NDT Advance Access published online on November 21, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn635
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Living donor kidney transplantation from relatives with mild urinary abnormalities in Alport syndrome: long-term risk, benefit and outcome
1 Department of Nephrology and Rheumatology, University of Goettingen, Goettingen 2 Merheim Medical Center, University of Witten-Herdecke, Campus Cologne 3 Department of Pathology, University of Cologne, Cologne, Germany
Correspondence and offprint requests to: Oliver Gross, Department of Nephrology and Rheumatology, University of Goettingen, Robert-Koch Str. 40, D-37075 Goettingen, Germany. Tel: +49-551-39-6331; Fax: +49-551-39-8907; E-mail: gross.oliver{at}med.uni-goettingen.de
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Abstract |
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Background. Alport syndrome is a hereditary nephropathy leading to renal failure during adolescence. This study evaluates the outcome of living donor transplantation (Tx) from heterozygous mothers to their affected children.
Methods. Seven mothers were evaluated, and donation was refused in one because of proteinuria.
Results. All of the remaining six donors had microhaematuria, and one had proteinuria. Renal function was monitored after Tx (average 6.7 years in donors and 5.3 years in acceptors). Three of six donors developed new onset hypertension, and two new onset of proteinuria. Renal function declined significantly in four donors: (1) –35% after 2 years; (2) –25% after 3 years; (3) –30% after 4 years and (4) –60% after 14 years versus before Tx. However, creatinine clearance remained >40 ml/min in all donors. All transplanted kidneys worked well 1 and 5 years after Tx, and one failed after 10 years. One patient died from meningitis, and the remaining four remained stable.
Conclusion. Living donor Tx from relatives in Alport families is an ambivalent option. Proteinuria should be an exclusion criterion. Yet, even in donors with isolated microhaematuria, families and their physicians should be aware of an increased risk of renal failure in donor and recipient. This risk might be minimized by careful donor evaluation including biopsy and nephroprotective strategies after Tx in both donor and recipient.
Keywords: Alport syndrome; benign familial haematuria; living donor transplantation; thin glomerular basement membrane disease; type IV collagen
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Introduction |
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Alport syndrome (AS) is a common hereditary nephropathy characterized by a family history of haematuria and proteinuria, progressive renal failure, sensorineural deafness and typical ocular changes [1,2]. As the frequency of X-chromosomal AS is estimated at 1:5000 and of autosomal recessive AS at 1:50 000, AS is the most common hereditary cause for end-stage renal failure (ESRF) during adolescence [2]. 2.2% of paediatric renal transplant recipients, 1.8% of paediatric patients on chronic dialysis and 1.4% of those with chronic renal insufficiency are diagnosed to have familial nephritis [3]. About 1% of adults on renal replacement therapy in Europe are estimated to have AS as underlying disease.
The disease is caused by mutations in type IV collagen genes, which code for a major constituent of basement membranes. While the 
1/2(IV) chains are ubiquitous in basement membranes, the 3(IV), 4(IV) and 5(IV) chains show a restricted distribution and are specifically expressed in the glomerulus, inner ear and eye [4]. Numerous mutations in the COL4A5 gene encoding the 5 chain of type IV collagen have been described to cause X-linked AS. Mutations of the 3(IV) or 4(IV) chain cause autosomal AS (homozygous patients) and benign familial haematuria (BFH) in heterozygous form [5,6]. Haematuria is the characteristic symptom of BFH in heterozygous AS carriers. Almost 1% of the total population are heterozygous carriers of mutations in the autosomal Alport genes and have familial benign haematuria. X-chromosomal (and autosomal?) carriers of Alport mutations can progress to renal failure in 5–20% [7,8].
According to previous studies, patients with AS have excellent transplant outcomes with good graft survival rates [9,10]. Shortage of organs raises the question of living donor transplantation (Tx). However, the number of family members is usually small in families with severe hereditary diseases. Many potential donors are asymptomatic or oligosymptomatic carriers of heterozygous AS mutations with an increased risk for chronic renal failure. Furthermore, the very important dogma in living donor Tx-‘first do not harm the donor’-stands in contrast to the parents’ strong demand on helping their young children with a severe disabling disease. For the first time, the present study addresses these problems by evaluation of the outcome, risk and benefit of seven Alport families. This evaluation includes the medical outcome in both recipient and donor, focussing on the yet unknown risk of developing chronic renal failure in the donors after uni-nephrectomy and includes the personal impression of Alport family members about risk and benefits up to 14 years after Tx.
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Methods |
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Patients’ data were collected via questionnaires, by contacting physicians and by direct contact to the families via our Alport homepage, outpatients clinic or phone. Creatinine clearance was either measured directly or calculated using the Cockcroft–Gault formula. All families agreed to add their anonymous patient characteristics into this study and hope that their data contribute to a better knowledge and outcome in future living donor transplantations. All transplantations were approved by the local ethical committee.
Family characteristics
Family 1
The recipient was born in 1976. He was diagnosed as having AS by a renal biopsy and developed ESRF at the age of 28. He has hearing loss but no ocular lesions. After his first renal transplant failed in 2005 (Tx 1996), his mother donated her kidney in 2006 (total time on dialysis 3 years). Two years after Tx, his renal function is good (Figure 2). His mother was born in 1944. She is an X-chromosomal carrier for AS; she has microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she did not have hypertension, but microalbuminuria (<0.3 g/day), and she still is a non-smoker. After donation she developed hypertension and proteinuria (maximum 0.5 g/day) and was treated with ACE inhibitors. Over the past 2 years, her creatinine clearance dropped by 35% (Figure 3).
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Family 2
The recipient was born in 1986. She was diagnosed as having AS by mutation analysis [11] and developed ESRF at the age of 17. She has hearing loss but no ocular lesions. Her mother donated her kidney in 2004 (total time on dialysis 6 months). Four years after Tx the daughter's renal function is good (Figure 2). Her mother was born in 1954. She is an autosomal recessive carrier for AS; she has intermittent microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she had a renal biopsy done showing thin basement membrane disease without tubulointerstitial damage. She did not have hypertension or microalbuminuria, and she still is a non-smoker. After donation she was treated with ACE inhibitors and did not develop hypertension or proteinuria. Over the past 4 years, her creatinine clearance dropped by
30% (Figure 3).
Family 3
The recipient was born in 1969. He was diagnosed as having AS by a biopsy and developed ESRF at the age of 25. He has no hearing loss but ocular lesions (cataract). After his first renal transplant failed in 2001 (Tx 1997), his mother donated her kidney in 2002 (total time on dialysis 4 years). Six years after Tx, his renal function is good (Figure 2). His mother was born in 1946. She is an X-chromosomal carrier for AS; she has microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she did not have hypertension and microalbuminuria, and she still is a non-smoker. After donation she developed hypertension, but no proteinuria. She is treated with ACE inhibitors, AT1 antagonists and diuretics. Over the past 6 years, her creatinine clearance dropped by <10% (Figure 3).
Family 4
The recipient was born in 1979. He was diagnosed as having AS by a renal biopsy and developed ESRF at the age of 25. He has hearing loss and ocular lesions (cataract). His mother donated her kidney in 2005 (total time on dialysis 1 year). Three years after Tx his renal function is good (Figure 2). His mother was born in 1951. She is an X-chromosomal carrier for AS; she has intermittent microhaematuria since adolescence and ocular lesions (cataract), but no hearing loss. Before Tx she did not have hypertension and microalbuminuria, and she still is a non-smoker. After donation she did not develop hypertension, but microalbuminuria (<0.3 g/day). She did not take any medications. Over the past 3 years, her creatinine clearance dropped by 25% (Figure 3).
Family 5
The recipient was born in 1963. He was diagnosed as having AS by a renal biopsy and developed ESRF at the age of 30. He has hearing loss but no ocular lesions. One year after starting dialysis, he received living kidney donation from his mother (1994) (total time on dialysis 1 year). In 2004, his transplant failed due to a chronic allograft nephropathy and he is on dialysis ever since then (Figure 2). His mother was born in 1938. She is an X-chromosomal carrier for AS; her kidney was biopsied 6 months after Tx showing thin basement membrane disease with additional splitting within the glomerular basement membrane plus chronic interstitial fibrosis (Figure 1). She has microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she did not have hypertension or microalbuminuria, and she still is a non-smoker. After donation she developed hypertension and proteinuria (maximum 0.9 g/day) and is treated with ACE inhibitor and AT1 antagonist. Over the past 14 years, her creatinine clearance dropped by 60% (Figure 3). At present, her renal function is stable at a low level (creatinine clearance 40–45 ml/min).
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Family 6
The recipient was born in 1965. He was diagnosed as having AS by a renal biopsy and developed ESRF at the age of 32. He had hearing loss and ocular lesions (cataract). His mother donated her kidney in 1998 (total time on dialysis 1 year). Six years after Tx he died from sepsis (meningitis after operation); until death his renal function was good (Figure 2). His mother was born in 1936. She is an X-chromosomal carrier for AS; she has microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she did not have hypertension and microalbuminuria, and she still is a non-smoker. After donation she did not develop hypertension and proteinuria. She did not take any medication. Over the past 8 years, her creatinine clearance dropped by
10% (Figure 3).
Family 7
The recipient was born in 1967. She was diagnosed as having AS by a renal biopsy and mutation analysis [7] and developed ESRF at the age of 33. She has hearing loss but no ocular lesions. She received a (cadaver) renal transplant in 2007 (total time on dialysis 7 years) after living donor Tx from the mother was rejected by several Tx centres. Her mother was born in 1944. She is an autosomal recessive carrier for AS; she has microhaematuria since adolescence, but no hearing loss or ocular lesions. Before Tx she did not have hypertension, but microalbuminuria (<0.5 g/day), and she still is a non-smoker. The microalbuminuria led to rejection of the mother as a possible donor; 8 years after the primary evaluation, she did not develop hypertension or progressive and is not treated with ACE inhibitors. Over the past 8 years, her creatinine clearance has been stable, >90 ml/min. Both mother and daughter plan to fulfil the living donation in the future (if the present transplant fails).
Donors and recipients data analysis
The average age of the recipients at Tx was 28.2 years (range 17–33 years), the average time on dialysis was 1.6 years (range 0–4 years) and two patients had a previous Tx. The average follow-up in the recipients was 5.3 years (range 2–10 years, Figure 2). All six transplants worked well after 1 year (serum creatinine <1.5 mg/dl in all patients), after 2 years (<1.8 mg/dl in all patients) and after 5 years (<1.8 mg/dl in all three patients). There was no decline in renal function after 1 and 2 years (n = 6, Figure 4), and a decline of about –15% after 5 years (n = 3). No one developed post-transplant anti-glomerular basement nephritis.
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The average age of the donors at Tx was 56.7 years (range 50–62 years). The average follow-up in the donors was 6.7 years (range 2–14 years, Figure 3). The donors’ renal function dropped by about –25% after 6 months (n = 6, Figure 4), recovered partly to about –20% after 5 years (n = 3) and proceeded to about –35% after 10 years (n = 2). The most significant decline of the donors’ renal function was documented in family number 5 (by
60% over 14 years). However, her creatinine clearance now seems to be stable at a low level (creatinine clearance 40–45 ml/min). All donors including family 5 point out that—knowing the present outcome—they would donate their kidneys again. |
Discussion |
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The major goal of the present study is to evaluate the benefit, risk and outcome of living donor Tx from oligosymptomatic heterozygous carriers to their affected homozygous children with Alport syndrome. The average follow-up was 6.7 years (range 2–14 years) in donors and 5.3 years (range 2–10 years) in recipients. This relatively long follow-up seems to be adequate to evaluate the long-term risk and benefits in recipients, but is actually short in terms of the lives of the donors.
Families with hereditary renal diseases are usually small; therefore, the number of potential living donors seems to be even more limited than that in families with non-hereditary renal diseases. Why is there such a strong demand for living donor Tx in Alport families? First of all, affected children develop early ESRF and shortage of organs increases the demand for early living donor Tx. However, the demand for living donor Tx from mothers to their affected children seems to have several other social-cultural aspects in hereditary renal diseases such as AS: (1) in most cases the heterozygous mothers are the ‘cause’ for the disease (85% X-chromosomal inheritance) and feel responsible for the disease of their child. (2) Even if mothers do not carry the defect Alport gene (15% de novo mutations), they usually still feel responsible for the disease of their child they have given birth to. Therefore, in our experience, in Alport families the demand of the mothers to donate their kidney to their affected child is usually higher than the demand of other family members. This demand is caused by the very close relation between mother and child and seems to be independent from impediments such as altered renal function of the mother. For example, several Tx centres refused the mother with mild proteinuria (family 7) as a donor due to her possibly impaired renal function. Renal function in the mother is still normal 8 years after rejection for donation, and one can only speculate about her renal function if she would have donated one kidney. At present, she still looks for a centre that accepts her as potential donor. In these cases, renal biopsy might help to demonstrate (or exclude) impaired renal function in the maternal kidney and to prove that this organ can or cannot be donated. According to our data, all potential donors with proteinuria should be rejected.
Following the demand to help the affected children, is living donor Tx of heterozygous carriers a reasonable option for the recipients with AS? The outcome in the six children in our study demonstrates a good renal function in all recipients 1 year after Tx and a good renal ‘survival’ after 5 years. A previous study showed that the risk of acute rejection due to auto-antibodies against the glomerular basement membrane is <5% [10,12]. In our study, one kidney failed after 10 years due to a chronic allograft nephropathy and one can only speculate if the thinned and split glomerular basement membrane of the maternal kidney (family 5, Figure 1) contributed to this chronic renal failure. Future studies in animal models should concentrate on the question if certain immunosuppressive regiments and/or early RAAS inhibition can preserve renal function in the recipient to a better extent.
As living donor Tx from oligosymptomatic heterozygous carriers seems to be a reasonable option for the recipients, how should one evaluate the potential donors [7,13,14]? As up to 25% of female carriers of X-chromosomal Alport mutations develop renal failure [8], microalbuminuria could exclude these mothers as potential donors. Similar rules could apply for (male and female) autosomal carriers with microalbuminuria. If any doubts appear in a donor with an otherwise normal renal function, this exclusion criterion should be strengthened by a renal biopsy. The same rules might apply for potential donors without proteinuria but additional risk factors such as smoking or hypertension. Potential donors with haematuria should undergo normal evaluation according to the standard of the transplantation centre. As even these oligosymptomatic carriers might have an increased risk for developing (mild or severe) renal disease, our data suggest to recommend an additional renal biopsy in all potential donors to exclude mild tubulointerstitial damage that might turn into progressive renal failure after Tx. Random X-inactivation seems to make it impossible to estimate renal damage in these female carriers without histological evaluation. These data are in accordance with previous recommendations that heterozygotes <45 years of age should be excluded as donors, unless they are asymptomatic obligate heterozygotes, and that heterozygotes over 45 with isolated haematuria could be considered as donors of last resort, in the event where other family members are not available [7]. Further, specific mutations were shown to have a potential impact on the risk of developing end-stage renal disease in female carriers of X-chromosomal Alport mutations [8]. Therefore, we recommend additional genetic analysis for the work-up of a potential donor.
In donors without proteinuria and with an (despite thin basement membrane disease) otherwise normal renal biopsy, how can nephrologists preserve donors renal function? In our hypothesis, hyperfiltration of the remaining kidney causes increased intraglomerular pressure and oxidative stress leading to expression of profibrotic factors and tubulointerstitial fibrosis. Early ACE inhibition might cause a mild increase of serum creatinine and an initial drop of the creatinine clearance. Strict blood pressure control by RAAS inhibition might explain the stabilization in donor renal function of family 5. According to our data, Alport carriers as donors have an increased risk for developing new onset hypertension and/or microalbuminuria compared to other living related kidney donors [15]. Hypertension and microalbuminuria can both be seen as signs for ongoing progressive renal damage and should be diagnosed and treated as soon as possible. Treatment includes ACE inhibitors as early inhibition of the RAAS system delays renal failure in Alport mice [16,17]. In our transplantation centres in Goettingen and Cologne, we recommend to start ACE inhibition in all donating carriers immediately after Tx in order to prevent hypertension and/or proteinuria and not to wait for these signs of already ongoing renal damage (see family 2). However, future studies in cooperation with the Alport registries in Europe and the States (Alport Syndrome Treatments and Outcomes Registry, ASTOR) should investigate if early RAAS inhibition really is capable of preventing or delaying renal failure in these oligosymptomatic patients.
In summary, living donor Tx from heterozygous relatives in Alport families is an ambivalent option with a satisfactory 1- and 5-year outcomes in both donor and recipient. Yet, Alport families and their doctors should be aware of an increased risk of renal failure in donor and recipient. This risk could be minimized by careful donor evaluation including a mandatory kidney biopsy before Tx and a close follow-up after Tx focussing on early diagnosis and subsequent therapy of renal risk factors such as hypertension and microalbuminuria. Further retro- and/or prospective studies should focus on genotype–phenotype correlation linking genotype and post-transplant outcome in a greater number of organ donors and recipients as well as on nephroprotective strategies in AS after Tx in both donor and recipient.
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Acknowledgments |
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The authors wish to thank all Alport families and their physicians for contributing data, Mrs Joanna Reinhardt for collecting parts of the data as well as the Association pour l'Information et la Recherche sur les maladies rénale Génétiques France and the KfH-Foundation Preventive Medicine for their support of the European Alport registry. Parts of the present paper were previously published in 2007 in abstract form at the annual meetings of the American and German Society of Nephrology.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 21.10.08
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