Transcript Living Donor Kidney Transplantation in Hereditary

Living Donor Kidney Transplantation in
Hereditary Nephropathy Patients
Reference: Niaudet P. Nat. Rev. Living
donor kidney transplantation in patients
with hereditary nephropathies. Nephrol.
2010;6:736–743.
• Kidney transplantation (KT) from living donors is regarded as the
best option for renal transplantation recipients.
• Those recipients who receive kidney grafts from the living donor
generally have shorter waiting times compared to those who
receive from deceased donors.
• However, grafts from living donors are not suitable for recipients
who had renal failure due to genetic causes.
• In recipients with a genetic disorder, the probable incidence of the
same disease in the associated potential donor should be debarred.
• In some cases, the disease can get elicited due to the graft donated.
• The living donor KT is generally thought to be suitable in patients
with nephronophthisis, autosomal recessive polycystic kidney
disease, congenital nephrotic syndrome of the Finnish type and
cystinosis.
• Table 1 depicts some of the key points related to living donor KT.
Autosomal Dominant Polycystic
Kidney Disease
• Autosomal dominant polycystic kidney disease (ADPKD), a very
common genetic renal disease, accounts for more than 5% of cases
of end-stage renal disease (ESRD) in Europe and North America.
• The KT recipients should be examined using direct sequence
analysis for ADPKD-related mutation and in case of positive results
the potential donor should also be tested for the same.
• In at-risk recipients <30 years old, CT scanning or heavily T2weighted MRI can help detect small cysts; but however, in case of
negative results, indirect and/or direct molecular genetic testing of
the polycystic kidney disease (PKD1) and PKD2 genes should be
considered.
• Living donation is contraindicated in potential donors aged <30
years old for whom imaging techniques do not show cysts but for
whom genetic tests show positive results for mutated PKD genes,
although no data exist on the risk of ESRD in such individuals.
Alport Syndrome
• Alport syndrome, an inherited glomerular disease, is
characterized by the familial occurrence of a progressive
hematuric nephropathy related with sensorineural
deafness and ultrastructural changes in the glomerular
basement membrane (GbM).
• In the X-linked form of Alport syndrome, renal disease is
seen to be more acute in males as compared to females,
with the affected males progressing to ESRD at a mean age
of 21 years.
• For transplant candidates with Alport syndrome, screening
tests for potential living kidney donors include urinalysis,
glomerular filtration rate estimation, and sight and hearing
test.
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Male siblings aged >20 years without hematuria are suitable donors for a recipient
with Alport syndrome.
Sisters of affected male recipients with Xlinked disease are at a 50% risk of being
carriers; however, in the affected brother associated with a neomutation there is
no potential risk.
Female carriers of the abnormal gene that leads to Xlinked Alport syndrome will
develop renal failure.
For a patient with Xlinked Alport syndrome, a female relative without hematuria
could be an appropriate donor.
The female heterozygous potential donors with no proteinuria, microhematuria,
and a normal glomerular filtration rate should only be permitted to donate a
kidney, after a detailed consultation with a nephrologist and a geneticist.
Individuals with isolated microhematuria are eligible donors; however, they should
be counseled about the ambiguity of long-term renal function.
In addition, both the potential kidney donor and the recipient with Alport
syndrome should also be educated about the possible occurrence of an anti-GbM
antibody disease that occurs in about 3% of renal transplant recipients with Alport
syndrome, with the male transplant recipients with Xlinked disease being at the
highest risk.
Fabry Disease
• Fabry disease, an Xlinked recessive metabolic disease is caused by
the deficient activity of the lysosomal enzyme α-galactosidase A.
• Most of the affected males require renal replacement therapy by
the time they reach 35–45 years of age.
• Heterozygote females have a different clinical course with variable
clinical manifestations owing to random X-chromosome
inactivation.
• Renal transplantation from the heterozygote female donor is unsafe
as the accumulation of globotriaosylceramide might be already
present in the donor, even in the absence of any clinical symptoms.
• It has been observed that the renal function of a heterozygous
female reduced 5 years after the kidney was transplanted to a male
relative with Fabry disease.
Hemolytic Uremic Syndrome
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Hemolytic uremic syndrome (HuS) can persist after renal transplantation. In
patients with Shiga-like toxinassociated HuS, who advance into ESRD and undergo
renal transplantation, reappearance of HuS in the transplanted kidney is very rare.
However, recurrence is a major concern in patients with non-Shiga toxinassociated (atypical) HuS.
Patients with an inherited form of HuS are at a higher risk of recurrence following
renal transplantation, with the risk being even greater in patients who have
complement factor I (CFI) mutations.
Living-related donation should be prevented in patients with complement factor H
or CFI mutations due to the high risk of HuS recurrence.
Living related donors, carrying the mutation, are at a risk of developing de novo
disease after donating a kidney to a family member with atypical HuS.
The risk of HuS recurrence is low in patients with CD46 mutations.
It is advised that genotyping for complement protein genes should be carried out
in patients who have atypical HuS and ESRD and are being considered for renal
transplantation.
Primary Hyperoxaluria
• Primary hyperoxaluria, a rare metabolic disease with an autosomal
recessive form of inheritance, is caused by a deficiency of alanine–
glyoxylate aminotransferase (AGT).
• In patients with primary hyperoxaluria, living donor KT is
controversial due to the associated risk of recurrence.
• However, according to some groups, early living donor
transplantation could be carried out, particularly in adults who have
late onset and slowly progressive disease that is responsive to
pyridoxine.
• Heterozygote family members of patients with primary
hyperoxaluria have vaguely lower AGT enzyme activity as compared
to controls, but they do not develop renal stones.
• A living related donor for an isolated renal transplantation for a
patient with primary hyperoxaluria should be examined for normal
oxalate and glycolate urine excretion levels.
Familial FSGS
• In patients with idiopathic nephrotic syndrome and focal
segmental glomerulosclerosis (FSGS), who progress to
ESRD, are at risk of recurrence of the nephrotic syndrome
following renal transplantation.
• The overall risk of recurrence being projected to be 20–
30%.
• Genetic analysis of patients with steroid-resistant nephrotic
syndrome is useful.
• It is advisable that a parent of a child carrying two
pathogenic mutations in NPHS2, undergoes test for the
Arg229Gln (p.R229Q) variant prior to living donor
transplantation, as they could be at adult-onset steroidresistant nephrotic syndrome risk.
Conclusion
• Prior to considering a living donor as a suitable choice for a patient
with a hereditary nephropathy, a careful evaluation involving both a
nephrologist and a geneticist is required to investigate the risks
involved for the recipient and donor.
• The transplantation outcomes are also affected by the age at onset,
the mode of inheritance and the clinical features of the original
disease.
• Genetic testing is suggested in case if the potential living donor is a
relative of the renal transplant recipient with a hereditary disease.
• Living donor transplantation should be prevented in patients who
have diseases with a high risk of posttransplantation recurrence,
like atypical primary hyperoxaluria or HuS.