Cystinuria and Transplantation

By David S Goldfarb, M.D.
Director, Kidney Stone Prevention Program, St. Vincents Hospital
Professor of Medicine and Physiology, NYU School of Medicine

There is a web-site journal called HDCN you probably know: hypertension, dialysis, clinical nephrology, run by John Daugirdas, a very prominent dialysis expert. Most of the content I believe is limited to health professionals. I’m on the editorial board, and review stone disease especially for John.

There’s an “ask the professor” feature, questions from other nephrologists, and recently a transplant surgeon asked whether cystinuria recurs after transplantation. I took the occasion to discuss some aspects of the disorder, then answered the question. The response is below.

Cystinuria

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, 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 37æmol/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).

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