Introduction:
Renal transplant is the treatment of choice for end-stage renal disease (ESRD). However, renal transplant becomes challenging in Alport syndrome (AS) due to the complex heterogeneous nature of the disease. AS is caused due to mutations in gene encoding type IV collagen chains 3, 4, and 5 (COL4A3-5). Genetic interpretation becomes crucial for donor and recipient’s safety and long-term outcomes. Depending on the gene variant involved, family members with heterozygous mutations in collagen IV genes have variable risks for progression to chronic kidney disease (CKD) and ESRD. We report the case of an adolescent with ESRD due to AS. Using targeted next-generation sequencing (NGS), we identified the mutation on the same gene in the father (donor), and the transplant was carried out.
Methods:
The renal transplant recipient, a 17-year-old male, an only child born of a consanguineous marriage, presented with advanced renal failure and deafness. On evaluation, we found that he had small kidneys with nephrotic range proteinuria and active urinary sediments. Ophthalmological examination showed anterior lenticonus confirming the diagnosis of AS. The family was counseled for a renal transplant. The mother’s initial workup showed ABO incompatibility, and urinalysis showed an RBCcount of 15-20 RBC/HPF. Therefore, further work up was deferred.The father, a 44 years old healthy lean, vegetarian male, ABO compatible, normotensive with no previous medical history, underwent donor evaluation and was found to have microscopic hematuria (30-40 RBC/HPF) (with normal urine PCR) on recurrent testing. Urine for dysmorphic RBC were absent, and cystoscopy was normal. Clinical and laboratory parameters of the donor and recipient are listed in table 1.NGS analysis showed the presence of a mutation on gene COL4A4 (-) (ENST00000396625.5) on exon 47, C4717del (p.Ala1573ProfsTer30), classified as likely pathogenic. https://clinvarminer.genetics.utah.edu/submissions-by- variant/NM_000092.5%28COL4A4%29%3Ac.4717del%20%28p.Ala1573fs%29
The son was homozygous, and the father was heterozygous. Ophthalmological examination showed no ocular abnormality, and pure tone
audiometry showed no SND in the donor. Although the particular gene varian in the mutation database was not clearly associated with progressive CKD/ESRD; it was a likely pathogenic variant, therefore, considered as high risk (ClinVar database, a single case report in August 2021, single submitter, i.e., insufficient information). Depending on the gene variant involved, family members with heterozygous mutations in collagen IV genes have variable risks for progression to CKD and ESRD and it also depends significantly on environmental epigenetic modifiers. We concluded that the donor was still at risk of developing CKD though it could be modified to some extent with lifestyle interventions. The following was communicated to the family and detailed discussion regarding the complexity and ambiguity of development of kidney disease in the donor was done. Mother’s genetic studies were not done as she was not considered a donor initially. A kidney biopsy of the mother was not carried out because NGS analysis revealed the exact heterozygous nature of the gene causing AS. Due to the unavailability of any other related donor,(mandatory in India) and the acceptance of a certain risk of kidney disease in the donor by a highly motivated family, we proceeded with the transplant after an informed high-risk consent. The renal transplant was performed with Basiliximab induction and showed excellent graft function with nadir creatinine of 0.9 mg/dl. The donor had a post-donation creatinine of 1 mg/dl and was put on low dose Ramipril to halt disease progression.
Results:
Three year follow-up showed a creatinine of 1 mg/dl in both the renal transplant recipient and the donor.The family has been counseled regarding the regular follow ups and long-term outcome of the donor is to be ascertained.
Conclusions:
Living-related renal transplant in autosomal AS is challenging and should be carried out after careful donor selection in consultation with genetic analysis.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.