Histamine excess and urinary tract disease

The scientific evidence which exists on histamine and the urinary tract has always been linked to its vasoactive functions related to inflammation. Decades later there has been renewed interest in other possible roles, such as the role of histamine in kidney disease.

Histamine, a known mediator of inflammation, causes physiological changes in the body by binding to its four subtypes of G protein-coupled receptors (GPCRs): H1, H2, H3 and H4 receptors. These receptors are distributed in different tissues of the body and, specifically, the kidney is one of them.

On the one hand, multiple studies suggest that the main source of histamine production and secretion is local production in the kidney; hence, the animal origin of the supplementation of the DAO enzyme, the main enzyme responsible for metabolizing histamine, is from the pig kidney extract. The correlation between histamine and kidney disease in humans stems from the observation that, compared to healthy subjects, plasma histamine levels are significantly higher in patients suffering from nephrotic syndrome, renal insufficiency, uremic pruritus, and who are undergoing hemodialysis or peritoneal dialysis.

On the other hand, different hypotheses have been put forward suggesting other sources of extrarenal histamine production, for example, mast cells. The presence of these cells, which synthesize and store histamine, could be an important source of this amine, although the number of mast cells is relatively low in this organ. In this way, the presence of mast cells correlates with the progressive loss of renal function in these situations.

Differential histamine receptor distribution in the mammalian nephron and collecting duct.

The current data available suggest that the regulation of albumin levels in the blood, the excretion of water and salt, and the clearance of creatinine and urea are mediated by H1 and H4 receptors. As detailed by Dr. José Luis Ponce, urologist and researcher at the A Coruña University Hospital Complex, this mechanism would explain the higher fluid retention at certain times or dehydration at others. In addition, H1 receptors are also involved in modulating renal blood flow. The properties of H1 receptors are shared by H2 receptors, the activation of which also causes the release of renin, a hormone that is usually secreted in arterial hypotension cases. Finally, activation of the H3 receptor may be involved in excessive urine production, known as polyuria.

As suggested by Dr. Ponce, a high intake of histamine can cause renal colic by altering the functions of the H1-H4 receptors in the kidney. This colic, not mediated by the presence of stones, can cause a contraction between the ureter and the bladder junction, causing a spasm of the ureter with accumulation of urine and sediment. In addition to the symptoms associated with histamine accumulation and renal colic, the patient may have bladder spasm. Although there is a little clinical evidence, it is true that there is some reference in this regard with good results using antihistamines in renal colic.

It is known that the intensity of histamine elimination in urine determines to a great extent the inter-individual variability in relation to the clinic. Despite this, there are other factors which influence, such as the type of receptors that the patient has (probably influenced by the doses of histamine eliminated in the urine) and the neurogenic reflex effects that can occur at the central level. For this reason, Dr. Ponce comments that the influence of histamine on renal pathophysiology is still under study, in order to translate experimental data into therapeutic applications through standardized and analytical parameters. In this sense, a hypothesis to be investigated would be whether following a low-histamine diet could be a coadjuvant treatment in patients with a lower urinary tract disease if it is related to a DAO deficiency and, as a consequence, decrease histamine levels in blood.

Thus, establishing the importance of histamine signaling in kidney function allows a step forward towards new approaches for the treatment of kidney diseases associated with inflammation. In addition, working together with the different health professionals let a more comprehensive approach of the case with a higher success rate for the patient.

From AD Dietistas we would like thank Dr. José Luis Ponce, urologist and researcher at the Complejo Hospitalario Universitario A Coruña, for having collaborated on this article, contributing by his personal and professional experience in this regard.

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RUNDY, L., CALDWELL, A., GARCIA CARABALLO, S., ERICKSON, A., SCHOBER, G., CASTRO, J., HARRINGTON, A. M. & BRIERLEY, S. M. 2020. Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1. American Journal of Physiology-Renal Physiology, 318, F298-F314.

STROMBERGA, Z., CHESS-WILLIAMS, R. & MORO, C. 2019. Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors. Scientific Reports, 9, 1-7.

Grange, C., Gurrieri, M., Verta, R., Fantozzi, R., Pini, A., & Rosa, A. C. (2020). Histamine in the kidneys: what is its role in renal pathophysiology?. British journal of pharmacology, 177(3), 503–515. https://doi.org/10.1111/bph.14619

Sudarikova, A. V., Fomin, M. V., Yankelevich, I. A., & Ilatovskaya, D. V. (2021). The implications of histamine metabolism and signaling in renal function. Physiological reports, 9(8), e14845. https://doi.org/10.14814/phy2.14845

Grange, C., Gurrieri, M., Verta, R., Fantozzi, R., Pini, A., & Rosa, A. C. (2020). Histamine in the kidneys: what is its role in renal pathophysiology?. British journal of pharmacology, 177(3), 503–515. https://doi.org/10.1111/bph.14619

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