Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Archive for the category “Hypertension”

The clock in the Kidney

One the one hand, there are huge advances being made in medicine, especially in the field of regenerative medicine, while on the other, it seems like we are just beginning to understand how intricate our bodies are. Exploring human body at a molecular level has only revealed how much of it still remains unknown. Hypertension is a chronic medical condition that has economic impact due to cost of care and also in terms of work days lost. Partly because of its ‘asymptomatic’ nature, it is still an unrecognized, underdiagnosed, untreated and undertreated condition. When it does come to attention, despite countless medications that are available and prescribed, they just do not seem to work. An important factor might be non adherence to diet and medications. But there may be some more things we need to know.

This article caught my attention, recently. It is a brief review article about the circadian clock in the kidney and how it might impact the blood pressure variations. It gives clinical and molecular evidence for its presence and effects, highlighting the need for more research in this direction, which may help to tackle this major cause of morbidity and mortality.

Glomerular Filtration Rate, Renal blood flow, urine and electrolyte excretion exhibit diurnal variations (healthy individuals produce more electrolytes and urine during the day), very similar to the one seen in other organ systems like the nervous system and the heart. Although observations in the kidneys have been made about a century ago, the underlying mechanisms are still incompletely understood. (Circadian –> Circa & dies from Latin)

This circadian variation partly depends on the retino-hypothalamic tract which carry light signals from the eyes. The supra-schismatic nucleus of the brain functions as a master clock. It probably is not a coincidence that this nucleus is also extremely important in salt and water balance via the arginine vasopressin pathway.

Cardiovascular events and cerebrovascular events peak in the morning hours, and reflects the blood pressure increases in the morning, which then plateaus during the day then dips at night.

Circadian variation of blood pressure entails a nocturnal dip in BP by 10-20%, the absence of which is associated with an increased risk of cardiovascular events, increased Left Ventricular Hypertrophy, myocardial infarctions, carotid artery wall thickness, cerebrovascular disease, microalbuminuria, Chronic Kidney Disease, dementia.

Circadian variation of blood pressure in turn is also controlled by aldosterone signaling. (hyperaldosteronism causes a non dipping pattern).

Renal transplant has also been shown to restore the pattern, and suggests an intrinsic renal pathology as the cause. Again supported by the classic dog experiment of ‘escape’ from aldosterone escape when renal blood vessels are maintained at normal pressure compared with systemic blood pressure.

Salt handling by the kidneys  is probably more important than the amount of dietary salt as a cause of hypertension (HTN), since it is uncommon in normal renal function. {This brings us back to the chicken and egg of conundrum of Hypertensive Nephropathy}

Joining all the dots available, It is probably a positive feedback loop with renal disease (not evident by normal laboratory parameters) causing anon dipping pattern and then HTN in the first place, which in turn causes further renal damage (and other organ damage) disrupting the salt handling ability of the kidneys. The initiating renal disease could be in inappropriate sodium handling due to disrupted circadian clock, which in turn could be a manifestation of dysfunctional or dysregulated clock genes.

Molecular evidence:

Many genes have been shown to exhibit rhythmic expression in the kidney- clock controlled genes. Some examples

1. expression of E-Cadherin and claudin-4 parallel the circadian changes observed in sodium excretion

2. Period 1 (Per 1) plays a role in aldosterone dependent transcription of Scnn1a which is the rate limiting subunit of epithelial sodium channel.

3. NHE3 (mRNA for) exhibits circadian variation

others include V2R, V1aR (vasopressin receptor) Aqp2, Aqp4 (aquaporins)

More evidence

Per 2 mutations cause a non dipping pattern in rodent models

In cry1/Cry2 null mice, rhythmic expression of NHE3 is blunted, aldosterone levels are elevated. This elevation is due to overexpressed gene for a dehydrogenase isomerase, Hsd3b6.

The critical issue in dealing with BP variation and the disrupted circadian rhythm is in differentiating abnormality in the intrinsic clocks as opposed to the supra-chiasmatic clock.

At bedside,

Chronotherapy is the administration of medications at different times of the day with the goal of restoring the circadian rhythm rather than just relying on day time blood pressure measurements. This approach is more effective and also decreases the risk of cardiovascular morbidity and mortality. (MAPEC Trial). This is further evidence for the important role of the clock.

At bench,

Accumulating molecular evidence offers potential targets for interventional therapy for hypertension

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