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Inflammatory cytokines and mineral loss in urine

Blog entry posted by MeSci, Jun 18, 2014.

Thanks to some threads here and some clicking around in scientific papers I have put together some notes about the subject matter. After the summary below I will just paste them here as I don't have time to edit them.

In summary

  • Exertion causes ME sufferers to overproduce inflammatory chemicals, such as IL-1 and PGE2.
  • These chemicals can produce polyuria of the solute diuresis type, i.e. passing excessive water AND minerals.
  • (Not included here) I also found one or more papers stating that lack of sleep causes polyuria - can't remember which type.
  • Anti-inflammatory substances can help to reduce levels of inflammatory chemicals and consequently reduce or prevent loss of minerals in urine.
  • Mineral deficiency has a range of adverse short-and long-term effects, including tooth and bone damage, vascular pathology, neuronal dysfunction, muscular dysfunction, etc., etc., so may be responsible for many of the symptoms of PEM, and perhaps ME generally, along with the dehydration resulting from uncontrolled polyuria.

Whilst anti-inflammatories (pharmaceutical, supplemental or dietary) are unlikely to be a cure for ME, they may help significantly with symptoms, and may be a useful adjunct to steps taken towards achieving remission/recovery by reducing/preventing the exacerbations that arise from over-exertion.

In a separate blogpost I will paste some info I have found on two very-promising supplements, which I know others have already tried, and I am thinking of doing the same. They are resveratrol and curcumin.

MY NOTES ON INFLAMMATORY CHEMICALS AND SOLUTE DIURESIS:

Polyuria papers of interest

http://www.ncbi.nlm.nih.gov/pubmed/16804103

(Study on children)

Am J Physiol Renal Physiol. 2006 Dec;291(6):F1232-40. Epub 2006 Jun 27.

Nocturnal polyuria in monosymptomatic nocturnal enuresis refractory to desmopressin treatment.

Kamperis K1, Rittig S, Jørgensen KA, Djurhuus JC.

Abstract

The transition from day to night is associated with a pronounced decline in diuresis with reductions in the amount of excreted water, electrolytes, and other end products of our metabolism. Failure to do so leads to a large urine output at night, a condition known as nocturnal polyuria, encountered in a large proportion of children with nocturnal enuresis. The aim of this study was to clarify the mechanisms responsible for the nocturnal polyuria seen in enuretics with inadequate response to desmopressin (dDAVP). Forty-six enuretics (7-14 yr of age) and fifteen age-matched controls were admitted for a 24-h protocol with standardized fluid and sodium intake, comprising urine collections, blood sampling, and blood pressure monitoring. We included patients with severe enuresis (5 +/- 1 wet nights/wk) showing <50% reduction in wet nights on dDAVP. We characterized the patients on the basis of their nocturnal urine production. The children with nocturnal polyuria excreted larger amounts of sodium and urea at night than nonpolyurics and controls. Solute-free water reabsorption as well as urinary arginine vasopressin and aquaporin-2 excretion were normal in polyurics, and no differences were found in atrial natriuretic peptide, angiotensin II, aldosterone, and renin levels. Urinary prostaglandin E2 (PGE2) excretion was significantly higher in polyurics. The nocturnal polyuria in children with dDAVP-resistant nocturnal enuresis seems to be the result of augmented sodium and urea excretion. The high urinary PGE2 levels found in these children point toward a role for increased prostaglandin synthesis in the pathogenesis of enuresis-related polyuria.

Free full text online at http://ajprenal.physiology.org/content/ajprenal/291/6/F1232.full.pdf


http://www.ncbi.nlm.nih.gov/pubmed/18554642

(study on children)

J Urol. 2008 Aug;180(2):707-13; discussion 713-4. doi: 10.1016/j.juro.2008.04.047. Epub 2008 Jun 13.

The effect of desmopressin on renal water and solute handling in desmopressin resistant monosymptomatic nocturnal enuresis.

Kamperis K1, Rittig S, Radvanska E, Jørgensen KA, Djurhuus JC.

Abstract

PURPOSE:

We sought to evaluate the effect of desmopressin on renal water and solute handling in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria compared to healthy controls.

MATERIALS AND METHODS:

A total of 12 patients with enuresis and nocturnal polyuria, normal bladder reservoir function and no response to desmopressin, and 10 age matched controls were enrolled in the study. Children were admitted to the hospital for a 48-hour protocol comprising urine collections and blood sampling. Sodium and water intake was standardized. During the second night children received 40 mug intranasal desmopressin. Parameters characterizing the renal water and solute handling were measured and compared between baseline nights and nights with desmopressin.

RESULTS:

Desmopressin markedly reduced nocturnal urine output in patients with enuresis, minimizing sodium, urea and overall solute excretion, despite the fact that these children were unresponsive to desmopressin at home. This effect on renal sodium handling was not mediated by atrial natriuretic peptide, angiotensin II, aldosterone or renin. Desmopressin did not influence urinary prostaglandin E(2) excretion. The antinatriuretic effect was seen only in patients with enuresis, and it was directly correlated with the reduction in urine output.

CONCLUSIONS:

Children with nocturnal enuresis and nocturnal polyuria who do not exhibit adequate response to desmopressin at home seem to respond well to the agent at the clinic. The effect of desmopressin in children with enuresis seems largely dependent on reductions in the amount of sodium excreted. Sodium regulating hormones remained unaffected by desmopressin, indicating a possible direct effect of the agent on renal sodium handling.


http://www.ncbi.nlm.nih.gov/pubmed/22999686

(study on children)

J Urol. 2012 Nov;188(5):1915-22. doi: 10.1016/j.juro.2012.07.019. Epub 2012 Sep 19.

Effect of indomethacin on desmopressin resistant nocturnal polyuria and nocturnal enuresis.

Kamperis K1, Rittig S, Bower WF, Djurhuus JC.

Abstract

PURPOSE:

We evaluated the acute effect of indomethacin on renal water and solute handling in children with coexisting monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria, and in healthy controls.

MATERIALS AND METHODS:

A total of 23 subjects were recruited, consisting of 12 children with monosymptomatic nocturnal enuresis and nocturnal polyuria with partial or no response to desmopressin, and 11 age matched controls. Children completed a 48-hour inpatient study protocol consisting of fractional urine collections and blood samples. Sodium and water intake were standardized. During the second night a dose of 50 mg indomethacin was administered orally before bedtime. Diuresis, urine osmolalities, clearances and fractional excretions were calculated for sodium, potassium, urea, osmoles and solute-free water. Renin, angiotensin II, aldosterone and atrial natriuretic peptide were measured in plasma. Prostaglandin E(2) was measured in urine.

RESULTS:

Indomethacin markedly decreased the nocturnal sodium, urea and osmotic excretion in children with enuresis and controls. The overall effect on nocturnal urine output was inconsistent in the group with enuresis. Subjects in whom nocturnal diuresis was decreased following administration of indomethacin remained dry.

CONCLUSIONS:

Prostaglandin inhibition leads to antidiuresis, reducing the amount of sodium, urea and osmotic excretion in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria. The sodium regulating hormones do not seem to mediate these processes. The overall effect in desmopressin nonresponders with nocturnal polyuria is variable. The extent to which indomethacin can be applied in the treatment of enuresis needs further evaluation.


http://www.ncbi.nlm.nih.gov/pubmed/10209568

(adolescents and adults)

Clin Endocrinol (Oxf). 1998 Dec;49(6):793-801.

The efficacy of DDAVP is related to the circadian rhythm of urine output in patients with persisting nocturnal enuresis.

Hunsballe JM1, Hansen TK, Rittig S, Pedersen EB, Djurhuus JC.

Abstract

OBJECTIVE:

Desmopressin may be a useful treatment in some, but not all, patients with nocturnal enuresis. We have evaluated a relation between nocturnal urine output in patients with primary monosymptomatic nocturnal enuresis and the treatment response to synthetic vasopressin.

DESIGN:

Adolescent or adult enuretics and normal subjects were enrolled in the study and admitted to hospital for a 24 hour investigation of the diurnal variation in urine output, plasma vasopressin (AVP) and plasma atrial natriuretic peptide (ANP). The enuretics were characterized prior to investigation as either 1-desamino-8-D-arginine vasopressin (DDAVP) responders or non-responders. During admission the fluid intake was restricted to 25 ml/kg per day.

PATIENTS:

Twenty-four patients (15-37 years) with primary monosymptomatic nocturnal enuresis and 9 normal subjects (24-31 years).

MEASUREMENTS:

Circulating levels of AVP, ANP, plasma electrolytes and plasma osmolality were measured (1400, 2000, 2300, 0200, 0500 and 0800 hours) together with urine volume, urine osmolality and urine electrolytes during daytime and nighttime. Tubular reabsorptive capacity for water, osmoles and creatinine were assessed as well as urinary and fractional excretion rates of sodium and potassium.

RESULTS:

Controls and DDAVP non-responders had a significant decrease in urine output at night concomitant with a significant plasma AVP amplitude in peak/nadir values although both groups lacked a significant nocturnal increase in AVP. In contrast, in DDAVP responders there was no circadian variation in urine output and thus a nocturnal polyuria together with no oscillation in plasma AVP. The DDAVP responding group had a nocturnal urine production significantly larger than the two other groups. However, the mean 24 hour AVP levels were similar in all groups. The excessive urine production at night in DDAVP responders was accompanied by nocturnal natriuresis due to an increased fractional excretion of sodium. In contrast, nocturnal antidiuresis in controls and DDAVP non-responding enuretics coincided with diminished sodium excretion. Average ANP levels were elevated in both enuretic groups compared to normals, whereas a circadian variation was detected only in the latter.

CONCLUSION:

It is concluded that DDAVP responsiveness is linked to the nocturnal urine production and that no pathophysiological role can be ascribed to AVP or ANP in DDAVP refractory adolescent and adult enuretics. Moreover, it is suggested that an abnormal tubular handling of sodium may contribute to the nocturnal polyuria seen in DDAVP responders.


http://www.ncbi.nlm.nih.gov/pubmed/9258093

(age 15-37)

J Urol. 1997 Sep;158(3 Pt 1):830-6.

Single dose imipramine reduces nocturnal urine output in patients with nocturnal enuresis and nocturnal polyuria.

Hunsballe JM1, Rittig S, Pedersen EB, Olesen OV, Djurhuus JC.

Abstract

PURPOSE:

We investigated the effect of imipramine on nocturnal urine output in patients with nocturnal enuresis.

MATERIALS AND METHODS:

There were 15 monosymptomatic enuretic patients 15 to 37 years and 8 control subjects 25 to 32 years old. We measured nocturnal urine output, urine osmolality, creatinine clearance, osmolal clearance, free water clearance, excretion of solutes, fractional excretion of sodium, fractional excretion of potassium and plasma vasopressin with and without a single oral dose of imipramine (1 mg./kg. of body weight) taken at 8 p.m.

RESULTS:

Baseline studies showed significantly larger and less concentrated nocturnal urine among enuretics compared with controls. We observed a marked antidiuretic effect of imipramine in 6 enuretics with severe nocturnal polyuria. The imipramine induced decrease in urine output was accompanied by reduced osmolal clearance. Approximately a third of the observed decrease in solute excretion was attributed to lower excretion of sodium and potassium. The remaining two-thirds were most likely caused by an increased tubular reabsorption of urea, which may be secondary to a sympathomimetic effect of imipramine tubules, possibly because of altered adrenal medullary function with an increase in proximal tubular sodium and water reabsorption. The resultant lower tubular flow rate facilitates tubular reabsorption of urea in the distal part of the nephron.

CONCLUSIONS:

Imipramine has a vasopressin independent antidiuretic effect if nocturnal polyuria is present. The antidiuretic effect of imipramine can be attributed primarily to increased alpha-adrenergic stimulation in the proximal tubules with a secondary increased urea and water reabsorption more distally in the nephron.


Paper at

http://www.name-us.org/ResearchPage...mmuneArticles/Patarca2000ImmuneReviewFull.pdf

Journal of Chronic Fatigue Syndrome 2000; 6(3/4): 69-107.

Review: Immunology of Chronic Fatigue Syndrome

Roberto Patarca, Timothy Mark, Mary Ann Fletcher and Nancy Klimas

E. M. Papper Laboratory of Clinical Immunology

Department of Medicine (R-42)

University of Miami School of Medicine

P.O. Box 016960

Miami, Florida 33101

says:

IL-1 induces prostaglandin (PGE2, PGI2) synthesis by endothelial and smooth muscle cells (140). These substances are potent vasodilators, and IL-1 administration in animals and humans produces significant hypotension. IL-1 has a natriuretic effect (141) and may affect plasma volume.
Thinktank, Sidereal and rosie26 like this.
MeSci

About the Author

Hopeful leaky-gut healing enthusiast!
  1. MeSci
    Thanks to halcyon for this interesting link - sorry but I don't think I can make it clickable: http://www.ncbi.nlm.nih.gov/pubmed/20736986 It's called 'Vasopressin regulation of renal sodium excretion'.
  2. MeSci
    BTW water can also of course be lost in sweat and faeces, especially diarrhoea.

    But maybe if you're not losing much in urine it's not DI.
  3. MeSci
    @halcyon - it looks like you need a proper work-up for diabetes insipidus. Has your doc offered this?
  4. halcyon
    So I went and had some testing done:

    ADH - 1.8 pg/mL (0.0 - 4.7)
    Plasma osmolality 292 mOsmol/kg (275-295)
    Aldosterone 24.5 ng/dL (0.0 - 30.0)
    Renin, plasma 5.94 ng/mL/hr (1.31 - 3.95)

    It seems to match my experience of being pretty close to dehydration constantly and my body seems to be trying to do the right thing to compensate by jacking up ADH/aldosterone/renin but I must still be losing water due to something else. I can't seem to find anywhere online to order a PGE2 blood test. May have to go see my doctor and ask for one.
  5. MeSci
    Glad you like it, halcyon! I too have thought about not reducing inflammatory cytokines too much. As you say, they do have important roles. That's why I am taking low doses of anti-inflammatory supplements.

    But our high level of inflammation (if we have it) may be a mistake by the body thinking that it is infected when it isn't. Trouble is, it's almost impossible to know whether/when our infection-like symptoms are due to infection or autoimmunity.

    We have to operate on guesswork an awful lot!

    My own experiment doesn't seem to be going that well, so I'm trying to tweak this and that, just hoping that I can hit on the right formula eventually.

    How I wish that we could get wearable devices that would tell us exactly what we needed and when. They will probably be available and affordable eventually, but for now there are only a few examples which are pretty expensive and probably don't do all we need them to.
  6. halcyon
    Thanks for posting this MeSci, this is very interesting. I've been stumped trying to figure out how to account for my mineral loss. The times when I've been most sick I present with borderline or actual hyponatremia and hypokalemia and other signs of dehydration, regardless of what I thought was adequate water intake. I've also experienced the episodes of polyuria a few times, luckily only while at home so far and it seems to be getting better.

    I'm a bit worried about trying anti-inflammatories though. I assume that the increase of inflammatory cytokines is an indication of my immune system fighting something. It seems like it would be a bad idea to suppress that and diminish the immune response.
  7. MeSci
    In case it wasn't clear or I haven't said it elsewhere, my assumption (and hope!) is that anti-inflammatories will reduce not only the mineral loss but also the fluid loss, thus combating both dehydration/low blood volume (and the consequences of this such as orthostatic intolerance/OI) and mineral deficiency.
  8. MeSci
    OK - here is how to convert from specific gravity to osmolality. NB the units are those used in the UK - not sure if different ones are used elsewhere, so I have given an example after the conversion method.


    1. Measure specific gravity of sample.
    2. Take temperature of sample.
    3. If sample is above 15.6 degrees C, add 0.001 to specific gravity figure for each 3 degrees above 15.6 degrees C. (e.g. if sample is at 21.6 degrees C, add 0.002.) (Not sure what you do if it is below 15.6 degrees, but if you do measurements soon after urine is produced it shouldn't be!)
    4. Multiply by 33194.
    5. Subtract 33247.

    That should give you the osmolality.

    NB there are some possible confounding variables, depending on the presence of certain solutes in the urine, but my own measurements were in line with my observations/experiences.

    Example of calculation:

    Specific gravity at 27.6 degrees C: 1.020
    Add 0.004 = 1.024
    Multiply by 33194 = 33990
    Subtract 33247 = 743.

    This is the approximate osmolality, assuming no other confounding variables.

    I don't expect anyone with ME to remember this. I had to refer to my instructions every time I did it!

    REFERENCES:

    Diseases of the Kidney and Urinary Tract, Eighth Edition, edited by Robert W. Schrier, MD, Professor of Medicine, University of Colorado School of Medicine, Denver, Colorado, Wolters Kluwer/Lippincott Williams and Wilkins, 2007 vol. 1 Ch.11, p.327

    Leech (S) and Penney (M.D.) (1987) Correlation of specific gravity and osmolality of urine in neonates and adults, Archives of Disease in Childhood, 1987, vol. 62, pp. 671-673, online at <http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1779236&blobtype=pdf>
  9. MeSci
    Have you tried desmopressin/DDAVP, @rosie26? The reason I ask is that many of us, myself included, (also) have a water diuresis, possibly classifiable as (partial) diabetes insipidus, which can be greatly alleviated by desmopressin. I had got to a stage where I was afraid to go out socially in case I had one of my episodes of having to urinate every 10 minutes, afraid to get on a bus, and going shopping was a nightmare, involving multiple diversions to (disgusting) public toilets. I sometimes had one of these bouts at night. The longest lasted 4 hours! So in this case it was the polyuria causing the lack of sleep rather than vice versa.

    This type of polyuria is likely to be due to dysfunction of the HPA axis, which is a characteristic of ME. Desmopressin transformed my life.

    But the solute diuresis developed later with me, I think, and has had me stumped - until I found this new info (new to me anyway!).

    A way to differentiate the two types of polyuria is by testing how concentrated the urine is. In medical terms the measure used is usually osmolality, but if you have this done via the health service you/the doctor may misinterpret the results due to the variation from day to day and hour to hour.

    So instead you could use a wine hydrometer which will give you the specific gravity of your urine. This can then be converted to osmolality via a series of calculations, which I will dig out and post here when I can.
    rosie26 likes this.
  10. rosie26
    That was interesting MeSci, in my severe insomnia years I was having to get up to pee about 3x during the night with a slight urgency to it as well. I don't have to get up in the night now as I am sleeping better mostly at moderate ME.
    I can't read all this post today but will come back.
    MeSci likes this.