and
*     lowered stimulus to RBC production.

  Out of range values observed with RAAS blockade can include:
*     high creatinine, 
*     high urea,
*     low sodium,
*     high potassium,
*     acidosis (low CO2 or bicarbonate),
*     low calcium,
*     high phosphate and
*     anemia.

  The out of range electrolytes (sodium, potassium, CO2 or bicarbonate, calcium and phosphate) 
  could be of immediate concern. But they can be simply modulated by:
*     limitation of potassium rich foods
*     increased intake of salt (sodium chloride)
*     daily dosage with sodium bicarbonate
*     dosage with calcium carbonate (or calcium acetate) with high phosphate meals as required.

Evidence of compromised kidney function such as a falling GFR may not appear until well after the initial occurrence of kidney damage because the kidneys adjust. One mechanism of adjustment triggers the renin-angiotensin-aldosterone-system (RAAS) to greater production of angiotensinII which increases glomerular filtration pressure to increase GFR. This is achieved by constricting the efferent capillaries more than the afferent ones. Unfortunately, this increases blood pressure which can increase damage to the kidneys, so that a vicious circle is established. Also the reduced blood supply flowing to the the tubulointerstitial cells from the glomerulus can cause damage to them by anoxia (Ref 1, Fig 2).

Lowering blood pressure by vigorous anti-hypertensive treatment is a recognised regime to slow the progression of chronic kidney disease. High dosage ARBs or ACE inhibitors or both have been preferred anti-hypertensives because they lack some side effects of other agents. With these high doses it is observed that that the eGFR can drop sharply (Ref 4). This effect can be particularly marked with olmesartan which combines the receptor blocking effect of an ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. with the angiotensin lowering effect of an ACEi (Ref 5).The latter effect arises from its activation of the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. (Ref 6) to repress the production of renin, the renin receptor, angiotensinogen, and also the angiotensinII receptor type 1 (ATR1) (Ref 7).

Low blood supply to the kidneys causes them to release renin which activates the production of angiotensin II to increase blood pressure and to stimulate the production of aldosterone. A major function of aldosterone is to promote absorption of sodium in the intestine and its reabsorption in the kidney. The reabsorption is driven by a sodium/potassium pump which exchanges sodium reabsorbed for potassium excreted. Low activity of the pump from low aldosterone levels will thus give low sodium and high potassium values.

Blocking the action of angiotensin II with olmesartan could be causing failure of the adrenals to produce aldosterone. But it would also be aiding the kidneys by improving their blood supply and having other positive effects.

One approach could be to take large amounts of salt (sodium chloride) with adequate water to compensate for the low activity of the sodium/potassium pump. If this was effective in raising blood pressure and lowering potassium (which is also involved in stimulating the production of aldosterone) it may turn off the anomalous hormone production.

On the other hand substitution of aldosterone with Florinef would be a more direct way to achieve this aim. IMO, this would not interfere with other aspects of the MP

be sure to take a regular, known, substantial amount of salt. Blocking of the action of the RAAS decreases sodium re-absorption in the kidney and the large intestine. So olmesartan influences you to be short of salt, maybe low in BP and blood volume.

These conditions generate signals to the adrenals to do something to rectify them. Some of what they do to respond involves the functioning of the RAAS, which is blocked by olmesartan, so they presumably have to try harder, and harder.

Removal of the olmesartan would relieve this futile pressure. However, it also allows the RAAS to constrict blood flow through your kidneys and so remove one of the healing effects that olmesartan provides. Provision of sufficient additional salt may remove the need to generate signals to the adrenals in the first place.

This reference says RAAS blockade exerts potent hemodynamic, antihypertensive, and antiinflammatory effects, and slows progression of kidney disease beyond that due to lowering of blood pressure. The benefit extends to those with advanced disease. In spite of established benefit, ACEi and ARB therapy remains underutilized, in part due to concerns about acute deteriorations in renal function that result from interruption of the RAAS.

The beneficial effects of ACEi/ARB therapy extend to those with significant renal disease. Combination ACEi/ARB is safe, and reduces proteinuria more than either agent alone in patients with macroalbuminuric nephropathy

Elevations in serum creatinine w… [Curr Opin Nephrol Hypertens. 2008] - PubMed - NCBI Olmesartan is like a combination ACEi/ARB plus a renin inhibitor all in one because of its ARB plus VDR activation effects.

from Nangaku M et al. J Am Soc Nephrol. (2006) ³⁾

Among various vasoactive substances, local activation of RAS is especially important because it can lead to constriction of efferent arterioles, hypoperfusion of postglomerular peritubular capillaries, and subsequent hypoxia of the tubulointerstitium in the downstream compartment. To clarify the mechanism of these effects, we used a remnant kidney model in rats induced by ligation of renal artery branches, in which RAS is markedly activated. Our computer-assisted morphologic analysis demonstrated narrowing and distortion of peritubular capillaries with decreased blood flow and hypoxia in a very early phase in this model, before the development of structural kidney damage (37). In addition, angiotensin II damages endothelial cells directly: Administration of angiotensin II to rats causes the loss of peritubular capillaries, an effect that is ameliorated by receptor blockade (38,39). A second important mechanism of angiotensin II–induced ischemia is inefficient cellular respiration and hypoxia via oxidative stress, which is detailed below. Thus, angiotensin II induces tubulointerstitial hypoxia via both hemodynamic and nonhemodynamic mechanisms. Intrarenal vasoconstriction may also occur secondary to increased local endothelin or a local loss of vasodilating nitric oxide (NO).

NF-kBA protein that stimulates the release of inflammatory cytokines in response to infection and CREB Are Required for Angiotensin II Type 1Receptor Upregulation in Neurons

Fig6? in the citation is a nice diagram of the interactions. It doesn't include the inhibitory actions of the VDR binding to CREB and IKK (the kinase that inhibits the inhibitor of NFKb).

Adding up all these interactions give enormous potential for VDR activation to turn down the inflammatory effects of the RAS.

Another citation reports inhibition of STAT1 by binding with unliganded VDR.

NF-kB and CREB Are Required for Angiotensin II Type 1 Receptor Upregulation in Neurons

Vitamin D Receptor and Jak–STAT Signaling Crosstalk Results in Calcitriol-Mediated Increase of Hepatocellular Response to IFN-α

Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. and Jak–STAT Signaling Crosstalk Results in Calcitriol-Mediated Increase of Hepatocellular Recent clinical research suggests a role for vitamin D in the response to IFN-α–based therapy of chronic hepatitis C. Therefore, we aimed to explore the underlying mechanisms in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory..

Huh-7.5 cells harboring subgenomic hepatitis C virus (HCV) replicons or infected with cell culture–derived HCV were exposed to bioactive 1,25-dihydroxyvitamin D3 (calcitriol) with or without IFN-α. In these experiments, calcitriol alone had no effect on the HCV life cycle.

However, calcitriol enhanced the inhibitory effect of IFN-α on HCV replication. This effect was based on a calcitriol-mediated increase of IFN-α–induced gene expression.

Further mechanistic studies revealed a constitutive inhibitory interaction between the inactive vitamin D receptor (VDR) and Stat1, which was released upon stimulation with calcitriol and IFN-α. As a consequence, IFN-α–induced binding of phosphorylated Stat1 to its DNA target sequences was enhanced by calcitriol.

Importantly, and in line with these observations, silencing of the VDR resulted in an enhanced hepatocellular response to IFN-α. Our findings identify the VDR as a novel suppressor of IFN-α–induced signaling through the Jak–STAT pathwayResponse to IFN-α (2014)

As a brief unreferenced comment: I understand angiotensin II to be classed as an inflammatory cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system., at least when acting through ATR1, that generates production of ROS and activates NFKb which further promotes production of inflammatory cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system..

I think NFkb also promotes ang II activity, including the production of angiotensinogen The VDR acts to block AngII ATR1 and related activities by a variety of mechanisms.

To prevent the NFKb effects it binds to a sub unit of an agent (IKKb)? that inhibits the kinase which inactivates NFKb. To inhibit prorenin, the precursor of renin, production it binds to CREB, which recognizes promoters of cyclic AMP stimulated genes.

These include those triggered in beta- adrenergic responses. It increases the production of ACE2 which converts ang II to ang-7,9 that then acts on different receptors.

Jigsaw posted: Sun Oct 3rd, 2010 09:08

Further, the plasma level of angiotensin II was significantly increased in olmesartan-treated rats.

This is another piece in the puzzle consistent with the accuracy of the finding from Dr. Marshall's molecular modelling that olmesartan activates the VDR in humans ,but not in rats. In humans olmesartan lowers angiotensin II levels whereas the other ARBs raise it. This effect of olmesartan can be explained by the observations that the VDR represses production of angiotensinogen and renin which contribute to angiotensin II formation. If olmesartan activates the VDR in humans, but not in rats; the lowering effect will happen in humans (as observed), but not in rats (as observed).

Jigsaw posted: Tue Oct 9th, 2012

Angiotensin II levels decreased significantly from a baseline of 20.4±3.2 pg/ml to a mean of 8.6±2.1 pg/ml and 6.8±1.8 pg/ml after 6 months and 1 year of treatment, respectively. Plasma aldosterone level also decreased significantly after 6 months of treatment.

In hypertensive patients, the long-term administration of olmesartan, a novel AT1 receptor antagonist, decreased both blood pressure and plasma angiotensin II levels. (Hypertens Res 2001; 24: 641-646) _pdf (application/pdf Object)

Jigsaw posted: Sun Apr 22nd, 2012

I am happy for now with the data on the effects of ARBs on angiotensin II levels. All raise the levels (as expected) except olmesartan which lowers them.

This is consistent with olmesartan agonism of the VDR which inhibits the production of angiotensinogen and renin. Renin catalyses the first step in the sequence: angiotensinogen —–> angiotensin I ——> angiotensin II

RAS refs

Elevations in serum creatinine with RAAS blockade: why isn't it a sign of kidney injury? 18695383 Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. 11768722

other refs went to, one went nowhere https://www.kidney-international.org/ also CO2 blood test https://www.kidney-international.org/ for elsewhere if not there & Hyperkalemia https://www.medicinenet.com/hyperkalemia/page4.htm

hyper K management https://www.fpnotebook.com/renal/potassium/hyprklmmngmnt.htm Bicarbonate supplementation slows progression of CKD and improves nutritional status. https://www.ncbi.nlm.nih.gov/pubmed/19608703 Metabolic Acidosis https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/metabolic-acidosis ** Mechanism of acid-induced bone resorption. 15199293 15199293 Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release 11704556

hyper K https://emedicine.medscape.com/article/241185-overview#a0104 hyper K https://www.unitedhealthdirectory.com/diseases-and-conditions/hyperphosphatemia/

tetany [defn] https://www.medicinenet.com/script/main/art.asp?articlekey=13312 https://en.wikipedia.org/wiki/Tumor_lysis_syndrome