An Unusual Course of a 2,8-Dihydroxyadeninuria Crystalline Nephropathy Secondary to Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder caused by an autosomal recessive genetic disease leading to the deposition of 2,8-dihydroxyadenine (2,8-DHA) in the kidney. The disease remains under-recognized, oftentimes diagnosed in late stages of renal insufficiency or a failed kidney allograft with biopsy-proven disease recurrence. Here, we present the case of a 59-year-old middle eastern male patient diagnosed with 2,8-DHA nephropathy after a very unusual presentation, and we show how the initiation of an appropriate therapy slowed down his evolution toward kidney replacement therapies. His disease was found to be secondary to a specific APRT gene variant c.188G>A p (Gly63Asp) also described in 4 other patients, all from middle eastern origins.

MO167AN UNUSUAL COURSE OF A 2,8 DHA CRYSTAL INDUCED NEPHROPATHY

Background and Aims 2, 8 dihydroxyadenine (DHA) deposition is a less known etiology of crystal-induced nephropathy, caused by a deficiency in a purine salvage enzyme, the adenine phosphoribosyl transferase (APRT). DHA is an insoluble molecule in urine leading to crystal formation, tubular obstruction or stone formation. The disease manifests as a history of urolithiasis, chronic kidney disease and even loss of renal allograft when the disease is undiagnosed in native kidneys. The cornerstone of treatment is the inhibition of xanthine dehydrogenase reducing thus the formation of 2,8-DHA and its renal excretion. Method A 59-year-old obese Lebanese male patient, born to a consanguineously married couple, was admitted to another hospital with desaturation, a history of progressive shortness of breath and a creatinine level of 2,8 mg/dl. He had no hypertension nor diabetes. His family history was positive for a sister with ESRD of unknown etiology. He was discharged on oxygen and continuous airway positive pressure therapy for severe obstructive sleep apnea. His renal function deteriorated leading to a creatinine level of 9.8 mg/dl three months later. There were no signs of systemic disease, no gross hematuria, no fluid overload. His blood pressure was normal. Laboratory work up showed anemia, low grade proteinuria, intermittent microscopic hematuria and negative serological and immunological workup. Kidney ultrasound showed normal size kidneys with no evidence of collecting system dilatation or urolithiasis. Due to this atypical presentation, the patient was admitted for a renal biopsy with a creatinine level of 11 mg/dl upon admission. Results The renal biopsy showed tubulo-interstitial nephritis associated with numerous brown-green crystals by Haematoxylin and eosin of various shapes birefringent under polarized light with the characteristic “maltese cross”. Crystals were found within tubular lumens and cytoplasm, interstitium, and macrophages. These findings were characteristic of 2,8 DHA crystals deposition in the kidney. The patient was started on 120 mg of Febuxostat with a low purine and high fluid diet. A genetic testing showed a pathogenic homozygous variant in the APRT gene which causes an amino acid change from Glycine to Aspartate at position 63. Two weeks later the patient was admitted to the ICU with pneumonia, respiratory failure, a creatinine of 9 mg/dl and severe metabolic encephalopathy. He received 4 sessions of hemodialysis followed by an improvement in his kidney function with a creatinine level down to 3.2 mg/dl a month after his discharge and he remains off dialysis until now. Conclusion Around 400 cases are currently recognized worldwide, emphasizing the under recognition of this autosomal recessive disease. Considering that the homozygoty causing a complete APRT deficiency should range between 1/50 000 and 1/100 000 cases, this would translate in at least 80 000 cases worldwide. The variant found in our patient has previously been described as disease causing for APRT deficiency in four cases. Reviewing the phenotype of these cases we find differences in terms of presentation and evolution, highlighting the variability in the APRT deficiency phenotype and underlining the fact that no correlation between phenotype and genotype was reported to date even for the same type of mutation. This case report shows us that the initiation of an adequate therapy is necessary even at advanced stages of the disease since it can improve our kidney outcome.

Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency

Adenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.

Rare crystalline nephropathy leading to acute graft dysfunction: a case report

Background Adenine phosphoribosyl transferase (APRT) deficiency is a rare genetic form of kidney stones and/or kidney failure characterized by intratubular precipitation of 2,8 dihydroxyadenine crystals. Early diagnosis and prompt management can completely reverse the kidney injury. Case presentation 44 year old Indian male, renal transplant recipient got admitted with acute graft dysfunction. Graft biopsy showed light brown refractile intratubular crystals with surrounding giant cell reaction, consistent with APRT deficiency. Patient improved after receiving allopurinol and hydration. Conclusion APRT forms a reversible cause of crystalline nephropathy. High index of suspicion is required for the correct diagnosis as timely diagnosis has therapeutic implications.

APRT deficiency: the need for early diagnosis

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder which leads to accumulation of poorly soluble 2,8-dihydroxyadenine in kidneys resulting in nephrolithiasis as well as chronic kidney disease from crystal nephropathy. This report describes a 55-year-old previously fit man who presented with shortness of breath and the investigative pathway that eventually led to a diagnosis of APRT deficiency. Early diagnosis has aided in timely institution of allopurinol, thereby improving his renal function and possibility of weaning off renal replacement therapy. Genetic testing has enabled early identification of other family members at risk and prevention of renal failure by commencing xanthine oxidoreductase (XOR) inhibitors. The issues surrounding kidney donation by a member of this family are also discussed. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition, complications of which can be easily prevented by early institution of XOR inhibitor therapy.