Is there any literature or experience about recurrent disease after kidney
transplantation for renal failure resulting from cystinuria, particularly from a living related
donor?
Thomas Diflo, M.D. (Director of Kidney and Pancreas Transplantation, New York University
Medical Center)
Response by David S. Goldfarb, M.D.
(Co-Director, Kidney Stone Prevention and Treatment Program;
Assistant Professor of Medicine,
New York University School of Medicine)
The question asked is whether cystinuria can recur after
renal transplantation. I'll review the basic pathophysiology with
an update on recent investigations of the defective cystine
transporter, and then examine this issue.
Cystinuria is an autosomal recessive disorder of
transepithelial transport of cystine and other dibasic amino
acids. Cystine is relatively insoluble, and its presence in the
tubular lumen at concentrations of more than 250 mg/l is
associated with precipitation and stone formation. Treatment
requires increasing urinary volumes to keep cystine
concentrations at or below 250 mg/l, urinary alkalinization with
potassium citrate, restriction of dietary sodium, and reduction
of cystine to the soluble cysteine with penicillamine or alpha-
mercaptoproprionylglycine.
The abnormal gene was mapped via linkage studies to human
chromosome 2p (1). At the same time, the mutated gene was
demonstrated to be rBAT (basic amino acid transporter) (2), a
cystine transporter previously identified in proximal tubular
membrane vesicles from humans, rats and rabbits. This transporter
mediates sodium-independent, electrogenic, apical membrane uptake
of cystine into the cells of the proximal straight tubule (S3).
It is also present in the apical brush border membranes of the
jejunum where it mediates absorption of cystine. When expressed
in Xenopus oocytes, this transporter also mediates transport of
dibasic amino-acids (lysine, ornithine, arginine) and some
neutral amino-acids as well (11). This high-affinity process is
augmented by a low-affinity process in the proximal convoluted
tubule (S1), the mediator of which is not yet identified. After
uptake across the apical membrane, cystine, essentially a
cysteine dimer, is reduced intracellularly to cysteine which
exits the cell across the basolateral membrane.
Studies by Harris (3) and Rosenberg (4) suggested that there
were 3 phenotypes of cystinuria. Type I, the most severe form,
appears to be caused most frequently by a mutation of rBAT
residue 467 from methionine to threonine. This mutation, called
M467T, accounted for 40% of the abnormal chromosomes in the
Spanish cohort studied by Calonge et al (2), and 30% of the
abnormal chromosomes studied in the entire group (n=36) from
Spain and Italy. Heterozygotes for Type I have normal urinary
levels of cystine and other amino-acids. Type II patients have
impaired in-vitro intestinal transport of lysine, but cystine
transport is present in the homozygote. Type II heterozygotes
have increased urinary levels of cystine, ornithine, arginine,
and lysine. Type III patients have some intestinal cystine
absorption, and can partially absorb an oral load. Type III
heterozygotes also have moderately increased urinary amino-acid
excretion. The molecular correlates for Type II and Type III have
not yet been described but presumably represent the
manifestations of other mutations in the rBAT gene, or in some
cases, combinations of M467T with other abnormal alleles.
In answer to the question about renal transplantation, one
would not expect cystinuria to recur after cadaveric renal
transplantation since the renal transport of cystine in the graft
would be expected to be normal. Intestinal absorption of cystine
would be absent in Type I patients and impaired in most Type II
and III patients, so cystinuria would not occur. There are no
demonstrations of other metabolic abnormalities of proven
clinical significance associated with failure of cystine
transport. Deficiency of other amino-acids, like lysine, are not
limiting, as their absorption as constituents of oligo-peptides
is not impaired (5).
One letter describes a patient who received a living-related
transplant, though it fails to describe the relationship of the
donor to the recipient (6). More than 3 years later, urinary
amino- acid levels were normal, with cystine excretion of 37
mmol/24 hours, and no recurrence of nephrolithiasis. This letter
cites an article purporting to have 3 cases of renal
transplantation; in fact, my review of this article finds no
mention of transplantation in it (7)! Another report of stones in
renal transplant recipients notes no cases of cystine stones in
88 cases (8). However, cystine stones account for (only) up to 3%
of stones in the general population, so not finding a case is not
very surprising.
One might expect increased urinary cystine levels in
recipients of living-related grafts obtained from heterozygotes
with Type II- and Type III phenotypes. Since I can find no
heterozygotes reported with active cystine stone disease, the
clinical significance of the finding would appear to be nil,
assuming of course that the prospective donor has no history of
nephrolithiasis. In Rosenberg's reports, levels of cystinuria
that occurred in Type II and III heterozygotes were below 250
mg/gm creatinine, levels unlikely to cause nephrolithiasis. The
utility therefore of measuring cystine levels would be
negligible. The cyanide-nitroprusside test can be used to screen
qualitatively for cystinuria with excellent sensitivity (5).
An additional issue is the relative frequency with which
patients with cystinuria, and perhaps their relatives, develop
calcium or urate stones. Other metabolic abnormalities accounting
for this have been described. Sakhaee (9) found that 5 of 27
cystinurics had hypercalciuria, 6 had hyperuricosuria, and 12 had
hypocitraturia. These abnormalities may or may not be resolved by
renal transplantation and recipients may then be at risk for
recurrent stone disease after transplantation. Of course it is
also possible that these abnormalities are intrinsic to the
native kidneys, or the result of recurrent stone disease (like
renal tubular acidosis with hypocitraturia). Morin (10) described
a family in which several heterozygotes for cystinuria had
hypercalciuria and/or hyperuricosuria.
References
1. Pras, E. et al. Localization of a gene causing cystinuria to
chromosome 2p. Nature Genetics 6:415-419 (94).
2. Calonge, M.J. et al. Cystinuria caused by mutations in rBAT, a
gene involved in the transport of cystine. Nature Genetics 6:420-
425 (94).
3. Harris, H. et al. Phenotypes and genotypes in cystinuria. Ann.
Hum. Genet. 20:57 (55).
4. Rosenberg, L.E. et al. Cystinuria: biochemical evidence of
three genetically distinct disease. J. Clin. Invest. 46:365 (66).
5. Halperin, E.C. and Thier, S.O. "Cystinuria" in
Nephrolithiasis, pp 208-230; Eds. Coe, F.L., Brenner, B.M.,
Stein, J.H., Churchill Livingstone, NY, 1980.
6. Tuso, P. et al. Cystinuria and renal transplantation. Nephron
63:478 (93).
7. Crawhall, J.C. Cystinuria: an experience in management over 18
years. Miner Electrolyte Metab 13:286-293 (87).
8. Urolithiasis after renal transplantation. Transplant. Proc.
21:1960-1 (89).
9. Sakhaee, K., et al. The spectrum of metabolic abnormalities in
patients with cystine nephrolithiasis. J. Urol. 141:819 (89).
10. Morin, C.L. et al. Biochemical and genetic studies in
cystinuria: observations on double heterozygotes of genotype
I/II. J. Clin. Invest. 50:1961 (1971).
11. Bertran, J. et al. Expression cloning of a human renal cDNA
that induces high affinity transport of L-cystine shared with
dibasic amino acids in Xenopus oocytes. J. Biol. Chem. 268:14842
(93).
(July, 1996)