Pediatr Nephrol (2001) 16:946–950
FESTSCHRIFT
M.F. Gagnadoux · F. Lacaille · P. Niaudet · Y. Revillon
P. Jouvet · D. Jan · G. Guest · M. Charbit · M. Broyer
Long term results of liver-kidney transplantation
in children with primary hyperoxaluria
Received: 7 June 2001 / Revised: 7 August 2001 / Accepted: 7 August 2001
Abstract From 1990 to 2000, we performed eight liver-
kidney transplants in eight children, aged 1–16 years,
with end-stage renal failure (ESRF) due to primary hy-
peroxaluria (PH1). The duration of dialysis before trans-
plantation ranged from 2 to 42 months (mean 14 months)
and was <1 year in four patients. Only the first patient
underwent postoperative hemodialysis; in the other five,
we chose to induce maximal diuresis from the first hours
with intravenous and intragastric hyperhydration (≥3 l/m2
per day). High water intake with nocturnal tube hydra-
tion was maintained for 6 months to 5 years, as long as
oxaluria exceeded 0.5 mmol/day. A quadruple sequential
immunosuppressive regimen was used. Two patients
died during liver graft surgery. The other six patients are
alive and well, with a mean follow-up of 7.4 years (range
5–11 years). Patient and graft survival is 75% at 5 years.
At latest follow-up, liver tests were normal in all six pa-
tients; creatinine clearance ranged from 55 to 95 ml/min
per 1.73 m2 (mean=74). Oxaluria was lower than
0.4 mmol/day in all patients (mean=0.22). The six pa-
Dedicated to Michel Broyer
M.F. Gagnadoux (✉) · P. Niaudet · G. Guest · M. Charbit
M. Broyer
Department of Pediatric Nephrology,
Hôpital Necker-Enfants Malades, 149 rue de Sèvres,
75743 Paris Cedex 15, France
e-mail: marie-france.gagnadoux@nck.ap-hop-paris.fr
Tel.: +33-1-44494463, Fax: +33-1-44494460
F. Lacaille
Department of Hepatology,
Hôpital Necker-Enfants Malades, 149 rue de Sèvres,
75743 Paris Cedex 15, France
Y. Revillon · D. Jan
Department of Surgery,
Hôpital Necker-Enfants Malades, 149 rue de Sèvres,
75743 Paris Cedex 15, France
P. Jouvet
Department of Intensive Care,
Hôpital Necker-Enfants Malades, 149 rue de Sèvres,
75743 Paris Cedex 15, France
© IPNA 2001
tients underwent 15 renal biopsies, 1–11 years after
transplantation. Chronic transplant nephropathy was
present in four patients and mild cyclosporin nephrotox-
icity in another. No oxalate crystals were seen and repeat
ultrasonography has been consistently normal in all pa-
tients. The three patients with bone oxalosis showed pro-
gressive complete healing of bone lesions. All six chil-
dren or adolescents now live a normal life. From this se-
ries, we conclude that early combined liver-kidney trans-
plantation is the treatment of choice for children with
ESRF due to primary hyperoxaluria.
Keywords Oxalosis · Renal transplant · Hepatorenal
transplant
Introduction
Primary oxaluria type 1 (PH1) is an autosomal recessive
metabolic disorder due to deficiency of the liver-specific
peroxisomal enzyme alanine:glyoxylate aminotransfer-
ase (AGT). The consequence is an oxalate overproduc-
tion, leading firstly to crystalline calcium oxalate depos-
its in the kidney, resulting in nephrocalcinosis and pro-
gressive renal failure (oxalosis). Dialysis does not re-
move calcium oxalate efficiently, and persistent overload
results in oxalate crystal deposits in bones, retina, heart,
vessels, and nerves. Isolated kidney transplantation is al-
ways followed by recurrence of nephrocalcinosis, due to
the unremitting oxalate overproduction by liver, and pa-
tient and graft survival is poor [1, 2]. The only definitive
treatment is combined liver and kidney transplantation
(LKT), introduced by Watts et al. at the end of the 1980s
[3], which has considerably improved patient and graft
survival in Europe [4, 5], provided it is performed before
the onset of heavy oxalate burden. However LKT in
young children is still considered hazardous. We report
here the long-term follow-up (5–11 years) of eight chil-
dren who underwent LKT for PH1 in our institution
since 1990.

Patients and methods
Patients
From 1990 to 2000, eight children (5 girls) who were diagnosed
with PH1 in severe renal failure underwent LKT at 1–16 years
of age; no child died from untreated PH1. Their clinical character-
istics are reported in Table 1. The age at first symptom was
3 months in two infants with renal failure, and 1.5–12 years in six
children with initial nephrolithiasis. The diagnosis of PH1 was
confirmed by liver AGT measurement in six children, presence of
a gene mutation in one (present also in two other patients), and
urine biochemistry (hyperoxaluria and glycolaturia) in one (patient
1). Three children had one or two affected siblings and the parents
of patient 1 were father and daughter. Pyridoxine sensitivity was
absent in the five children in whom it could be tested before end-
stage disease.
The age at the start of dialysis ranged from 3 months (in the
2 infants) to 15 years (mean 7.7 years). Only patient 5 was not
yet on dialysis at the time of LKT (glomerular filtration rate
17 ml/min per 1.73 m2). The average time on dialysis before LKT
was 18 months (range 2–42 months), but it was shorter than 1 year
in five of eight patients.
Four children showed oxalate bone deposits, severe in one, and
two infants had retinal deposits without visual impairment. Growth
before LKT was normal in three and impaired (–1 to –3 SD) in five
patients. One child had an unexplained hypoalbuminemia from en-
teral loss. In the last three recipients, cardiac Holter recording was
systematically performed in order to detect arrhythmia.
LKT was performed at a median age of 8.5 years (range 1–16
years). Four recipients were younger than 6 years of age (age: 1, 2,
5.1, and 5.8 years).
Methods
Four donors were children (age 2–11 years), the other four were
young adults (age 20–32 years). In three cases (patients 1, 2, and
8) the liver had to be reduced. Biliary anastomosis was a Roux-
en-Y hepaticojejunostomy in five patients and direct bilio-biliary
anastomosis in three patients.
947
Kidney allograft was set on the left side, in a quasi-orthotopic
position; renal artery and vein were anastomosed to aorta and vena
cava. Uretero-ureteral anastomosis was used in all cases.
The immunosuppressive protocol was the same as in non-PH1
patients of the same period. Initial regimen included induction
therapy in six patients (with OKT3 or antithymocyte globulin), in-
travenous cyclosporin started from day 1 to 6 (mean day 4), meth-
ylprednisolone then prednisone (60 mg/m2 tapered to 15 mg/m2 at
day 60), and azathioprine 2 mg/kg. Later, tacrolimus and myco-
phenolate mofetil (MMF) were introduced in four patients,
and prednisone was given on alternate days in four children after
1–6 years. The present immunosuppressive regimen is a double
therapy with prednisone and tacrolimus for one patient, and a tri-
ple therapy with prednisone, cyclosporin, and azathioprine (n=2)
or MMF (n=3) for the other five surviving children (Table 2).
The prevention of recurrence of oxalate deposits on the grafted
kidney was a major concern during the postoperative period. Post-
operative hemodialysis sessions were not performed, except in pa-
tient 1, in whom hemodialysis resulted in oliguria and massive
calcium oxalate crystalluria and was subsequently stopped [6].
Permanent urine hyperdilution was obtained through massive hy-
dration (≥3 l/m2 per day) with intravenous fluid, associated as
soon as possible with a large oral intake through a nasogastric tube
or a gastrostomy. Hydrochlorothiazide was added in patients 2, 3,
and 4. Urine dilution was assessed by daily follow-up of oxalate
crystalluria, including oxalate crystal volume measurement, in or-
der to maintain a crystal volume <100 µm3/mm3 [6]. After the
postoperative period, high fluid intake, with nocturnal tube hydra-
tion, was maintained for 6–45 months, as long as oxaluria exceed-
ed 0.5 mmmol/24 h. During this same time, sodium or potassium
citrate or bicarbonate was given to obtain a urinary pH≥7, and
magnesium salts were added, in order to inhibit oxalate crystalli-
zation.
Routine follow-up included, at each outpatient visit, study of
crystalluria on fresh morning urine samples, measurement of 24-h
oxalate excretion, and usual assessment of hepatic and renal func-
tion. Renal and hepatic ultrasonography was performed at least
annually. Kidney biopsy was performed routinely 1 year after
LKT, and in the case of alteration of renal function. Liver biopsy
was performed when clinically or biologically indicated, and rou-
tinely in patient 1 10 years after LKT.

Table 1 Clinical characteristics of the eight patients (ESRF end-stage renal failure, LKT liver-kidney transplantation, NC nephrocalcinosis)

Patient Family history First symptom Age at Extrarenal Age at LKT Donor age
no. and age ESRF signs

1 Consanguinity NC; 1.5 years 4.7 years – 5.1 years 11 years (reduced liver)
2 – ESRF; 3 months 3 months Bone, retina 1 year 6 years (reduced liver)
3 – ESRF; 3 months 3 months Bone, retina 2 years 2.5 years
4 Consanguinity Stones; 4 years 7 years Bone 10.5 years 11 years
5 Consanguinity, 1 affected sister Stones; 1.5 years 6 years – 5.8 years 32 years
6 – Stones; 6 years 15 years – 15.5 years 26 years
7 1 affected brother ESRF; 12 years 12 years – 13 years 23 years
8 Consanguinity, 2 affected siblings ESRF; 12 years 12 years Bone 16 years 20 years (reduced liver)

Table 2 Outcome of the six surviving patients at latest follow-up (CTN 1/3 chronic transplant nephropathy, grade 1 or 3, AR acute rejection,
Ntox nephrotoxicity, ND not done, Pred prednisone, Tacro tacrolimus, CsA cyclosporin, MMF mycophenolate mofetil, Aza azathioprine)

Patient Follow-up Age Creatinine Latest kidney biopsy Liver Late liver biopsy Immunosuppression
no. (µmol/l) tests

1 11 years 16 years 120 11 years: CTN3+AR+Ntox N 10 years: normal Pred+Tacro→Pred+CsA+MMF

2 10 years 11 years 98 7 years: CTN1 N ND Pred+CsA+MMF
3 7.5 years 9.5 years 85 2 years: borderline N ND Pred+CsA+Aza
4 6 years 16 years 110 5 years: CTN1 N 6 years: AR Pred+CsA→Pred+Tacro+MMF
6 5 years 21 years 109 5 years: CTN1+Ntox N ND Pred+Tacro
7 5 years 18 years 145 3 years: Ntox N ND Pred+CsA+Aza
948
Results
Postoperative period
Two of the eight children died in the immediate postop-
erative period. Patient 5 experienced cardiac arrhythmia
and hypotension during surgery, then hepatic artery
thrombosis. He died of refractory cardiac failure during
liver retransplantation surgery on day 7. Patient 8 under-
went additional surgery for abdominal bleeding on day
2, did not recover renal function, and died of peritoneal
and systemic infection on day 18.
The other six patients had immediate diuresis and
rapid normalization of renal and hepatic function. One
mild rejection on day 6 was rapidly reverted with meth-
ylprednisolone boluses. Early complications included
ascites in three patients (chylous in 1), bowel obstruc-
tion in two, and pancreatitis in one patient. Only one
complication was life-threatening (bowel obstruction
with shock). Four children developed moderate cyto-
megalovirus (CMV) infection; one of them (patient 4)
who had concomitant Epstein-Barr virus infection de-
veloped a mild lymphoproliferative disorder, which re-
gressed with a decrease in immunosuppression. Early
liver biopsies disclosed mild rejection in one patient,
CMV hepatitis in one, and a normal liver in a third
child.
Long-term results
Six patients are alive and well with a follow-up of
5–11 years (mean 7 years) and both grafts functioning
(Table 2). The patient and graft survival is thus 75% in
this series.
The enzymatic replacement was immediately effec-
tive, but hyperoxaluria was prolonged until all oxalate
deposits were eliminated. The duration of hyperoxaluria
(>0.5 mmol/day) ranged from 6 to 45 months and was
related to the duration of end-stage renal disease before
LKT (Fig. 1). At latest follow-up, oxaluria ranged from
0.12 to 0.35 mmol/24 h – mean 0.22 mmol (normal
<0.5 mmol/1.73 m2 per day). Plasma oxalate normalized
within 1–8 weeks (mean 3.3 weeks).
One liver rejection occurred 6 years after transplanta-
tion in patient 4 (likely from non-compliance) and re-
quired conversion to tacrolimus and mycophenolate.
Liver biopsy was normal in two other patients after
4 months and 10 years, respectively. At latest follow-up,
liver function and ultrasonography were normal in the
six patients.
No episode of kidney rejection was observed in the
first 10 years of follow-up. Patient 1 experienced an
acute renal deterioration 11 years after LKT, and renal
biopsy showed a mixture of chronic and acute rejection
and drug nephrotoxicity; renal function improved after
methylprednisolone bolus and switch from tacrolimus to
cyclosporin and mycophenolate. In the whole group, lat-
est creatinine level ranged from 85 to 145 µmol/l (mean
Fig. 1 Correlation between duration of dialysis and duration of
hyperoxaluria
111.5), and latest clearance creatinine ranged from 55 to
95 ml/min per 1.73 m2 (mean 74). No nephrocalcinosis
was observed on repeat ultrasonography and abdominal
X-rays.
Fifteen kidney biopsies have been performed 4
months to 11 years after LKT (mean 3 years). Except for
a few crystals in tubular lumina within the first months,
no oxalate crystals were present as late as 11 years post
transplantation.
Early biopsies (<2 years post LKT) were normal or
borderline in four patients and showed chronic transplant
nephropathy (CTN) grade 1 in patient 1 and mild neph-
rotoxicity in patient 6. Late biopsies (≥3 years post LKT)
showed CTN grade 1 in four patients (worsening to
grade 3 in patient 1) and/or calcineurin inhibitor nephro-
toxicity on three samples.
The improvement of extra-renal oxalosis was dramat-
ic as regards bone deposits, which were progressively
cleared in the three patients with oxalate bone disease.
We observed complete healing, permitting successful
surgery for a femoral neck fracture in patient 4, who un-
derwent 42 months of dialysis before LKT (Fig. 2). Con-
versely, retinal deposits had not disappeared 5 years after
transplantation, but did not impair vision. No other ox-
alate localization was observed.
No long-term complications have occurred. All six
patients, now 10–21 years old, have a normal social inte-
gration. Growth was normal in four children and im-
paired (–2 to –4 SD) in two: patient 1 with daily predni-
sone therapy for 6 years and patient 4 with severe bone
lesions.
Three affected siblings of these patients, detected at
birth (2) or at 5 years of age (1), are currently receiving
active conservative management, including hyperhy-
dration (≥2 l/m2 per day) through gastrostomy, inhibi-
tors of crystallization, and pyridoxine. The three chil-
dren, now respectively 1, 4, and 9 years old, have no
apparent nephrocalcinosis and maintain a normal renal
function.

Fig. 2 Healing of bone oxalosis in patient 4: X-rays of hips at
transplantation and 4 years later
Discussion
PH1, which is a rare disease in developed countries
(1/120,000 live births in France), accounts for as much
as 13% of childhood end-stage renal failure (ESRF) in
some developing countries with high consanguinity rates
[7]. Dialysis treatment is unable to remove the amount of
oxalate continuously produced, so that oxalate overload
progressively involves most tissues, primarily those
where calcium concentration is high, such as bones,
causing crippling disability.
The early experience of isolated kidney transplanta-
tion (KT) in the 1970s demonstrated that this procedure
offered only a temporary solution because of the con-
stant recurrence of oxalate deposits on the graft. Al-
though some authors have reported an improvement of
patient and graft survival with the use of living donors
and an aggressive pre- and postoperative management,
including daily dialysis and permanent urine hyperdilu-
tion [8, 9], the long-term results of KT alone in children
949
are generally poor, even in recent years [10]. Only com-
bined LKT, which normalizes oxalate production, can of-
fer a long-term cure for this disease. LKT was intro-
duced by Watts in 1984 and by 1999, 98 LKT in 93 pa-
tients were recorded in the European PH1 Transplant
Registry, with excellent 5-year patient and grafts survival
of 79 and 71%, respectively [5]. The shorter the duration
of dialysis before transplantation, the better the results.
After a disastrous experience of KT alone in the
1970s, with graft survival of 0% at 3 years in seven chil-
dren with PH1, since 1990 we have performed LKT in
children with PH1 as soon as possible after reaching
ESRF. The ten children with PH1 referred to our center
in severe renal failure since 1990 have undergone LKT,
and their 4-year patient and graft survival is 75%. The
three youngest children (1–5 years old at the time of
transplantation) have a 100% 7-year graft survival, in
contrast to the poorer results (60% at 5 years) reported
for young children (<6 years of age) in the European ex-
perience (Oxalosis Registry Report 1987–1999).
The long-term results in the six surviving children are
very encouraging. Kidney and liver survival rates are
100%; only two rejection episodes occurred (in 1 liver
and 1 kidney) after 6 and 11 years, respectively. As al-
ready hypothesized, the presence of the same-donor liver
may protect the kidney from rejection [11]. The absence
of any oxalate deposit on the kidney graft on repeat bi-
opsies must be emphasized. We think this is attributable
to our protocol of permanent hyperdiuresis through gas-
tric tube, continued until complete normalization of ox-
alate excretion, sometimes for years. To reduce the dura-
tion of post-LKT hyperhydration, the dialysis period
should be as brief as possible or, ideally, avoided. The
complete healing of severe bone oxalate disease after
LKT is also very encouraging.
However, the 25% mortality rate is very high com-
pared with that of KT alone in children, which is lower
than 10% at 10 years; however, it is comparable to that
of liver transplantation alone in children (75%–80% pa-
tient survival at 10 years) [12, 13]. The two deaths in our
series were complications of the liver transplantation. In
patient 8 the abdominal bleeding was probably the
source of the lethal complications; in addition this pa-
tient underwent nearly 4 years of dialysis before LKT
and was in a poor nutritional condition. However patient
5, with preterminal renal failure, had no apparent risk
factors, and the cause of his death was not fully under-
stood.
However, the mortality risk due to liver transplanta-
tion itself (never less than 10% in the most-experienced
hands) makes the decision for preemptive LKT (which
was the case in patient 5) a difficult one. Still more prob-
lematic is the decision for an isolated liver transplant in
order to cure the enzymatic defect before the occurrence
of renal failure. This procedure has been successfully
performed in a few children in the last decade [14, 15];
but its risk and its timing should be carefully weighed
[16]. Permanent hyperhydration, which in our experience
avoided the appearance or the progression of nephrocal-
950
cinosis and maintained a normal glomerular filtration
rate in three siblings of our patients for up to 5 years,
may be a less risky option for children with PH1 detect-
ed before advanced renal failure.
In conclusion, we recommend early combined LKT
as the treatment of choice for children with ESRF due to
PH1, with 5-year patient and graft survival of 75% and
an excellent long-term rehabilitation. The indication and
the timing for preemptive liver or liver-kidney transplan-
tation remain a matter of debate.
References
1. Broyer M, Brunner FP, Brynger H, Dykes SR, Ehrich JHH,
Fassbinder W, Geerlings W, Rizzoni G, Selwood NH, Tufve-
son G, Wing AJ (1990) Kidney transplantation in primary oxa-
losis: data from the EDTA registry. Nephrol Dial Transplant
5:332–336
2. Scheinman JI, Alexander M, Campbell ED, Chan JC, Latta K,
Cochat P (1995) Transplantation for primary hyperoxaluria in
the USA. Nephrol Dial Transplant 10 [Suppl 8]:42–46
3. Watts RWE, Calne RY, Rolles K, Danpure CJ, Morgan SH,
Mansell MA, Williams, R, Purkiss P (1987) Successful treat-
ment of primary hyperoxaluria type I by combined hepatic and
renal transplantation. Lancet II:474–475
4. Jamieson NV (1995) The European Primary Hyperoxaluria
Type I Registry: report on the results of combined liver/kidney
transplantation for primary hyperoxaluria 1984–1994. Nephrol
Dial Transplant 10 [Suppl 8]:33–37
5. Abstracts of 5th Workshop on Primary Hyperoxaluria (1999)
Nephrol Dial Transplant 14:2784–2789
6. Jouvet P, Priqueler L, Gagnadoux MF, Jan D, Beringer A,
Lacaille F, Ravillon Y, Broyer M, Daudon M (1998) Crystal-
luria: a clinically useful investigation in children with primary
hyperoxaluria post-transplantation. Kidney Int 53:1412–1416
7. Kamoun A, Lakhoua R (1996) End-stage renal disease of the
Tunisian child: epidemiology, etiologies and outcome. Pediatr
Nephrol 10:479–482
8. Scheinman JI, Najarian JS, Mauer SM (1984) Successful strat-
egies for renal transplantation in primary oxalosis. Kidney Int
25:804–811
9. Saborio P, Scheinman JI (1999) Transplantation for primary
hyperoxaluria in the United States. Kidney Int 56:1094–1100
10. Tejani A, Sullivan EK (2000) Should liver-related renal trans-
plants be performed for primary oxalosis. Pediatr Transplant 4
[Suppl 2]:131–132
11. Rasmussen A, Davies HS, Jamieson NV, Evans DB, Calne RY
(1995) Combined transplantation of liver and kidney from the
same donor protects the kidney from rejection and improves
kidney graft survival. Transplantation 59:919–921
12. European Liver Transplant Registry. Data December 2000
13. Alonso H, Ryckmann FC (1998) Current concepts in pediatric
liver transplant. Semin Liver Dis 18:295–307
14. Schürmann G, Schärer K, Wingen AM, Otto G, Herfarth C
(1990) Early liver transplantation for primary hyperoxaluria
type I in an infant with chronic renal failure. Nephrol Dial
Transplant 5:825–827
15. Nolkemper D, Kemper MJ, Burdelski M, Vaisman I, Rogiers
X, Broelsch CE, Ganschow R, Muller-Wiefel DE (2000)
Long-term results of pre-emptive liver transplantation in pri-
mary hyperoxaluria type I. Pediatr Transplant 4:177–181
16. Cochat P, Schärer K (1993) Should liver transplantation be
performed before advanced renal failure in primary hyperoxa-
luria type I? Pediatr Nephrol 7:212–218