Nephrolithiasis and Nephrocalcinosis in Childhood-Risk Factor-Related Current and Future Treatment Options

Abstract

Nephrolithiasis, urolithiasis, and nephrocalcinosis (NC) have become common causes of hospitalization and referral to pediatric outpatient clinics. It is of utmost importance to start with diagnostic evaluation directly after the first passage of a kidney stone, or if NC is diagnosed, in each pediatric patient. This is necessary, as in about 80% of children a metabolic reason for stone disease is detected. Current treatment options are scarce and mainly include general measures like an increased fluid intake or elevating the solubility of a lithogenic substance. According to the given lithogenic risk factor(s), specific treatment options are available and are being summarized in this review. Furthermore, an outlook on potential future treatment options, including innovative strategies such as mRNA-based or recombinant enzyme substitution therapy, is given.

Keywords: nephrocalcinosis; nephrolithiasis; therapy; treatment; urolithiasis.

Figure 1

Schematic figure of the mode of action of two new experimental drugs for primary hyperoxaluria I. CRID 3 inhibits inflammasome-mediated inflammation in dendritic cells of the kidney and thus reducing kidney fibrosis. R-7050 is a TNF-receptor inhibitor, delaying the progression of nephrocalcinosis since it seems to prevent adhesion of calcium oxalate (Ca-Ox) crystals to renal tubules.

Figure 2

Schematic figure of the mode of action of experimental drugs for primary hyperoxaluria (PH) I. ALN-GO1 and DCR-PH I are RNA interference (RNAi)-based drugs, preventing the translation of glycolate oxidase (GO) and thus reducing endogenous oxalate production. DCR-PHXC as well is an RNAi-based drug targeting the liver-specific lactate dehydrogenase A (LDHA), also reducing endogenous oxalate production. Dequalinium chloride (DECA) prevents the misslocation of alanine:glyoxylate aminotransferase (AGT). This is only applicable for a certain PH I mutation (P11LG170R allele), since other mutations do not cause a misslocation of AGT.

Figure 3

Schematic figure of the mode of operation of experimental drugs for primary hyperoxaluria I. Oxalobacter formigenes uses oxalate as its sole carbon source. Orally administered, it degrades intraluminal oxalate in the intestine. By a concentration gradient and through activation of the intestinal oxalate transporter, oxalate is transported from the blood into the intestinal lumen. ALLN-177 is a recombined, microbial oxalate decarboxylase leading to the same intraluminal effect as O. Formigenes, however, maybe unable to increase the shift of blood oxalate into the intestinal lumen, as it cannot directly activate the intestinal oxalate transporter.