Adenine Phosphoribosyltransferase Deficiency Research Articles

#2633 Navigating complexity: a case report of chronic kidney disease with renal stone unravelling a rare metabolic disorder

Abstract Clinical Presentation A 48-year-old female of Asian heritage was referred for renal assessment after experiencing recurrent acute kidney injury (AKI) with incomplete recovery between episodes. This was initially attributed to dehydration and interstitial nephritis stemming from long-standing vomiting, a manifestation of gastroscopy-proven erosive gastritis, compounded by the use of high-dose proton pump inhibitors (PPI). Her relevant medical history is of right nephrectomy in 1996 due to recurrent urinary tract infections (UTIs), and previous left renal calculus in 2019 with no visible stones on further CT imaging. Despite living with a single kidney, her baseline eGFR had been normal prior to referral. While unaware of her mother's medical history, her father was recently diagnosed with kidney disease (no clear history) and her sister Wilson's disease. A kidney biopsy was undertaken given the incomplete eGFR recovery between episodes. The biopsy revealed adequate tissue including 24 glomeruli, no significant glomerular pathology was seen. There is 65% tubulointerstitial atrophy and fibrosis, and yellow to red-brown-tinged crystals within tubular lumina and epithelial cells, prompting a histiocytic reaction. These crystals were birefringent under polarized light and did not stain with Perl's and Von Kossa stain (Fig. 1a-d). Immunofluorescence was negative for all immunoglobulins and complement fractions. No immune complex/substructure deposits were seen in the glomeruli on electron microscopy. Blood tests assessing APRT activity indicated values within the carrier range (Table 1). The patient and her family have been referred for a comprehensive genetic testing for APRT genetic mutations. Treatment with Allopurinol 300 mg daily resulted in a sustained eGFR improvement from 19 to 33 ml/min/1.73m2 at 6 months after initiation (Fig. 1). Discussion Adenine phosphoribosyl transferase (APRT) deficiency, also known as Dihydroxyadenineuria, is a rare autosomal recessive inherited condition leading to kidney stones. If left untreated, up to 25% progress to end-stage kidney disease (ESKD). Although inherited, half of patient present in adulthood and may do so with laboratory findings of CKD rather than specifically with stones [1]. This case highlights the significance of precise diagnosis in calculi-related kidney diseases. Early intervention can alter the trajectory of specific conditions, averting progression to ESKD. This case is unusual in being a carrier of an autosomal recessive condition presenting with full manifestations of the disease. Patient Consent The patient has given verbal, documented consent for case publication. Acknowledgment We thank all renal and pathology staff members at Salford Care Organisation who contributed to the diagnosis and management of our case.

#2556 Therapeutic monitoring in patients with APRT deficiency using UPLC-MS/MS-based plasma assay

Abstract Background and Aims Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder of purine metabolism, characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to nephrolithiasis and chronic kidney disease (CKD). Treatment with xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces DHA excretion and slows or halts CKD progression. The aim of the study was to optimize and validate an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based assay for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma, for monitoring of pharmacotherapy in patients with APRT deficiency. Method The UPLC-MS/MS-based assay was optimized employing the chemometric approach design of experiments, using the software Modde Pro 13 (Sartorius, Umeå, Sweden). The assay was validated and used for absolute quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in plasma samples from both untreated and treated APRTd patients and healthy controls. Results Accuracy and precision were within ±15% for all analytes, and the analytes were stable in plasma for 12 months at −80°C. The median (range) concentration of DHA in plasma samples from six APRT deficiency patients was 204.0 (187.2–315.8) ng/mL when they were untreated and 69.2 (below the limit of quantification [BLQ]–131.6) ng/mL when treated with allopurinol (400 mg/day), and BLQ when febuxostat (80 mg/day) was the therapeutic agent. The median (range) plasma adenine concentration was 238.1 (218–502) ng/mL in the untreated patients, and 561.1 (418–2104) and 856.0 (726–1711) ng/mL in those on treatment with allopurinol and febuxostat, respectively. DHA was not detected in plasma samples from healthy controls. The median (range) plasma concentration of allopurinol, oxypurinol and febuxostat in patients receiving XOR inhibitor therapy was 1657 (BLQ-3266) ng/mL, 8102 (4778–34906) ng/mL and 109 (BLQ-1657) ng/mL, respectively. Conclusion The UPLC-MS/MS-based assay provides accurate and precise quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma. Measurement of plasma DHA is being implemented as a diagnostic test for APRT deficiency and the full assay for monitoring of XOR inhibitor treatment in patients with the disorder.

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila.

Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch-Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia, and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients. Here, we studied LND-related mechanisms in the fruit fly. By combining enzymatic assays and phylogenetic analysis, we confirm that no HGPRT activity is expressed in Drosophila melanogaster, making the APRT homolog (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed that Drosophila Aprt mutants show both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by Aprt re-expression in neurons and reproduced by knocking down Aprt selectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies, or glia subsets. Ingestion of allopurinol rescued uric acid levels in Aprt-deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine or N6-methyladenosine (m6A) during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to Aprt deficiency. Overall, our results suggest that Drosophila could be used in different ways to better understand LND and seek a cure for this dramatic disease.

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch–Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia, and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients. Here, we studied LND-related mechanisms in the fruit fly. By combining enzymatic assays and phylogenetic analysis, we confirm that no HGPRT activity is expressed in Drosophila melanogaster, making the APRT homolog (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed that Drosophila Aprt mutants show both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by Aprt re-expression in neurons and reproduced by knocking down Aprt selectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies, or glia subsets. Ingestion of allopurinol rescued uric acid levels in Aprt-deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine or N6-methyladenosine (m6A) during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to Aprt deficiency. Overall, our results suggest that Drosophila could be used in different ways to better understand LND and seek a cure for this dramatic disease.

A case of APRT deficiency – a rare cause of nephrolithiasis and kidney failure

A case of APRT deficiency – a rare cause of nephrolithiasis and kidney failure

Adenine Phosphoribosyl Transferase (APRT) Deficiency as an Under-recognized Cause of Kidney Graft Failure: A Case Report

Adenine Phosphoribosyl Transferase (APRT) Deficiency as an Under-recognized Cause of Kidney Graft Failure: A Case Report

Tracking Molecular and Phenotypic Changes in Kidney Cells in 2D and 3D Cultures Following DHA Exposure: An Approach to Understand Cellular Changes in Adenine Phosphoribosyltransferase (APRT) Deficiency

Tracking Molecular and Phenotypic Changes in Kidney Cells in 2D and 3D Cultures Following DHA Exposure: An Approach to Understand Cellular Changes in Adenine Phosphoribosyltransferase (APRT) Deficiency

Adenine phosphoribosyl transferase (APRT) deficiency and a novel sequence variant in APRT with phenotypic diversity and a literature review.

Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8-dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11-year-old brother and his 14-year-old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484_486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere-like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male.

Urinary 2,8-dihydroxyadenine crystals in a patient with adenine phosphoribosyltransferase deficiency.

Urinary 2,8-dihydroxyadenine crystals in a patient with adenine phosphoribosyltransferase deficiency.

Foreign body granuloma with crystals, recurrent kidney stones, in a patient with adenine phosphoribosyltransferase (APRT) deficiency.

Foreign body granuloma with crystals, recurrent kidney stones, in a patient with adenine phosphoribosyltransferase (APRT) deficiency.

Modelling APRT Deficiency in Kidney Cells In Vitro

Modelling APRT Deficiency in Kidney Cells In Vitro

Inflammation plays a critical role in 2,8-dihydroxyadenine nephropathy

Adenine phosphoribosyltransferase (APRT) deficiency is a genetic disease characterized by an increased production of 2,8 dihydroxyadenine (2,8-DHA) precipitating in urine, leading to a crystalline nephropathy and end-stage renal disease. Here, we describe the high prevalence of granuloma (88%) in biopsies from patients with APRT deficiency. A murine model of 2,8-DHA nephropathy was generated, showing that anakinra or dexamethasone, combined with allopurinol, improved renal function to a larger extent than allopurinol alone, the standard therapy. Inflammation plays a critical role in the development of 2,8-DHA nephropathy, and therapy based upon drugs targeting innate immunity could improve renal function recovery.

Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells

The pathogenesis of crystal nephropathy involves deposition of intratubular crystals, tubular obstruction and cell death. The deposition of 8-dihydroxyadenine (DHA) crystals within kidney tubules, for instance, is caused by a hereditary deficiency of adenine phosphoribosyl transferase in humans or adenine overload in preclinical models. However, the downstream pathobiological patterns of tubular cell attrition in adenine/DHA-induced nephropathy remain poorly understood. In this study, we investigated: (i) the modes of adenine-induced tubular cell death in an experimental rat model and in human primary proximal tubular epithelial cells (PTEC); and (ii) the therapeutic effect of the flavonoid baicalein as a novel cell death inhibitor. In a rat model of adenine diet-induced crystal nephropathy, significantly elevated levels of tubular iron deposition and lipid peroxidation (4-hydroxynonenal; 4-HNE) were detected. This phenotype is indicative of ferroptosis, a novel form of regulated necrosis. In cultures of human primary PTEC, adenine overload-induced significantly increased mitochondrial superoxide levels, mitochondrial depolarisation, DNA damage and necrotic cell death compared with untreated PTEC. Molecular interrogation of adenine-stimulated PTEC revealed a significant reduction in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the significant increase in 4-HNE compared with untreated PTEC, supporting the concept of ferroptotic cell death. Moreover, baicalein treatment inhibited ferroptosis in adenine-stimulated PTEC by selectively modulating the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) and thus, suppressing mitochondrial superoxide production and DNA damage. These data identify ferroptosis as the primary pattern of PTEC necrosis in adenine-induced nephropathy and establish baicalein as a potential therapeutic tool for the clinical management of ferroptosis-associated crystal nephropathies (e.g., DHA nephropathy, oxalate nephropathy).

A deficiência de adenina fosforibosiltransferase leva à disfunção do aloenxerto renal em receptores de transplante renal: uma revisão sistemática

Background:Adenine phosphoribosyl transferase (APRT) deficiency has great implications on graft survival in kidney transplant patients. This systematic review investigated the diagnostic pattern, treatment approach, and kidney transplant outcomes among kidney transplant patients with adenine phosphoribosyl transferase deficiency.Material and methods:Articles reporting the APRT enzyme deficiency and kidney allograft dysfunction were retrieved from PubMed/Medline, ScienceDirect, Cochrane library and Google scholar databases. Descriptive analysis was used to draw inferences.Results:The results from 20 selected studies covering 30 patients receiving 39 grafts had an average age of 46.37 years are presented. Graft survival time of more than 6 months was reported in 23 (76.7%) patients, while other 7 (23.3%) patients had graft survival time of less than 6 months. Only 4 (13.3%) patients had APRT deficiency before transplantation. After follow-up, one-third of the patients 10 (33.3%) had stable graft function, 1 patient had allograft loss, 8 (26.6%) patients had delayed graft function while the remaining 11 (36.6%) patients had chronic kidney graft dysfunction.Conclusions:APRT deficiency is an under-recognized, treatable condition that causes reversible crystalline nephropathy, leading to loss of allograft or allograft dysfunction. The study results showed that inclusion of genetic determination of APRT deficiency in the differential diagnosis of crystalline nephropathy, even in the absence of a history of nephrolithiasis, can improve renal outcomes and may improve allograft survival.

Ultra-rare renal diseases diagnosed with whole-exome sequencing: Utility in diagnosis and management

BackgroundThis study aimed to use whole-exome sequencing (WES) to diagnose ultra-rare renal diseases and the clinical impact of such an approach on patient care.MethodsClinical, radiological, pathological, and genetic findings were reviewed in the patients and their family members.ResultsNine patients from nine unrelated Korean families were included in the study and evaluated. WES identified eight different conditions in these patients, i.e., autosomal dominant tubulointerstitial kidney disease associated with UMOD mutation; recurrent urinary stones associated with APRT deficiency; Ayme-Gripp syndrome associated with MAF mutation; short rib-thoracic dysplasia associated with IFT140 mutation; renal coloboma syndrome associated with PAX2 mutations; idiopathic infantile hypercalcemia associated with CYP24A1 mutation; and hypomagnesemia associated with TRPM mutation. Eleven different mutations, including seven novel mutations, were identified, i.e., four truncating mutations, six missense mutations, and one splice-acceptor variant. After genetic confirmation, strategies for the management of the following: medications, donor selection for renal transplantation, and surveillance for extra-renal manifestations were altered. In addition, genetic counseling was provided for the patients and their family members with respect to family member screening for affected but yet unidentified patients and future reproductive planning.ConclusionAs WES can effectively identify ultra-rare genetic renal diseases, facilitate the diagnosis process, and improve patient care, it is a good approach to enable a better understanding of ultra-rare conditions and for the establishment of appropriate counseling, surveillance, and management strategies.

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

Abstract 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.

アデニンフォスホリボシルトランスフェラーゼ欠損症の診断のガイドラインに関する考察 －GC/MS-尿メタボロミクスを診断の入り口と確定診断に－

アデニンフォスホリボシルトランスフェラーゼ欠損症の診断のガイドラインに関する考察 －GC/MS-尿メタボロミクスを診断の入り口と確定診断に－

Are conventional stone analysis techniques reliable for the identification of 2,8-dihydroxyadenine kidney stones? A case series.

We have recently encountered patients incorrectly diagnosed with adenine phosphoribosyltransferase (APRT) deficiency due to misidentification of kidney stones as 2,8-dihydroxyadenine (DHA) stones. The objective of this study was to examine the accuracy of stone analysis for identification of DHA. Medical records of patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium in 2010-2018 with a diagnosis of APRT deficiency based on kidney stone analysis were reviewed. The diagnosis was verified by measurement of APRT enzyme activity or genetic testing. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of pure crystalline DHA and a kidney stone obtained from one of the confirmed APRT deficiency cases were generated. The ATR-FTIR spectrum of the kidney stone matched the crystalline DHA spectrumand was used for comparison with available infrared spectra of stone samples from the patients. Of 17 patients referred, 14 had sufficient data available to be included in the study. In all 14 cases, the stone analysis had been performed by FTIR spectroscopy. The diagnosis of APRT deficiency was confirmed in seven cases and rejected in the remaining seven cases. Comparison of the ATR-FTIR spectrum of the DHA stone with the FTIR spectra from three patients who did not have APRT deficiency showed no indication of DHA as a stone component. Misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. Since current clinical protocols used to interpret infrared spectra for stone analysis cannot be considered reliable for the identification of DHA stones, the diagnosis of APRT deficiency must be confirmed by other methods.

Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.