Renal transplantation in Alport syndrome

Soyeon Kim; Soon Hyo Kwon

doi:10.23876/j.krcp.24.143

Kidney Res Clin Pract > Epub ahead of print

Kim and Kwon: Renal transplantation in Alport syndrome

Review Article

Kidney Research and Clinical Practice 2024;j.krcp.24.143.

Published online: November 12, 2024

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

Renal transplantation in Alport syndrome

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

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited.

Abstract

Kidney transplantation is recognized as an effective treatment for end-stage renal disease in Alport syndrome, demonstrating outcomes comparable to or even superior to those in other causes of renal failure. When considering living related donor kidney transplantation for Alport syndrome patients, it is crucial to consider genetic factors during the donor selection process. In addition to a comprehensive health check, genetic testing is strongly recommended for potential donors at risk of carrying mutations in COL4A3-COL4A5 before undergoing kidney transplantation. Individuals carrying these mutations face an inherent risk of kidney disease and due to the possibility of further deterioration in renal function after nephrectomy for transplantation, they are not suitable as priority donors. Posttransplant anti-glomerular basement membrane nephritis is rare but can lead to graft loss, especially in males with X-linked Alport syndrome.

Keywords: Alport syndrome, Anti-glomerular basement membrane nephritis, COL4A3-COL4A5 gene mutation, End-stage renal disease, Kidney transplantation, Living related donor

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.

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.

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.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and Technology Information and Communication (NRF-2022R1A2C1007571), Medical Research Center (RS-2023-00219563), and Soonchunhyang University Research Fund.

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request.

Authors’ contributions

Conceptualization: SK, SHK

Funding acquisition: SHK

Writing–original draft: SK

Writing–review & editing: SHK

All authors read and approved the final manuscript.

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.

Table 1.

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

Study	Year	Relations	Recipient		Donor
Study	Year	Relations	Sex/age (yr)	Genetic pattern	Sex/age (yr)	Hypertension	Proteinuria (g/day)	MHU	Deafness	Renal biopsy	Post-KT kidney function
Sakai et al. [16]	2003	Father → daughter	Female/30	AR	Male/60	-	-	+	+	TBMN	45 days, stable (serum creatinine, 1.41 mg/dL)
Gross et al. [15]	2009
1		Mother → son	Male/30	XR	Female/62	-	<0.3	+	-	NA	2 yr, dropped by 35%
2		Mother → daughter	Female/18	AR	Female/50	-	-	+	-	Thin GBM	4 yr, dropped by ~30%
3		Mother → son	Male/33	XR	Female/56	-	-	+	-	NA	6 yr, dropped by <10%
4		Mother → son	Male/26	XR	Female/54	-	-	+	-	NA	3 yr, dropped by ~25%
5		Mother → son	Male/25	XR	Female/56	-	-	+	-	Thin GBM, GBM splitting, chronic interstitial fibrosis	14 yr, dropped by 60%, stable at a low level (eGFR, ~40–45 mL/min/1.73 m²)
6		Mother → son	Male/33	XR	Female/62	-	-	+	-	NA	8 yr, dropped by ~10%
Petzold et al. [17]	2019	Father → son	Male/26	XR	NA	-	-	-	-	Normal	7 yr, stable (60 mL/min/1.73 m² with modest microalbuminuria)
Katayama et al. [18]	2021
1		Mother → son	Male/34	De novo	Female/59	NA	-	-	NA	NA	5 yr, stable (eGFR, 64.2 mL/min/1.73 m²)
2		Mother → son	Male/26	XR	Female/59	-	0.1	+	-	Thin GBM	9 yr dropped (eGFR, 50.4 mL/min/1.73 m²; proteinuria, 0.2 g/gCr)

AR, autosomal recessive inheritance; eGFR, estimated glomerular filtration rate; GBM, glomerular basement membrane; KT, kidney transplantation; MHU, microscopic hematuria; NA, not available; TBMN, thin basement membrane nephropathy; XR, X-linked recessive inheritance.

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