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Could potassium explain the mystery of malaria immunity in babies?

December 3, 2014 - 18:41 -- Pierre Lutgen

Although 80% of malaria occurs in children under five years of age, infants under six months of age are known to have low rates of infection and disease. It is not clear why this youngest age group is protected. The perception that malaria is uncommon in young infants has resulted in the paucity of information currently available and the lack of evidence-based treatment guidelines in this population, Many children are dying before malaria is diagnosed and the death toll for infants under aged under six months is estimated at 200 000 – 300 000 annual casualties.

The general belief was that foetal blood cells predominant in the newborn were relatively resistant to penetration by the malaria parasite. A recent paper however shows that in an in vitro culture using fœtal erythrocytes from malaria infected mothers comparable growth rates are found for those with maternal red blood cells and those from non-malaria exposed individuals. But cultures in foetal plasma showed both significantly lower growth rates than a positive control using non-malaria exposed donor plasma. These data challenge the concept that fœtal hemoglobin is an intrinsic inhibitor of Plasma falciparum growth in the first months of life. However addition of cord plasma led to reduced in vitro growth (U Sauerzopf et al. Malaria Journal, 2014, 13:146). Similar experiments had been run already in 1984. Erythrocytes in standard culture medium showed a heavy invasion with young rings of previously uninfected red cells. In a medium of high potassium content this invasion was inhibited and many free merozoites were present (W Trager et al., J Protozool, 1984, 31, 562-567).

It is likely that potassium plays a key role.

The potasssium concentration in the plasma of neonates is much higher than in the plasma of the mothers: 5.9 mmol/l versus 3.8 mmol/l (L Martinerie et al., Pediatric Res. 66.3, 323-328, 2009). It appears that everything is done to protect the fœtus and the neonate against hypokalemia. The fœtal homeostatis for potassium appears to be very efficient. In maternal rats fed a diet deficient in potassium during pregnancy the plasma level of K fell to one-half the normal value. The K concentration in fœtal plasma did not change significantly. However in the case of depleted sodium feeding the fœtal plasma sodium concentration did not stay constant but decreased (J Dancis et al., Pediatric Res. 1970, 4, 345-351). For prematures the mean potassium value is significantly higher in the lowest weight group, which could be related to the fact that high potassium concentrations are vital for the fœtus (JB Pincus et al., Pediatrics, 18, 19565, 39-49). Dietary potassium in sows during-pre-farrowing till weaning gave a numerical increase in the number of piglets born alive. Furthermore, the number of weaned piglets per sow and the total weight of weaned piglets per sow were significantly increased (C Lückstädt et al Tropentag 2013, Stuttgart, Germany).

The renal potassium secretory channels are uniquely adapted for K retention early in life. In contrast to the high rates of K secretion observed in adult cortical conducting ducts, segments isolated from neonatal animals show no significant net K transport until after nthe third week of postnatal life (LM Satlin, Curr Opin Nephrol Hypertens 2004, 13-4, 445-450).

Normal blood serum sodium levels are 135-145 mEq/L, thus 50 times higher than for potassium. In milk however potassium levels (13 mEq/L) are 3 times higher than sodium (4 mEq/L). This may explain why milk has antimicrobial and anti-inflammatory properties. In human milk the potassium concentrations decrease between 3 and 18 week postpartum from 15.2 to 13.3 mEq/l. Already in 1952 it was found that milk had a suppressive effect on Plasmodium berghei in rat. The effect was not affected by changes in vitamin content, iron content, congelation or pasterurisation. As the authors state it seems clear that milk contains something that can inhibit or restrict the development of the asexual phase (BG Maegraith et al., British Medical Journal, 1952, Dec 27, 1382-1384). Could it be potassium ?

In young and premature infants the upper limit for hyperkalemia may be considerably higher, up to 6.5 mEq/L. Infant metabolisms use more potassium per day than adults. A baby needs to intake on average ar least 2 to 3 mEq/kg/day of potassium, compared to the 1 to 1,5 mEq/kg/d that adults require.

Birthweight seems to be related to the inflammatory interleukin-1β (P Boeuf et al, PLoS Pathog 9-2:e1003153, 2013). At a concentration of 100 pg/mL of IL-1β the birthweight is 1 500 grams and for 20 pg/mL it is 3000 grams. Interleukin-1β is an important cytokine produced in response to inflammatory stimuli. Potassium ion channels are involved in cytokine production by activated human macrophages (MR Qiu et al., Clin Exp Immunol., 2002, 130, 67-74). Several studies from the University of Mainz show that potassium depletion triggers IL-1β maturation. This maturation was totally blocked when cells were suspended in medium that contained high K͘͘., but could be induced by replacing extracellular K with Na (I Walev et al., The EMBO Journal, 14, 1607-1614, 1995).

Artemisinin and its derivatives certainly are not recommended in late pregnancy and during breastfeeding. They have a strong immunosuppressive effect (JK Wang et al., Brit J Pharmacol, 2007, 150, 652-661). Furthermore the generation of hydrogen peroxide has been implicated in the pathogenesis of acute kidney tubular cell injury (A Shahbazfar et al., Interdiscip Toxicol, 2012,. 5, 30-37).

Artemisia annua extract (Mi Hye Kim et al., PLoS One, 8-7, e101486). however exerts a protective and antioxidant effect in kidney cells.