Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure.


| INTRODUC TI ON
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). 1 Due to incomplete ascertainment, the prevalence of ADTKD is not known, although some authors have suggested that it may account for up to 2% of cases of ESRD. 2 Indeed, recent data suggest that ADTKD is one of the most common monogenic kidney diseases after autosomal dominant polycystic kidney disease. 2,3 Pathogenic mutations in the gene coding for mucin (MUC-1), uromodulin (UMOD), hepatocyte nuclear factor 1-ß (HNF-1B), renin (REN), and translocon subunit alpha (SEC61A1) have been identified in individuals with ADTKD. [4][5][6][7][8] These mutations result in production of abnormal proteins which accumulate within the tubular epithelial cell, or, in the case of SEC61A1, altered post-translational modifications, folding and sorting of secretory and transmembrane proteins. 3 Ultimately, these processes result in cell death with tubular atrophy and surrounding interstitial fibrosis. 9 These are the characteristic histological findings in individuals with ADTKD. 10 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that a diagnosis of ADTKD be suspected in individuals with compatible clinical characteristics and a family history consistent with autosomal dominant inheritance CKD or in individuals with compatible clinical characteristics and who have a kidney biopsy with histological changes consistent with ADTKD or compatible extrarenal manifestations, for example, gout in ADTKD-UMOD or diabetes in ADTKD-HNF1B. 5 The diagnosis can be established either when a mutation in one of the four relevant genes is identified or in individuals who have both a compatible family history and a compatible renal biopsy. Depending on the genetic mutation identified, ADTKD may be further categorized as ADTKD-MUC1, ADTKD-UMOD, ADTKD-HNF1B, ADTKD-REN, ADTKD-SEC61A1, or ADTKD-NOS (where no mutation is identified but diagnosis is made based on family history and biopsy).
At present, there is no specific disease-modifying treatment available for individuals with ADTKD. 5 Management of other factors, for example, which expedite CKD progression, is appropriate as is treatment of extrarenal manifestations, for example, gout in individuals with mutations in the uromodulin gene. 11 Progressive renal impairment with ESRD occurring in middle age is the typical clinical course in individuals with ADTKD. Such individuals will have an otherwise good life expectancy and therefore require renal replacement therapy for several decades.
As in other causes of ESRD, renal transplantation is the preferred modality of renal replacement therapy due to both mortality and quality-of-life considerations. 12,13 Two previous reports of renal transplant outcomes in individuals with ADTKD due to MUC1 mutations suggested that it does not recur in the allograft. 14,15 In this report, we compare outcomes of renal transplantation in individuals with ADTKD to outcomes in individuals with other causes of ESRD and reviewed any available transplant biopsy results for individuals with ADTKD who had undergone transplantation. the protocol for which has been described previously. 16 Informed consent was given by all patients at enrollment in IKGP for survey completion, review of healthcare records, and permission to re-contact in the future.

| ME THODS
We reviewed clinical records and kidney biopsy (both native and transplant) results for individuals identified to determine whether they met criteria for a suspected/confirmed diagnosis of ADTKD. These techniques have been previously described. 11,17,18 One individual included in this report was categorized as ADTKD-MUC1 after detection of frameshift MUC1 on urinary cell smear in the First Faculty of Medicine, Charles University, Prague, as previously described. 19 Further individuals were recruited after referral to the renal genetics clinic in Beaumont Hospital, and two other families with a known pre-existing diagnosis of "hereditary tubulointerstitial nephritis" were included as they met KDIGO criteria for established ADTKD.
After review of clinical records, we created an access file database with clinical characteristics for all individuals included in this report. Further information regarding transplant outcomes was obtained from the Irish Kidney Transplant Registry.
All statistical analyses were conducted with the statistical software package Stata (Version 13). A P-value of <.05 was deemed significant.
Graft and patient survival for the cohort of patients with ADTKD was compared with outcomes for all other Irish renal transplant recipients who received a renal transplant over a 37-year period (1982-April 2019) using a log-rank test for equality of survivor functions. This period corresponded with the timeframe within which transplants were K E Y W O R D S ADTKD, genetics, graft survival, kidney disease, rare renal disease performed in the ADKTD group. A death-censored graft survival analysis was also performed. Comparisons between baseline characteristics were made using either Mann-Whitney of Pearson chi-squared testing.

| Baseline characteristics at transplantation
We next compared the baseline clinical information at time of transplantation between this the group of individuals with ADTKD and individuals included in the Irish renal transplant registry with a different etiology of renal failure. These comparisons are shown in Table 2. We did not identify any significant differences in baseline characteristics between the cohort of individuals with ADTKD and the comparator group with the exception of donor sex. Male donor sex was more common in the comparator group than the ADTKD group (58.2% vs 41.2%, P = .045). Although living donation was more common in the group with ADTKD (19.4% vs 9.9%, P = .060), this did not reach statistical significance.

| Patient and graft outcomes after transplantation
We wished to determine whether there was a significant difference between groups in terms of either patient survival or graft survival in individuals with ESRD due to ADTKD vs individuals undergoing transplantation after a different cause of renal failure. A log-rank   Our center previously published data demonstrating superior graft and patient survival for patients with ESRD due to polycystic kidney disease compared to other causes of ESRD, after adjusting for age at transplant. 26 We did not demonstrate a statistically significant difference for patients with ADTKD, although this is may be limited by the relatively small number of patients in the ADTKD cohort.

| D ISCUSS I ON
In recent years, a number of advances have been made which increase the yield of genetic testing in individuals with suspected and it is clear that transplantation should be the treatment of choice for patients with ESRD due to ADTKD.