Nephrol Dial Transplant (2002) 17: 1695-1697
© 2002 European Renal Association-European Dialysis and Transplant Association
Case Reports
Recurrence of familial interstitial nephritis following renal transplantation
Christopher F. Wong1,
Kottarathil A. Abraham1,
Anthony M. Dorman2 and
J. Joseph Walshe1,
1 Department of Nephrology and Transplantation and
2 Department of Renal Pathology, Beaumont Hospital, Dublin, Ireland
Keywords: familial interstitial nephritis; recurrence; renal transplantation
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Introduction
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Hereditary renal disease is not an uncommon cause of end-stage
renal failure (ESRF) and accounts for 15.7% of the patients
in the Irish dialysis population [
1]. Adult polycystic kidney
disease was the underlying diagnosis in the majority (68%) of
these individuals. Although familial interstitial nephritis
is rare, we have previously reported two siblings who developed
ESRF as a consequence [
2]. They also had retinitis pigmentosa
but did not fit into any previously described renal-retinal
syndrome. Both patients have since undergone successful cadaveric
renal transplantation but have subsequently developed recurrence
of their disease with ultimate graft loss. The implications
of these findings are discussed.
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Case 1
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A 16-year-old female was admitted with worsening night blindness
and renal failure in 1988. She was obese and her IQ was estimated
at 130 using the Wechsler Adult Intelligence Scale (normal WAIS
being 85–115). She had retinitis pigmentosa and syndactyly
of the second and third digits of her hands and feet, but developed
normal secondary sexual characteristics. Renal histology from
a biopsy performed in 1988 showed chronic tubulointerstitial
disease characterized by a patchy but almost diffuse infiltrate,
predominantly comprising lymphocytes and plasma cells. The majority
of the tubules showed atrophic changes. There was no evidence
of crystal deposition (Figure 1
). She was commenced on peritoneal
dialysis. Three and a half years later, she received a cadaveric
renal allograft and was commenced on quadruple immunosuppression
consisting of antithymocyte globulin, cyclosporin, azathioprine
and prednisolone. The patient was discharged 2 weeks later with
a serum creatinine of 140 µmol/l. After 3 years of relatively
stable graft function and cyclosporin levels that were consistently
in the therapeutic range, she developed a subacute deterioration
of kidney function from a baseline creatinine of 144 to 360
µmol/l over 5 months. Imaging of the renal transplant
revealed no abnormalities. The graft was biopsied and histology
confirmed recurrence of interstitial nephritis (Figure 2
) with
infiltrates of predominantly lymphocytes and plasma cells, similar
to the histology from her native biopsy. Minimal tubulitis was
noted in very occasional non-atrophic tubules. However, tubular
atrophy was widespread and interstitial fibrosis involved 90%
of the cortex. Seven of 15 glomeruli were sclerosed. Moderate
hyaline arteriosclerosis was present with mild sclerosis in
the arteries. These findings were identical to those found in
the original biopsy from her native kidney. She was recommenced
on peritoneal dialysis in 1995, almost 2 years after graft dysfunction
began. She subsequently received another renal transplant in
1999, and, 22 months on, her serum creatinine remains stable
at 120 µmol/l with a tacrolimus, mycophenolate mofetil
and prednisolone based immunosuppressive regimen.
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Fig. 1. Renal histology from Case 1 showing interstitial nephritis in the native kidney (PAS stain; original magnification: x200).
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Case 2
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A 19-year-old male, who is the brother of Case 1, presented
with symptoms of uraemia in 1991. Renal histology confirmed
tubulointerstitial nephritis with features very similar to his
sister's biopsy findings. There was a patchy, almost diffuse
infiltrate of predominantly lymphocytes and plasma cells, with
interstitial fibrosis affecting almost 100% of the renal cortex
in the presence of normal arteries and relatively mild glomerulosclerosis.
He was also obese and had retinitis pigmentosa, but his extremities,
IQ and secondary sexual characteristics were normal. He was
commenced on peritoneal dialysis and 1 year later received a
renal transplant. However, complications at the time of surgery
resulted in graft loss. The patient received a second cadaveric
renal transplant after 14 months. Induction of immunosuppression
was with antithymocyte globulin, cyclosporin, azathioprine and
prednisolone. The postoperative course was uncomplicated and
the patient's serum creatinine dropped from its preoperative
level of 1468 to 150 µmol/l within 1 week. Three years
on, similar to that seen with his sister and despite long-term
therapeutic cyclosporin levels, a subacute decline in renal
function was noted with a rise in serum creatinine, from a baseline
of 130 to 226 µmol/l over 4 months. The renal transplant
ultrasound and DTPA scans were essentially normal. A renal biopsy
was performed and histology confirmed recurrence of tubulointerstitial
nephritis with patchy foci of tubular atrophy. The infiltrating
inflammatory cells (again mainly lymphocytes and plasma cells)
were most significant in the areas of interstitial fibrosis
and tubular atrophy. Occasional areas of mild tubulitis were
noted in the surviving tubules. Nodular hyaline arteriosclerosis
without any evidence of endotheliatis and mild arterial sclerosis
without significant concentric fibrointimal proliferation were
present. Only one of 10 glomeruli was sclerosed. As borderline
cellular rejection could not be entirely ruled out, he was treated
with high dose steroids without any improvement in renal function.
He was subsequently placed back on our chronic dialysis programme,
4 years after the decline in his graft function commenced.
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Discussion
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Rejection and patient death with a functioning graft are the
most common reasons for renal graft loss [
3]. While recurrence
of the original disease in the transplanted kidney is not uncommon,
it leads to ESRF in
5% of cases [
4,
5]. To date, there have been
no reports describing the recurrence of familial interstitial
nephritis as a cause of transplant loss. However, there are
only four families reported (in addition to our cases) with
ESRF due to interstitial nephritis in the absence of medullary
cystic disease [
6–
9], and members of only one of these
families have undergone renal transplantation [
7]. Our two patients
are the first to demonstrate that familial tubulointerstitial
nephritis can recur in renal transplants and, more importantly,
that they can be of sufficient severity to result in graft loss.
In both siblings, allograft function started to deteriorate 3 years after transplantation. (Of note, there were no features of tubulointerstitial nephritis on the histology acquired 1 month after the sister received her latest renal transplant.) Other causes of acute interstitial nephritis, including infections, hypersensitivity, crystal deposition disorders and autoimmune disease, were ruled out in both patients by history, clinical examinations, laboratory investigations and renal histologies. In addition, there was no convincing evidence of acute rejection in our patients’ renal histologies. The long-term maintenance of cyclosporin levels within the therapeutic range and the histological findings made cyclosporin toxicity less likely, but not impossible. Chronic allograft nephropathy could also have resulted in comparable renal pathology, although the 3 years over which renal impairment occurred in our two patients would be an unusually short period for this process to cause the degree of graft dysfunction observed in them [10]. Also, despite the almost 100% interstitial fibrosis seen in our cases, arterial changes were mild and <50% of the glomeruli were sclerosed. Given this disproportionate involvement of the interstitium and tubules, the similarity of their transplant histology to the native biopsies in both cases, the time sequence and the lack of response to increased immunosuppression, we conclude that the cause of renal impairment in both our transplant recipients was recurrence of their familial interstitial nephritis.
Our patients are unique in that they developed this recurrence and also because they cannot be categorized into any previously described renal-retinal syndrome. The clinical entity that most resembles our cases is Bardet–Biedl syndrome (BBS), an autosomal recessive condition with renal defects that are most often structural in nature [11]. Despite some similarities, our patients have many features that distinguish them from BBS cases, including normal I.Q.s and the lack of hypogenitalism or dysmorphic extremities in the male sibling. In addition, the pattern of renal disease in our cases differs from those described in BBS patients. While renal failure does occur in BBS [12], tubulointerstitial nephritis is rare [13] and has not been reported as the reason for ESRF in any BBS patient. Also, renal transplantation has been performed successfully in patients with BBS [11] without the recurrence of native disease ever being recorded.
The question remains of whether our patients represent a unique renal-retinal syndrome or form part of the spectrum of BBS. Ongoing genetic studies will hopefully clarify this issue. What is clear, however, is that familial interstitial nephritis can recur in renal transplants with sufficient severity to result in graft failure.
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Notes
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Correspondence and offprint requests to: Prof. J. J. Walshe,
Department of Nephrology and Transplantation, Beaumont Hospital,
Dublin 9, Ireland. Email:
joseph.walshe{at}beaumont.ie 
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References
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- O'Dea D, Parfrey PS, Harnett JD, Hefferton D, Cramer BC, Green J. The importance of renal impairment in the natural history of Bardet–Biedl syndrome. Am J Kidney Dis1996; 27: 776–783[Medline]
- Sato H, Saito T, Yamakage K, Kyogoku Y, Furuyama T, Yoshinaga K. Renal histopathology of Laurence Moon Biedl Syndrome: tubulointerstitial nephritis without specific glomerular changes. Nephron1988; 49: 337–338[Medline]
Received for publication: 5.12.01
Accepted in revised form: 6. 3.02
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Introduction
Case 1