Donor-derived hypouricemia in irrelevant recipients caused by kidney transplantation

Abstract

Background: Hereditary renal hypouricemia (HRH) is a genetically heterogenetic disease. Patients with HRH are almost asymptomatic; but some may experience exercise-induced acute kidney injury (EAKI) and nephrolithiasis which may bring concerns regarding the risk-benefit ratio as marginal kidney donors. This study examined the pathogenic mutations of hypouricemia in two recipients after receiving kidney transplantation, providing preliminary evidence for the mechanism of hypouricemia.

Methods: Two participants underwent detailed biochemical examinations. DNA and RNA were extracted from transplant specimens for sequencing. The whole-genome sequencing and polymerase chain reaction (PCR) amplification were performed to confirm the pathogenic genes. Functional effects of mutant proteins were verified by bioinformatics analysis. RNA-sequencing (RNA-seq) was used to study the transcriptome of hypouricemia.

Results: Both of the recipients had the low serum uric acid (UA) (45-65 µmol/l), high fraction excretion of UA (44% and 75%) and an increase in the UA clearance (35.9 and 73.3 mL/min) with a functioning graft. The sequencing analyses revealed 7 kinds of potential mutational genes in this case, two novel mutations p.R89H and p.L181V in SLC22A12 gene which were revealed by bioinformatics could be pathogenic in nature.

Conclusions: Two novel mutations of SLC22A12 were identified. Preliminary functional analysis revealed a potential deleterious effect of these mutations in the grafts derived from the donor and sequencing analysis expand the molecular mechanisms of renal hypouricemia.

Keywords: Hereditary renal hypouricemia (HRH); SLC22A12; kidney transplantation; single nucleotide polymorphism (SNP).

Figure 1

Clinical data of the patients. (A) We collected the implants transplanted into the two recipients immediately (S1 and S2) and followed for three and a half years post-transplantation (S3) and a healthy control (HC). Variation of serum creatinine (B) and uric acid (C) within years of follow-up in the two recipients.

Figure 2

Mutations found in implants (S1, S2, S3) with hereditary hypouricemia. (A) The homozygous mutation of SLC2A9-p.R294H (c.G881A) discovered in the implants (S1, S2, S3) and the healthy control had happened to find the heterozygous mutation as well; (B) the other mutations discovered in this study; (C) SLC22A12 p.R89H mutation is predicted to be possibly damaging with a score of 0.809 (sensitivity: 0.84; specificity: 0.93); p.L181V mutation is predicted to be probably damaging with a score of 0.996 (sensitivity: 0.55; specificity: 0.98).

Figure 3

Screening for differentially expressed genes in hypouricemia. (A) The clustering of differential genes in heatmap. The color in the heatmap represents the log 2-fold change of expression values. Text on the right of heatmap indicates the enriched gene ontology terms for each cluster of genes; (B) top 30 pathways from Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The x-axis represents KEGG enrichment scores and the y-axis represents pathway terms. The colors of circle indicate P values and the size of circle indicates the numbers of differential RNAs. The circle with redder and larger indicating that the enrichment of the pathway is higher and differential RNAs number is larger in the pathway.