A functional disorder of the kidneys, usually caused by a genetic defect, leads to hyperacidity of the blood, which in turn impairs the recovery of important nutrients and minerals from the urine. An international research team led by Jena University Hospital has now been able to elucidate this disease mechanism in more detail, thereby contributing to a better understanding of chronic kidney failure, which is also associated with hyperacidity in its advanced stages.

The kidney consists of many tiny functional units—the so-called renal tubules or nephrons. At their beginning, the blood is filtered to produce urine, which is then modified during its passage through the nephron in a variety of transport processes.

Distal renal tubular acidosis, or dRTA for short, is a rare congenital disorder in which the kidneys are unable to excrete acid adequately. This leads to hyperacidity of the blood. If this is not compensated for by a lifelong supply of alkali, the disease causes metabolic disorders such as rickets, growth retardation or muscle weakness. In addition, some dRTA patients exhibit Fanconi syndrome, which is characterized by the loss of important nutrients and minerals via the urine.

This is surprising as Fanconi syndrome originates in the early sections of the nephron, whereas dRTA affects a later section of the nephron. ?Looking back at previous research results, we suspected that hyperacidity of the blood could damage the early sections of the nephron, thereby leading to Fanconi syndrome?, says Dr Christopher Hennings from Jena University Hospital (JUH).

Hyperacidity damages the kidney’s back-filtering function

Together with researchers in France, the biochemist studied mice in which severe dRTA was induced by switching off a gene. These mice exhibited the typical Fanconi-like symptoms: increased loss of phosphate and protein. However, whenthe animals' drinking water was enriched with bicarbonate to correct the hyperacidity of the blood, their kidney function improved significantly.

The kidney tissue of animals that had not received this drinking water treatment showed changes in early nephron sections. Christopher Hennings: ?The changes mainly affected proteins that are important for the recovery of phosphate from urine and for the function of lysosomes, which play a central role in intracellular degradation and recycling processes. This explains the Fanconi-like syndrome.?

The researchers then wanted to test whether hyperacidity could damage the early nephron to such an extent that Fanconi syndrome develops. To do this, they gave mice without the genetic defect acidified drinking water, thereby achieving hyperacidity in the blood, albeit to a lesser extent than in the dRTA mice. Would these mice also develop a Fanconi-like syndrome? In fact, despite the weaker hyperacidity, they found similar changes in the early nephron section.

Christopher Hennings: ?This is a clear indication that it is not the genetic defect, but the hyperacidity resulting from the genetic defect that is responsible for Fanconi syndrome.? In collaboration with researchers in Cologne, the study team was able to confirm these results in experiments with human kidney organoids. As in the body, these mini-organs from human cells develop the same functional tissue structures as in the kidney. When the pH value of the nutrient fluid was reduced, this hyperacidity disrupted the nephrons in the same way, with the lysosomes being particularly affected.

These findings, now been published in the journal ?Science Translational Medicine?, may be relevant not only for those affected by the congenital kidney diseases studies, but for many more patients. An estimated nine million people in Germany suffer from severe kidney failure, which in advanced stages is also associated with hyperacidity, or acidosis.

?Our work shows that acidosis further accelerates the loss of organ function and therefore requires consistent countermeasures to protect the function of the nephrons?, emphasizes Prof. Dr Christian Hübner, last author of the study and member of the steering committee of the Center for Rare Diseases at the JUH.