Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of purine metabolism causing 2,8-dihydroxyadenine urinary tract stones and crystal nephropathy. Disease manifestations include acute kidney injury (AKI), progressive chronic kidney disease (CKD), and not infrequently, kidney failure. A significant proportion of affected individuals remain asymptomatic into adulthood. The diagnosis of APRT deficiency should be considered in all children presenting with renal colic, radiolucent urinary stones and/or AKI, as well as in infants with a history of reddish-brown diaper stain. Indeed, the disorder should be considered in any person with radiolucent urinary stones and in young and middle-aged individuals with progressive CKD, particularly when a kidney biopsy reveals tubulointerstitial nephropathy of unknown cause. The presence of biallelic pathogenic APRT mutations identified through targeted multi-gene panels or single-gene testing confirms the diagnosis of APRT deficiency. As kidney stone analysis can be false-positive, this method can only be considered suggestive of APRT deficiency, and confirmatory testing must be carried out in all cases. Timely diagnosis and treatment with a xanthine oxidoreductase inhibitor, either allopurinol or febuxostat, have in several studies, based on different levels of evidence, been found to be both highly effective and safe in APRT deficiency. Appropriate pharmacotherapy significantly reduces kidney stone recurrence, slows CKD progression and appears to prevent the development of kidney failure. The outcome of kidney transplantation in individuals with APRT deficiency is comparable to those with other causes of kidney failure when allopurinol or febuxostat therapy is initiated before the transplant procedure.

Historically, the management of patients with nephrolithiasis has been primarily delivered by urologists. In recent decades nephrologists have had an increasing role in caring for these patients not only in advanced stages of chronic kidney disease (CKD) but also in the diagnosis and management of underlying systemic disease, and metabolic and genetic risk factors. Globally the burden of kidney stone disease has been increasing, with metabolic disorders strongly associated with nephrolithiasis and stone-promoting urinary risk factors, including hypercalciuria, hyperoxaluria and hypocitraturia. At a healthcare level, kidney stones account for a relatively large number of emergency department visits, while individually the impact of kidney stones and the fear of recurrence often result in loss of work and high levels of psychological distress, in addition to an increased CKD risk. Kidney stones in the context of CKD of unknown cause can be the signature of an inherited disorder such as Dent disease, primary hyperoxaluria or adenine phosphoribosyltransferase deficiency (among others). Diagnosing these diseases is imperative in the current age of new treatments (e.g. small interfering RNA therapies), to avoid further deterioration of kidney function and disease recurrence post-transplantation. We outline 10 practical tips to guide clinicians in the diagnostic evaluation and management of nephrolithiasis in CKD.

Adenine phosphoribosyltransferase (APRT) deficiency is an autosomal recessive disorder that causes accumulation of 2,8-dihydroxyadenine (DHA) in the urinary tract, leading to kidney stones and chronic kidney disease (CKD). Progression to end-stage kidney disease can occur without timely treatment. The xanthine oxidoreductase inhibitors, allopurinol and febuxostat, block DHA generation and halt or delay stone formation and CKD progression. Some patients do not tolerate xanthine oxidoreductase inhibitor treatment, necessitating new therapeutic approaches. This study aimed to investigate how DHA influences structural and molecular changes in HK-2, HEK293, and MDCK kidney cells. DHA exposure reduced cell viability and impaired migration in all cell lines. Increased expression of the adhesion protein CD44 was observed adjacent to DHA crystals in HEK293 and HK-2 cells. Transepithelial electrical resistance measurements in MDCK cells indicated reduced epithelial integrity following DHA exposure. RNA sequencing of DHA-treated HK-2 cells revealed gene expression changes, with upregulation of TNF-α and mTORC1 signaling and downregulation of epithelial to mesenchymal transition and oxidative phosphorylation. Functional enrichment analysis highlighted pathways related to cell cycle regulation, inflammation, and metabolic processes. These findings show that dose-dependent DHA toxicity interrupts cell migration and epithelial integrity. CD44 may contribute to crystal adhesion, and thus, represents a potential therapeutic target in DHA crystal nephropathy. KEY MESSAGES: DHA reduces kidney cell viability and migration in a dose-dependent manner. DHA disrupts epithelial integrity in MDCK cells, lowering TEER values. CD44 expression increases adjacent to DHA crystals with increased DHA concentration. RNA sequencing shows that DHA upregulates TNF-α, mTORC1, and stress pathways. DHA alters gene expression, affecting inflammation, metabolism, and EMT.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, autosomal recessive disorder characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. Treatment with the xanthine oxidoreductase (XOR) inhibitors allopurinol and febuxostat reduces DHA production. DHA and adenine were measured in 122 paired plasma and urine samples from 26 individuals with confirmed APRT deficiency, using ultra-performance liquid chromatography-tandem mass spectrometry assays. The relationship between plasma DHA and adenine concentrations, urine DHA-to-creatinine (DHA/Cr) and adenine-to-creatinine (adenine/Cr) ratios, and age and estimated glomerular filtration rate (eGFR) was evaluated in a subset of 87 paired plasma and urine samples from 23 individuals using Spearman's rank correlation. Allopurinol and febuxostat treatment reduced plasma DHA, with the median (range) concentration decreasing from 249 (123-1315) ng/mL in untreated individuals to below the limit of detection in those receiving higher doses. Plasma adenine increased during XOR inhibitor treatment. In untreated individuals, a strong negative correlation was observed between plasma DHA and eGFR (rs = -0.74, p < 0.0001). Plasma DHA correlated with urine DHA/Cr ratio in individuals treated with allopurinol or febuxostat (rs = 0.65, p < 0.0001), while no significant correlation was observed in untreated individuals (rs = -0.26, p = 0.14). Treatment with XOR inhibitors effectively reduces the plasma concentration and urinary excretion of DHA. The strong correlation between plasma DHA and eGFR, combined with the lack of correlation between plasma DHA and urine DHA/Cr ratio in untreated individuals, suggests that plasma DHA may be a more reliable marker of systemic DHA burden.

The rare metabolic disease, adenine phosphoribosyl transferase (APRT) deficiency, is asymptomatic in many cases until it is discovered in terminal renal failure. The most frequent complication is 2,8-dihydroxyadenine (2,8-DHA) urolithiasis. Stones, which are frequently bilateral and recurrent, appear in childhood in one-third of cases. An 8-year-old girl presented with urinary tract infection and coralliform urolithiasis in the right kidney. Initial radiological examination showed emphysematous pyelonephritis stage 1 due to obstructive lithiasis. Stone analysis helped confirm the diagnosis of APRT deficiency. The diagnostic difficulties, clinical manifestations, and the impact of early detection and management on preventing stone recurrence and complication were discussed. The therapeutic strategies available, including dietary modifications and allopurinol therapy, were reviewed. Early intervention with therapeutic and dietetic measures could preserve the normal renal function of the young patient.