Renal transplantation in Alport syndrome

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Korean J Nephrol. 2024;.j.krcp.24.143

Publication date (electronic) : 2024 November 12

doi : https://doi.org/10.23876/j.krcp.24.143

Soyeon Kim, Soon Hyo Kwon

Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea

Correspondence: Soon Hyo Kwon Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Republic of Korea. E-mail: ksoonhyo@schmc.ac.kr

Received 2024 June 4; Revised 2024 July 31; Accepted 2024 August 26.

Abstract

Introduction

Alport syndrome is a genetic condition that affects the kidneys and can lead to end-stage renal disease (ESRD) in adolescents, accounting for approximately 1.5% to 3% of children on renal replacement therapy (RRT) in Europe and the United States [1]. Male patients with Alport syndrome typically progress to ESRD in their 20s to 30s and initiate RRT [2].

When kidney transplantation (KT) is performed in patients with ESRD due to Alport syndrome, both patient and graft survival outcomes have been comparable or even superior to KT in patients with ESRD due to other causes [2–4]. Preemptive KT is preferred, but it is important to note that patients undergoing hemodialysis or peritoneal dialysis have a favorable prognostic outlook. This is crucial to consider when evaluating treatment option for Alport syndrome [2].

In general, living donor KT tends to result in fewer rejections, better graft function, and longer expected lifespans when compared to deceased donor KT [5]. In a retrospective multicenter study, the living related donors for recipients with Alport syndrome consisted of mothers (n = 12, 48%), fathers (n = 8, 32%), siblings (n = 4, 16%), and grandparents (n = 1, 4%) [6]. However, in cases with genetic disorders such as Alport syndrome, genetic factors should be considered in the donor selection process [5]. Before performing living donor transplantation in a patient with hereditary nephropathy, it is crucial to rule out the possibility of the same disease developing in the potential living donor [7].

In cases with Alport syndrome with severe gene mutations, symptom severity is more pronounced, and the incidence of posttransplant anti-glomerular basement membrane (anti-GBM) nephritis increased compared to cases with mild mutations [8]. Despite this, patient and graft survival outcomes after KT remain consistent, irrespective of mutation severity [8].

When the transplanted kidney has normal glomerular basement membranes, Alport syndrome does not recur in the transplanted organ.

Donor selection

Living related kidney donors are advised to undergo an extensive health assessment. This should include a 24-hour urine test, urine analysis, and an evaluation of vision and hearing [5]. Additionally, individuals who are potential carriers of COL4A3-COL4A5 mutations warrant genetic testing before KT [9]. This testing is crucial for making a diagnosis, determining the genetic inheritance pattern, and identifying specific characteristics of any mutations associated with a poor prognosis [9]. Fig. 1 illustrates a suggested genetic testing algorithm for assessing living related donors in Alport syndrome. Individuals with COL4A3-COL4A5 mutations are at inherent risk of kidney disease and there is a potential for further deterioration in kidney function after nephrectomy for transplantation, making them less suitable candidates for kidney donation [9]. Male relatives of a patients with X-linked Alport syndrome (XLAS) without hematuria are suitable candidates. Female relatives who are heterozygotes for XLAS should not be donors. However, they may be considered in special cases.

Figure 1.

Donor selection in living related donor kidney transplantation in Alport syndrome.

Revised from Caliskan and Lentine (Pediatr Nephrol 2022;37:1981-1994) [5] with a permission of Springer Nature.

AR, autosomal recessive; AD, autosomal dominant; NGS, next-generation sequencing; XLAS, X-linked Alport syndrome.

Genotype-phenotype considerations

Women with X-linked Alport syndrome (X-linked Alport syndrome, COL4A5 heterozygotes)

The risk of progression to ESRD in females with XLAS who are heterozygous carriers is approximately 12% by age 45 years, 30% by age 60 years, and 40% by age 80 years [10]. Therefore, they are not recommended as priority donors. As proteinuria and hearing impairment are the risk factors for ESRD [10], individuals with proteinuria or hearing impairment should be excluded from consideration as kidney donors [11].

However, if there are no other potential donors and a woman over the age of 45 years has normal renal function, no proteinuria, normal hearing, and evidence of no kidney damage based on renal tissue examination, she may be considered as a potential donor after receiving sufficient explanation about the potential risks associated with kidney donation and providing informed consent [12].

Individuals heterozygous for COL4A3 or COL4A4 mutation

Individuals who are heterozygous for mutations in COL4A3 or COL4A4 exhibit a spectrum of phenotypes, ranging from asymptomatic to isolated hematuria to progression to chronic kidney disease and ESRD [13]. Therefore, individuals in this category are not recommended as donors because of the inherent risk of kidney impairment and the potential risk of deterioration after donation [9]. However, in the absence of other potential donors, consideration may be given to individuals with normal renal function and no proteinuria, taking into account the genotype-phenotype correlation [11].

There is limited research on the long-term outcomes of donors in living related donor KT for Alport syndrome. In one case report of a living related donor KT from a mother to her son, 54 months after the transplant, the donor had stable renal function without proteinuria or hypertension [14]. Conversely, Gross et al. [15] reported cases of living related donor KT in Alport syndrome in which five mothers with XLAS donated to their sons and one mother who was heterozygous for autosomal recessive Alport syndrome (ARAS) donated to her daughter. Four of the donors experienced a decline in renal function ranging from 25% to 60% over a period of 2 to 14 years [15]. Table 1 [15–18] summarizes the results of studies of donor outcomes in living related donor KT in Alport syndrome. Some donors presumed to have mutations experienced renal function loss. Therefore, the selection of living related donors should be approached with caution, and the appropriate use of genetic testing can assist in making informed donor selections.

Table 1.

Summary of reported cases of living related donor KT in Alport syndrome

When transplantation is performed, both the donor and the recipient should undergo renal protective therapy, including a renin-angiotensin blocker such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker [19]. Additionally, several randomized controlled trials have demonstrated the renoprotective effect of sodium glucose cotransport 2 inhibitors [20,21] and finerenone [22]. Given these findings, the administration of these relatively new medications should be considered for both the donor and the recipient.

Alport posttransplant anti-glomerular basement membrane nephritis

Posttransplant anti-GBM nephritis in Alport syndrome is rare but can lead to graft loss if it occurs. It primarily occurs in males with an X-linked inheritance pattern, observed in approximately 3% to 5% of patients [12]. Rare reports have also documented its occurrence in females with ARAS [12].

In males with XLAS, the autoantibodies causing anti-GBM nephritis are directed against the collagen IV alpha 5 chain [23]. In contrast, autoantibodies found in females with ARAS target the collagen IV alpha 3 chain [23].

Those who develop posttransplant anti-GBM nephritis are typically male, progress to end-stage renal failure under the age of 40 years, and experience hearing impairment [12]. Its occurrence is reported to be more frequent in cases with deletion mutations or missense mutations in the COL4A5 genes, whereas its prevalence is noted to be low in cases with nonsense mutations [11].

Most often, it arises within the first year after transplantation, but there are cases where the period between transplantation and diagnosis spans several years [12]. The clinical presentation varies and may include microscopic hematuria, proteinuria, and an increase in creatinine. When posttransplant anti-GBM nephritis occurs, graft loss has been observed in approximately 75% of cases [11].

In the serum, there is an elevation of anti-GBM antibodies. In renal biopsy tissue, linear staining of immunoglobulin G and C3 along the basement membrane and crescentic glomerulonephritis can be observed [11]. Most cases occur within the first year after transplantation, so in addition to periodically monitoring the function of the transplanted kidney, it is possible to measure anti-GBM antibodies monthly using enzyme-linked immunosorbent assay in the first year. However, the benefits of this approach have not been sufficiently proven [11].

Given the current lack of research on the treatment of posttransplant anti-GBM nephritis, one can explore treatment options such as plasma exchange, steroids, and immunosuppressive agents like cyclophosphamide, similar to primary anti-GBM nephritis. However, previous studies have shown that preventing graft loss has been unsuccessful [11].

Patients who experience graft loss due to posttransplant anti-GBM nephritis in Alport syndrome may face a higher recurrence rate with re-transplantation [12]. Therefore, the pros and cons of re-transplantation should be carefully considered [12].

Conclusion

KT is an effective treatment for Alport syndrome-induced ESRD, yielding favorable outcomes. When considering living related donor KT in Alport syndrome patients, careful donor selection with genetic testing for COL4A3-COL4A5 mutations is crucial. Individuals with these mutations may not be suitable as priority donors due to the potential risk of renal function deterioration. While posttransplant anti-GBM nephritis is rare, it poses a risk of graft loss.

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