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Original Clinical Science—General

Kidney Transplant Outcomes in Patients With Adenine Phosphoribosyltransferase Deficiency

Runolfsdottir, Hrafnhildur Linnet MD1,2; Palsson, Runolfur MD1,2; Agustsdottir, Inger M. Sch. RN3; Indridason, Olafur S. MD, MHS2; Li, Jennifer MD4; Dao, Myriam MD5; Knebelmann, Bertrand MD, PhD5,6,7; Milliner, Dawn S. MD8; Edvardsson, Vidar O. MD1,3

Author Information
doi: 10.1097/TP.0000000000003088
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Abstract

INTRODUCTION

Adenine phosphoribosyltransferase (APRT) deficiency (OMIM 102600) is a rare autosomal recessive disorder of purine metabolism. Absence of a functional APRT enzyme results in the conversion of adenine to 2,8-dihydroxyadenine (DHA), catalyzed by xanthine oxidoreductase (XOR; also known as xanthine oxidase/dehydrogenase). DHA is poorly soluble in the urine at physiological pH, leading to precipitation and formation of recurrent radiolucent kidney stones and crystal nephropathy. DHA nephropathy is characterized by widespread DHA crystal deposits, predominantly in the form of large aggregates in the tubular lumen, and smaller crystals in tubular epithelial cells and the interstitium, accompanied by tubulointerstitial inflammation and fibrosis.1,2

Chronic kidney disease (CKD), sometimes without a history of nephrolithiasis, is a common presenting feature of APRT deficiency in adults, and 15%–20% of patients have already reached end-stage kidney disease (ESKD) at the time of diagnosis.3-5 Furthermore, the disorder is often first recognized in the setting of disease recurrence following kidney transplantation. Three case series2,6,7 and several single-patient reports8-13 of kidney transplantation in patients with APRT deficiency have previously been published, commonly describing disease recurrence and unfavorable outcomes.

Treatment with the XOR inhibitors, allopurinol or febuxostat, reduces DHA production, and in turn, its renal excretion and can prevent or halt the progression of crystal nephropathy,14 preserving and even improving kidney function.3 Allopurinol is frequently prescribed in the daily dose of 200–300 mg/day although higher doses (400–600 mg) are likely needed to minimize or prevent recurrent kidney stone formation and renal parenchymal DHA crystal deposition in the native kidney.2,3 Early disease recurrence in transplanted kidneys and accelerated allograft loss has been noted in both untreated and treated patients, suggesting that higher doses of allopurinol may be needed to preserve graft function.6,8

Limited data exist on the outcome of kidney transplantation in patients with APRT deficiency and the role of XOR inhibitor treatment in preserving kidney allograft function. The aim of this study was to examine the outcome of kidney transplantation in patients with APRT deficiency, in particular the effect of XOR inhibitor treatment status at the time of transplantation.

MATERIALS AND METHODS

Ethics

The study was approved by the National Bioethics Committee of Iceland (NBC 09–072) and the Icelandic Data Protection Authority. All living patients consented to participation in the study. The clinical and research activities reported herein are consistent with the principles of the Declarations of Helsinki and Istanbul.

Study Population

Thirteen (21%) of the 61 patients enrolled in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (http://www.rarekidneystones.org/) who had undergone kidney transplantation were included in the study. These patients were from Austria (n = 1), Iceland (n = 2), India (n = 1), Italy (n = 2), and the United States (n = 7). In addition, 2 patients from Australia and 2 patients from France who had received a kidney transplant were included. Transplant outcome data on 8 of these 17 patients have previously been reported.2,6,7,11,15 The diagnosis of APRT deficiency was confirmed by the identification of biallelic pathogenic APRT mutations or completely abolished APRT enzyme function.

Clinical Data

Sources of data included the APRT Deficiency Registry of the Rare Kidney Stone Consortium and individual patient records at participating hospitals through June 2019. In addition to basic demographic information, the following data were collected: age and clinical characteristics at presentation and diagnosis of APRT deficiency; age at onset of renal replacement therapy; dialysis before kidney transplantation; age at transplantation, number of kidney allografts and donor type; date and cause of graft loss; date and cause of death; immunosuppressive therapy; treatment with allopurinol or febuxostat, including dose before and after transplantation; laboratory studies, including serum creatinine (SCr) measurements, results of urine microscopy, including assessment of DHA crystals, APRT genotype and APRT enzyme activity measurements; results of urological imaging; and kidney allograft biopsy findings.

Glomerular filtration rate estimates (eGFR) were calculated from SCr using the modified Schwartz (CKiD) equation in children16 and the Chronic Kidney Disease Epidemiology Collaboration equation in adults.17 As previously described, nonstandardized SCr values were reduced by 5% before eGFR was calculated.18 Staging of CKD was according to the Kidney Disease: Improving Global Outcomes classification system.19 Graft loss was defined as initiation of dialysis, retransplantation, or death with a functioning graft. Delayed graft function was defined as the need for dialysis in the first posttransplant week. Posttransplant acute kidney injury (AKI) was defined according to the Kidney Disease: Improving Global Outcomes AKI criteria.20

Analytical Considerations

Data are presented as number, percentage and median (range). In the analysis, allografts were grouped according to whether or not the patients were receiving XOR inhibitor treatment before kidney transplantation, and the Wilcoxon-Mann-Whitney test and Fisher’s exact test were used to compare the group of patients who initiated XOR inhibitor treatment pretransplant to those who first started such treatment following transplant surgery. Patients receiving dialysis were assigned an eGFR of 10 mL/min/1.73 m2. Kaplan-Meier analysis was used to estimate death-censored allograft survival and groups were compared using the log-rank test. Statistical analyses were performed using SPSS (IBM SPSS Statistics version 21.0, 2012, Armonk, NY).

RESULTS

Clinical Characteristics of Patients at Diagnosis of APRT Deficiency

Of 17 patients who had undergone kidney transplantation, 9 (53%) were females.

The clinical characteristics of the patients at the time of diagnosis of APRT deficiency are presented in Table 1. The median age at diagnosis was 44.5 (11.9–67.9) years, by which time 13 of the 17 patients (76%) had initiated renal replacement therapy for ESKD. Of the 17 patients, 15 had a diagnostic delay of 7.8 (1.1–47.9) years following presentation of APRT deficiency. Eleven patients (65%) were diagnosed with APRT deficiency before the first kidney transplantation; 1 of the 11 patients had CKD stage 3a, 3 had reached CKD stages 4–5, and 7 were already on hemodialysis. The diagnosis of APRT deficency was suggested by detection of DHA crystals on urine microscopy in 2 of these 11 cases, kidney stone analysis in 1 case and renal histological findings of crystal nephropathy in 5 individuals. Three patients were diagnosed through family screening of index cases, 2 of whom had a personal history of kidney stone disease.

TABLE 1. - Clinical characteristics at the time of diagnosis of APRT deficiency
Patient Sex History of kidney stones Age at diagnosis (y) Diagnostic delay (y) Kidney function (eGFR, mL/min/1.73 m2) Age at kidney biopsy (y) Original native kidney biopsy findings
1 M No 62 1.1 ESKD 62 DHA crystal nephropathy; global glomerulosclerosis (21 of 45 glomeruli), severe, interstitial fibrosis and arteriosclerosis
2 F No 43 5.1 ESKD 38 Crystals thought to be consistent with primary hyperoxaluria
3 M Yes 43 11.1 ESKD NA
4 F Yes 68 47.9 ESKD NA
5 F No 52 7.5 ESKD NA
6 F No 52 6.0 ESKD 45 Interstitial inflammation with inflammatory infiltrate; refractory golden-brown crystalline material seen
7 F Yes 59 24.0 ESKD NA
8 M Yes 12 10.4 ESKD NA
9 F Yes 49 7.8 9 42 Tubulointerstitial fibrosis; presumed calcium oxalate crystal deposits
10 M Yes 42 39.2 17 42 DHA crystals; interstitial inflammation
11 F Yes 45 1.4 ESKD NA
12 F No 21 0 ESKD 21 Tubulointerstitial nephritis with extensive calcium oxalate deposits
13 M No 40 4.7 ESKD 35 Chronic interstitial nephritis; crystals seen but not identified
14 F Yes 24 4.0 54 NA
15 M Yes 50 20.0 ESKD 50 Small number of scattered tubules contain intraluminal polarizable crystals believed to be calcium oxalate
16 M No 43 0.2 ESKD 42 DHA crystals with advanced glomerulosclerosis, tubular atrophy and interstitial fibrosis
17 M Yes 52 20.0 6 NA
APRT, adenine phosphoribosyltransferase; DHA, 2,8-dihydroxyadenine; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; NA, not available.

The diagnosis of APRT deficiency was not made until after kidney transplantation in 6 patients. In 5 of the patients, the diagnosis was made following their first transplantation and in 1 individual after the failure of 2 kidney allografts. The presumed cause of ESKD in these 6 patients was primary hyperoxaluria (n = 2), chronic interstitial nephritis (n = 2), kidney stone disease (n = 1), and CKD of unknown cause (n = 1).

Pharmacotherapy of APRT Deficiency and Kidney Allograft Outcomes

The 17 patients received 22 kidney allografts as outlined in Table 2. The first kidney transplantation was carried out at the median age of 47.2 (14.9–67.0) years, 1.8 (0.7–13.5) years after reaching ESKD in 14 cases, while 3 patients underwent preemptive transplantation. The maintenance immunosuppression regimen consisted of a calcineurin inhibitor (18 allografts) or sirolimus (1 allograft) in conjunction with mycophenolate mofetil and steroids; 2 patients received cyclosporine and azathioprine without steroids and azathioprine was the sole immunosuppressive agent in 1 case.

TABLE 2. - Pharmacotherapy of APRT deficiency and kidney allograft outcomes
Patient Treatment before Tx Age at RRT (y) Graft number Age at Tx (y) Type of donor Treatment with XOR inhibitor Outcome Last follow-up (y after Tx) Latest eGFR (mL/min/1.73 m2)
1 No 62 1 65 DD Febuxostat 40 mg/d from 3 wk post-Tx Recurrence of DHA nephropathy 3 wk post-Tx; functioning graft 1.6 25
2 No 38 1 39 DD None Graft lost due to recurrence of DHA nephropathy 1 mo post-Tx 0.1 ESKD
No 39 2 42 DD Allopurinol 200 mg/d from 6 mo post-Tx Recurrence of DHA nephropathy 3 d post-Tx and allograft failure at 13 mo post-Tx; died while on dialysis 1.1 ESKD
3 No 42 1 43 DD Allopurinol 300 mg/d from 4 mo post-Tx Died with a functioning graft 0.5 41
4 No 65 1 67 DD Allopurinol 150 mg/d from 3 wk post-Tx Functioning graft 6.5 28
5 No 45 1 46 DD Allopurinol 150 mg/d from 3 y post-Tx Died with a functioning graft 5.4 29
6 No 50 1 51 DD Allopurinol 300 mg/d from 5 wk post-Tx, later febuxostat 80 mg/d Recurrence of DHA nephropathy 24 d post-Tx; graft lost after 19 mo 1.7 AKI/dialysis
7 No 44 1 58 LRD Allopurinol 300 mg/d from 2 mo post-Tx Functioning graft 9.7 37
8 No 12 1 15 DD None Graft lost 18 mo post-Tx 1.5 ESKD
No 16 2 17 DD Allopurinol 300 mg/d from d 28 post-Tx Recurrence of DHA nephropathy 1 mo post-Tx; graft lost after 3.4 y 3.4 ESKD
Yes 20 3 21 DD Allopurinol 300 mg/d Chronic allograft failure 7.8 ESKD
No 27 4 35 DD Allopurinol 150 mg twice-a-wk, from d 36 post-Tx Recurrence of DHA nephropathy 1 mo post-Tx; died with a functioning graft 1.4 15
9 Yes 54 1 56 DD Allopurinol 300 mg/d for 7 y pre-Tx, subsequently 600 mg/d Functioning graft 13.3 50
10 Yes 46 1 46 LUD Allopurinol 400 mg/d for 3 y pre-Tx Functioning graft 4.4 71
11 Yes 43 1 47 DD Allopurinol 300 mg/d for 2 y pre-Tx Functioning graft 4.4 45
12 Yes 21 1 22 LRD Allopurinol 300 mg/d for 1 y pre-Tx, later also febuxostat 120 mg/d Graft lost due to recurrence of DHA nephropathy 5 y post-Tx 5.2 ESKD
Yes 28 2 29 LUD Allopurinol 600 mg/d and febuxostat 120 mg/d Functioning graft 1.8 69
13 Yes 36 1 41 LRD Allopurinol 200 mg/d for 1 mo pre-Tx, subsequently 400 mg/d Died with a functioning graft 0.3 39
14 Yes 41 1 41 DD Allopurinol 300-400 mg/d for 15 y pre-Tx, subsequently 600 mg/d Functioning graft 3.9 80
15 Yes 50 1 53 LUD Allopurinol for 2 y pre-Tx, subsequently 600 mg/d Functioning graft 2.8 65
16 Yes 42 1 47 DD Allopurinol 150 mg/d for 4 y pre-Tx, subsequently 300 mg/d and febuxostat 40 mg/d Recurrence of DHA nephropathy 10 d post-Tx; functioning graft 1.0 60
17 Yes 66 1 66 DD Allopurinol 200 mg/d for 12 y pre-Tx, subsequently 300 mg/d Functioning graft 2.1 82
The shaded area denotes allografts where xanthine oxidoreductase treatment was not initiated prior to kidney transplantation.
AKI, acute kidney injury; APRT, adenine phosphoribosyltransferase; DD, deceased donor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; LRD, living-related donor; LUD, living-unrelated donor; RRT, renal replacement therapy; Tx, kidney transplantation.

Ten patients received treatment with allopurinol 200 (100–300) mg/day for 2.6 (0.1–15.6) years before the transplantation of 11 allografts (Table 2). Delayed graft function was noted in the case of 3 kidney allografts, all from deceased donors, and AKI in 4 allografts, occurring within the first posttransplant week in 2 cases. A transplant biopsy was obtained from 8 allografts in 7 patients (Table 3). Recurrence of DHA crystal nephropathy (Figure 1) was found in 3 of these allografts, at 10 days, 8 weeks, and 4 months after transplantation. At the time of biopsy, 1 of the patients (No. 16) was taking allopurinol in the daily dose of 150 mg, while the remaining 2 allografts were from the same patient (No. 12) who was prescribed allopurinol 300–600 mg/day before and following both transplants, though significant medication nonadherence following the first transplant was acknowledged. Renal histopathological findings suggestive of acute rejection were found in 2 cases, immediately posttransplant in 1 case and 1 month following transplant surgery in the other: no crystals were observed. One patient (No. 13) died with a functioning graft 4 months after transplantation from bacterial sepsis associated with peritonitis, and 1 graft was lost nearly 8 years posttransplant with an allograft biopsy consistent with chronic allograft nephropathy (patient No. 8). No DHA crystals were detected.

TABLE 3. - Clinical features at the time of kidney allograft biopsy and renal histopathological findings
Patient Allograft Delayed graft function Time from Tx (mo) Treatment with XOR inhibitor Renal histolopathogical findings eGFR (mL/min/1.73 m2)
1 1 No 0.75 Febuxostat 40 mg/d Numerous intratubular DHA crystal deposits 23
2 1 No 0.75 None Extensive crystal deposits Dialysis
2 No 0.03 None Acute tubular necrosis; no crystals 6
0.1 None Intratubular crystal deposits 25
4 None Extensive crystal deposits within the interstitium 29
5 None Mild focal interstitial fibrosis and tubular atrophy associated with mild inflammation; polarizable intraluminal crystals in several tubules 20
12 Allopurinol 200 mg/d Minimal interstitial fibrosis and focal tubular atrophy; occasional intratubular crystals 17
3 1 No 3.5 None Intratubular crystal deposits 40
4 None Subjectively more crystals within the tubules
4 1 No 0.75 None Diffuse intratubular crystals identified as DHA 8
5 1 No 36 None Intratubular crystals assumed to be uric acid 20
37 None Diffuse crystal nephropathy with tubulointerstitial inflammatory infiltrates; crystals thought to be uric acid 10
39 Allopurinol 150 mg/d Persistence of intratubular brown crystals 23
6 1 Yes 0.1 None No crystals detected Dialysis
0.75 None Crystal deposits presumed to be oxalate 24
1.2 Allopurinol 300 mg/d Crystal deposits suspected to be DHA 26
2.1 Allopurinol 300 mg/d DHA crystals identified 43
12 Febuxostat 80 mg/d Crystals present (15%); severe tubular atrophy and interstitial fibrosis (>50%) 48
7 1 No 2 Allopurinol 300 mg/d DHA crystals present 52
12 Allopurinol 300 mg/d No crystals detected 47
8 2 Yes 1 None Multiple strongly birefringent DHA crystals in tubules
12 Allopurinol 300 mg/d Crystal deposits within tubules and interstitium
19 Allopurinol 300 mg/d No crystals detected
3 Yes 1 Allopurinol 300 mg/d No crystal detected
4 No 0.25 None No crystals detected
1.2 None Intratubular crystal deposits
2 Allopurinol 150 mg/d × 2/wk Multiple deposits of highly birefringent crystals 11
9 1 Yes 0.25 Allopurinol 300 mg/d Acute tubular necrosis; no crystals
12 1 No 0.75 Allopurinol 600 mg/da 51
4 Allopurinol 300 mg/da Extensive DHA crystal deposits 20
5 Allopurinol 450 mg/da 20%–30% reduction in DHA crystals 20
12 Allopurinol 300 mg/d, febuxostat 80 mg/da Some reduction in DHA crystals 28
24 Allopurinol 300 mg/d, febuxostat 80 mg/da Rare crystals within the interstitium 24
36 Allopurinol 300 mg/d, febuxostat 80 mg/da >100 crystals within the parenchyma 23
2 No 2 Allopurinol 300 mg/d, febuxostat 80 mg/d Rare intratubular DHA crystal deposits 69
13 1 No 3 Allopurinol 400 mg/d No crystals detected 39
15 1 No 4 Allopurinol 600 mg/d 50
12 Allopurinol 600 mg/d 64
16 1 Yes 0.3 Allopurinol 150 mg/d DHA crystals in ~30% of tubules Dialysis
0.6 Allopurinol 300 mg/d DHA crystals in ~40% of tubules Dialysis
2 Allopurinol 600 mg/d Subjectively fewer DHA crystals 33
12 Allopurinol 300 mg/d, febuxostat 80 mg/d Scant DHA crystals 45
17 1 No 3 Allopurinol 300 mg/d No crystals detected 99
The shaded area denotes allografts where xanthine oxidoreductase inhibitor treatment was not initiated before kidney transplantation.
aReported nonadherence to XOR inhibitor treatment.
DHA, 2,8-dihydroxyadenine; eGFR, estimated glomerular filtration rate; Tx, kidney transplantation; XOR, xanthine oxidoreductase.

FIGURE 1.
FIGURE 1.:
Recurrent 2,8-dihydroxyadenine nephropathy in an allograft from one of the patients (No 12; Table 2). A, On a hematoxylin and eosin stained section, numerous brown crystals (arrows) are seen within tubular lumens and within the tubular epithelial cytoplasm (left panel). Upon examination under polarized light, these crystals are strongly birefringent (right panel). B, On high magnification (×600) of the hematoxylin and eosin stained section, small brown crystals (arrows) are often seen within the tubular epithelial cytoplasm.

Eight patients did not receive XOR inhibitor therapy before transplantation of 11 kidney allografts (Table 2). In the case of 9 allografts, XOR inhibitor treatment was initiated at a median of 0.1 (0.1–2.9) years posttransplant. Delayed graft function was noted in 2 allografts, both coming from deceased donors, and AKI was observed in 7 transplants. Recurrence of DHA nephropathy was observed in all 10 allograft biopsies that were performed (Table 3), which was significantly more common than in those receiving treatment pretransplant (P = 0.004; Table 4). Four allografts belonging to 2 patients were lost due to disease recurrence, 1.3 (0.1–3.4) years posttransplant. Both patients were untreated before and after their first transplant, but initiated treatment with allopurinol 200 and 300 mg/day at 1 and 7 months following the second transplant, respectively. Five patients who initiated pharmacotherapy posttransplant had persistent biopsy-proven DHA allograft nephropathy, 4 of whom were treated with allopurinol in doses ranging from 150 mg twice a week to 300 mg daily. Three patients died with a functioning graft (Table 2); 1 patient (No. 3) from miliary tuberculosis at 5 months posttransplant, 1 patient (No. 5) from breast cancer 5.8 years posttransplant, and the third one (No. 8) from sepsis 1.4 years following a fourth kidney transplant. One patient (No. 2), who had lost 2 allografts due to disease recurrence, expired while on hemodialysis 8 years after the second transplant. Another patient (No. 6) developed acute liver failure 1.5 years posttransplant, suspected to be drug-induced, though the offending agent was not identified. The patient died while on hemodialysis for AKI 2 months later, in the setting of multiorgan failure.

The median eGFR at 6 months posttransplant was 61.5 (22.5–93.0) mL/min/1.73 m2 in patients who received XOR inhibitor therapy pretransplant, while it was 24.9 (9.6–53.3) mL/min/1.73 m2 in those who did not receive such treatment before transplantation (P = 0.003; Table 4). Similarly, the graft function was superior in the XOR inhibitor-treated group at 2 years posttransplant, with a median eGFR of 61.3 (24.0–90.0) mL/min/1.73 m2 compared with 16.2 (10.0–39.0) mL/min/1.73 m2 in the untreated group (P = 0.009; Table 4). At 2 years posttransplant, the allograft survival was 91% in the group receiving XOR inhibitor treatment pretransplant versus 55% in the untreated group, but the difference did not reach statistical significance (P = 0.16; Figure 2). In general, patients receiving higher allopurinol doses appeared to be less likely to experience disease recurrence (Tables 2 and 3).

TABLE 4. - Allograft outcomes in patients who initiated xanthine oxidoreductase inhibitor treatment before kidney transplantation compared with those who did not receive such treatment until posttransplant, or not at all
No XORi pretransplant XORi pretransplant P
Number of patients 8 10
Number of grafts 11 11
Age at transplant, y 42.8 (14.9–67.0) 45.5 (20.7–66.2) 0.974
Delayed graft function 2 3 1.0
Posttransplant acute kidney injury 7 4 0.395
eGFR, mL/min/1.73 m2
 At 6 mo 24.9 (9.6–53.3) [9 grafts] 61.5 (22.5–93) [10 grafts] 0.003
 At 12 mo 27.5 (10.0–67.5) [9 grafts] 64.8 (28–93.8) [10 grafts] 0.035
 At 2 y 16.2 (10.0–39.0) [6 grafts] 61.3 (24.0–90.0) [8 grafts] 0.009
Biopsy-proven recurrence of DHA nephropathy 10 3 0.004
Graft loss due to recurrence of DHA nephropathy 4 1 0.31
Death 5 1 0.043
Death with a functioning graft 3 1 0.275
Data are presented as median (range).
eGFR, estimated glomerular filtration rate; XORi, xanthine oxidoreductase inhibitor.

FIGURE 2.
FIGURE 2.:
Kaplan-Meier curve of death-censored kidney allograft survival from the time of kidney transplantation in patients who received treatment with a xanthine oxidoreductase inhibitor pretransplant (solid line) and those who did not (broken line).

DISCUSSION

In this study of kidney transplant outcomes in patients with APRT deficiency, allograft function was superior in patients who initiated XOR inhibitor therapy pretransplant compared with those who either first started this therapy posttransplant or did not receive such treatment at all. Timely initiation of pharmacotherapy in adequate doses appears to be a major determinant of kidney allograft function in patients with APRT deficiency.

Most previously reported cases of kidney transplantation in patients with APRT deficiency have demonstrated premature allograft loss or chronic allograft dysfunction in patients who were not on XOR inhibitor treatment at the time of transplantation,6,8,10-12,21,22 usually due to missed diagnosis of this rare disorder. Similar observations were also evident in our study as all 10 allografts biopsies from untreated patients showed disease recurrence, which lead to the premature loss of 4 grafts in 2 patients. These 2 patients were first placed on treatment with allopurinol at 4 weeks and 6 months following their second transplant in the setting of decreased graft function, and subsequently progressed to allograft failure. By contrast, patients who were receiving treatment with an XOR inhibitor at the time of kidney transplantation demonstrated better long-term allograft function and survival. One patient treated with low dose of allopurinol experienced early biopsy-proven disease recurrence which prompted a dose increase. Poor adherence to pharmacotherapy was reported for 1 patient in the present study due to episodic eye symptoms, including blurry vision, burning pain, and photophobia, resulting in subsequent allograft loss. Although our small study sample precludes meaningful statistical analysis of allograft outcomes, the patients who initiated XOR inhibitor therapy in adequate doses pretransplant and remained compliant with the treatment appeared to experience graft survival similar to what has been reported for kidney transplantation in general.

Delayed graft function requiring dialysis in the first posttransplant week was reported in roughly a quarter of the cases described herein, both in patients who initiated XOR inhibitor therapy before transplantation and those who did not, all of whom received deceased donor transplants. In patients receiving treatment pretransplant, delayed graft function prompted a large increase in allopurinol dosage in 2 of the 3 cases, with subsequent stabilization of allograft function. One of these 2 patients underwent a kidney biopsy revealing extensive tubular crystal deposition that diminished with higher doses of allopurinol, as observed on a repeat biopsy, with improved kidney function. A kidney biopsy performed a month later in the third patient on a stable allopurinol dose of 300 mg/day showed signs of acute cellular rejection but no crystal deposits. Two patients who experienced delayed graft function and did not receive treatment with an XOR inhibitor pretransplant had early biopsy-proven disease recurrence. Treatment with allopurinol was subsequently started in both patients. It is noteworthy that the diagnosis of APRT deficiency had been made some years before kidney transplantation in 1 of these 2 patients but treatment with an XOR inhibitor was not initiated for unknown reasons. In addition to ischemic kidney injury, DHA crystal nephropathy likely contributed to the delay in allograft function in the cases where XOR inhibitor treatment was lacking.6,21,23

Our data clearly demonstrate superior allograft outcomes among patients on XOR inhibitor therapy at the time of kidney transplantation and through the posttransplant period compared with those who did not initiate treatment until several weeks posttransplant, or not at all. Initiation of XOR inhibitor treatment before transplantation may be important as the risk of disease recurrence appears to be particularly high in the early posttransplant period. Most patients in our study who received XOR inhibitor therapy pretransplant had initiated the treatment >12 months before the transplant surgery. Interestingly, DHA crystal-induced injury seems to be much more aggressive in allografts than in native kidneys.3 As plasma DHA measurements are currently unavailable, it has not been determined if and how effectively dialysis clears DHA from plasma. Hence, it is conceivable that DHA may accumulate before transplantation in patients with kidney failure in the absence of XOR inhibitor therapy and flood the kidney allograft immediately following the transplant surgery, resulting in early graft dysfunction.6,10,11,22 Furthermore, ischemia-reperfusion injury at the time of transplantation may render the graft more susceptible to crystal deposition.

We noted disease recurrence in all allograft biopsies from patients who either did not receive XOR inhibitor treatment pretransplant or received inadequate doses. By contrast, no signs of DHA crystal nephropathy were noted in the majority of transplants treated with allopurinol in the daily dose of 300 mg or greater pretransplant. One patient who began treatment with a low dose of allopurinol (150 mg/d) before transplantation had early disease recurrence and required hemodialysis for 3 weeks posttransplant. Recurrence of DHA nephropathy in patients treated with similarly low allopurinol doses has been reported previously,6,22 indicating that higher doses are needed. Even in cases of delayed diagnosis, prompt initiation of XOR inhibitor therapy can have beneficial impact on graft outcomes, as seen in the present study where graft function improved in several cases following institution of allopurinol therapy.

The XOR inhibitor dose and duration of treatment pretransplant required to successfully prevent progressive DHA allograft nephropathy is currently not known and requires further study. However, based on our experience we recommend treatment with allopurinol in the dose of 400 mg/day for a minimum of 3 months before the transplantation. Recent data do not suggest increased risk of adverse effects in individuals with advanced CKD,24 and therefore we do not routinely lower allopurinol doses in APRT deficiency patients with reduced kidney function. In fact, patients with progressive allograft dysfunction may need higher allopurinol doses. In patients who do not tolerate allopurinol, febuxostat should be prescribed in the daily dose of 80 mg. Microscopic assessment of crystalluria is widely used to monitor XOR inhibitor treatment but lacks precision and is associated with significant interobserver variations. Our group recently developed a UPLC-MS/MS assay for quantification of urine DHA that holds great promise for the future.25 However, additional studies must be performed to determine the level of urine DHA that must be achieved to prevent crystal deposition and kidney allograft injury.

Traditionally, DHA crystal deposition has been believed to cause diffuse tubular obstruction, resulting in progressive CKD. More recent studies suggest that inflammatory mechanisms do play an important role in crystal-induced kidney injury, including NLPR3 inflammasome activation provoked by crystal uptake into intracellular lysosomes, leading to nephron destruction.1 Future studies will provide better understanding of the pathobiological mechanisms in crystal nephropathies, hopefully leading to the discovery of novel therapeutic options.

Misinterpretation of kidney biopsy findings was common in the present study, similar to previously reported cases.6,21,26 Observation of crystal deposits in the renal parenchyma should always prompt further evaluation, in which case it is particularly important to rule out DHA nephropathy as effective treatment is available. When kidney sections are viewed under light microscopy, the crystals are brown with hematoxylin and eosin stain, have a needle, rod, or rhomboid shape, and are strongly birefringent. Importantly, caution must be taken not to confuse DHA crystals with oxalate deposits.6 Indeed, primary hyperoxaluria was the original histologic diagnosis that was erroneously made in 4 patients (5 allografts) in the current study, significantly delaying the initiation of pharmacotherapy.

Our study has limitations, including the small sample size and retrospective observational design which is hampered by variable level of documentation, testing and duration of follow-up. Nevertheless, the series of APRT deficiency patients in this report represents the largest transplant dataset described for this rare disease to date.

In conclusion, this study demonstrates improved allograft outcomes among patients with APRT deficiency who receive treatment with an XOR inhibitor before or at the time of kidney transplantation. Thus, increased awareness among clinicians is imperative for promoting early diagnosis of APRT deficiency and initiation of XOR inhibitor treatment pretransplant. Notably, large doses of allopurinol may be needed to adequately prevent recurrence of DHA nephropathy, apparently 400 mg/day or greater. Moreover, it may be necessary to initiate the treatment several weeks or even months before transplantation to minimize the risk of disease recurrence due to enhanced susceptibility of the kidney allograft. As delay in diagnosis and appropriate pharmacotherapy is a major cause of premature graft loss in patients with APRT deficiency, it is important to increase the awareness of the disorder among physicians caring for patients with kidney failure.

ACKNOWLEDGMENTS

The authors are indebted to the following physicians for their invaluable assistance in clinical data and biosample collection: John Lieske (Mayo Clinic, Rochester, MN), David Goldfarb (New York University, New York, NY), Mirna Vucak-Dzumhur (Westmead Hospital, Sydney, Australia), Gopala Rangan (Westmead Hospital, Sydney, Australia), Philipp Eller (Medical University of Graz, Graz, Austria), Varun Agrawal (University of Vermont College of Medicine, Burlington, VT), Claudio Musetti and Piero Stratta (Maggiore della Carità Hospital, Novara, Italy), Bharat V. Shah (Global Hospital, Mumbai, India), Chukwuma Eze (Good Samaritan Hospital, Dayton, OH), Amrik Sahota (Rutgers University, Piscataway, NJ), and Lynette Fairbanks (Guy’s and St. Thomas’ Hospital NHS Foundation Trust, London, UK). We would to like to extend our gratitude to Lynn D. Cornell, MD, Associate Professor of Laboratory Medicine and Pathology and Consultant, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, for providing the photomicrographs of the kidney biopsy specimens.

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