Recurrence Of 2,8-dihydroxyadenine Crystalline Nephropathy in A Kidney Transplant Recipient: A Case Report And Literature Review

Abstract: We herein report the case of a kidney transplant patient with a recurrence of obstructive nephropathy that was not diagnosed as adenine phosphoribosyltransferase (APRT) deficiency until gene testing identified a pathogenic homozygous variant three years after renal transplantation. Subsequently, the patient was treated with allopurinol, and the allograft function increased progressively to normal. In addition, 20 cases of APRT deficiency in renal transplant recipients were also reviewed. We hope this case increases awareness of APRT deficiency in repeated obstructive nephropathy post-transplantation, which is a treatable disease for which misdiagnosis or delayed diagnosis should be avoided. 

Keywords: adenine phosphoribosyltransferase deficiency, 2,8-dihydroxyadenine, kidney transplantation, renal biopsy, graft loss

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Introduction 

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive metabolic disorder of adenine that is frequently overlooked by physicians, due to the absence of specific clinical manifestations and laboratory evidence (1). Recurrence of the disease in renal transplant recipients is an underdiagnosed etiology of graft dysfunction. Cases of APRT deficiency resulting in allograft dysfunction are rarely reported. We encountered a case of recurrences of obstructive allograft nephropathy that was diagnosed as homozygous APRT deficiency by a genetic analysis three years after renal transplantation. The serum creatinine level was increased during the clinical follow-up period, and an allograft biopsy showed obstructive nephropathy caused by tubular crystal deposits. The serum creatinine level returned to normal after treatment with allopurinol. Other cases of APRT deficiency in the literature were also reviewed. 

Case Report 

The patient we encountered had bilateral kidney stones and left ureterolithiasis at 9 years old in 2003, and the serum creatinine was 200 μmol/L. The results of a urinalysis were not available. He had no flank pain and gross hematuria. He was diagnosed with obstructive nephropathy, and left ureterolithotomy was performed, but the stones were not sent for a chemical analysis. His serum creatinine level fluctuated between 200-300 μmol/L at regular follow-up visits and then increased gradually, eventually reaching 1,400 μmol/L in 2010. Subsequently, maintenance hemodialysis was begun and performed for six years. In September 2016, the patient received an allograft from a 45-year-old male donor after brain and cardiac death (China type III) and all procedures followed the Principles of the Declaration of Istanbul. Primary hyperoxaluria was ruled out (negative genetic testing of AGXT, GRHPR, and DHDPSL genes in 2015). An allograft biopsy was performed immediately after blood reperfusion, showing normal tubular epithelial cells without crystal deposition (Fig. 1A). Immunosuppressants included basiliximab as induction and mycophenolate, tacrolimus, and steroid as maintenance. Twenty days after transplantation, the serum creatinine level remained high at 204 μmol/L, and the serum uric acid level increased to 578 μmol/L. The patient then underwent a second allograft biopsy, which revealed tubular epithelial cell injury with scattered crystalline deposition (Fig. 1B-D). Thus, the patient received allopurinol 100 mg twice a day to treat his high level of uric acid. At 6 months post-operation, the serum creatinine levels had gradually decreased to 120 μmol/L. He had no family history of marriage between cousins or renal diseases.

From January 2019, allopurinol was withdrawn, as the uric acid level had decreased to 326 μmol/L and the serum creatinine level to 132 μmol/L. Six months later, however, the allograft function deteriorated again, with a serum creatinine level of 202 μmol/L. Histopathology results revealed acute T cell-mediated rejection (type IB) based on the 2017 Banff criteria, complicated by tubular epithelial cell injury and crystallization formation in the lumen (Fig. 2). The patient received methylprednisolone intravenous injection at 500 mg/day for 3 days and successive anti-human thymocyte immunoglobin at 50 mg/day for 5 days. The patient was discharged when the serum creatinine level had decreased to 168 μmol/L. A regular follow-up laboratory examination showed that the serum creatinine level had been maintained at 180-190 μmol/L.

Two months after hospital discharge, the serum creatinine level had increased to 228 μmol/L, with the uric acid level again at 416 μmol/L. A fourth renal allograft biopsy showed no obvious T cell-mediated rejection, but tubular epithelial cell injury was noted, along with crystal formation with inflammation cells around the crystal (Fig. 3). A genetic analysis was then performed and showed one homozygous variant with deletion of phenylalanine as well as serine and an insertion of serine into amino acids 174 and 175; NM_ 000485(of the APRT gene): c.521_523delTCT (p.174_175 delFSinsS), defined as having pathogenic significance according to The American College of Medical Genetics and Genomics (ACMG) guideline. The patient was subsequently treated with allopurinol, 200 mg/day, and a low-purine diet as well as ensuring sufficient fluid intake. His renal function eventually improved, with a follow-up serum creatinine level of 124 μmol/L and uric acid level of 297 μmol/L in July 2020.

Literature review

Twenty cases of APRT deficiency in renal transplantation patients were identified in our search of PubMed (2-18), summarized in Table. The following keywords were used: "Adenine phosphotransferase deficiency" OR "APRT deficiency" OR "2,8-dihydroxyadenine" OR "2,8-DHA" in combination with "transplant." The search publication date was from January 1, 1974, to July 1, 2020. There were 24 grafts in total. Information on the clinical manifestation was not available for one graft and was urolithiasis in five grafts, cloud urine in one graft, a delayed graft function in nine grafts, acute graft dysfunction in three grafts, and chronic graft dysfunction in five grafts. The diagnostic methods were a stone/crystal analysis (3 cases); a stone/crystal analysis and enzyme assay (5 cases); an enzyme assay only (5 cases); a stone/crystal analysis, enzyme assay, and gene analysis (3 cases); a gene analysis (1 case); and a stone/ crystal analysis and gene analysis (1 case). Details concerning the specific treatment were not available in one graft and were no treatment in five grafts; allopurinol, low purine, and hydration in five grafts; allopurinol and low purine in five grafts; allopurinol in five grafts; febuxostat, low purine, and hydration in one graft; and allopurinol and febuxostat in two grafts. Outcomes were unavailable in 1, graft loss in 11 (with no treatment in 5 and treatment in 6), and renal function improvement in 12.

Discussion 

APRT deficiency is a rare autosomal recessive hereditary disease of purine metabolism dysfunction. Adenine is normally converted to adenine monophosphate by APRT but is