Excellent long-term outcome of renal transplantation in cystinosis patients

We report, to our knowledge, one of the largest cohorts of adult patients with cystinosis undergoing renal transplantation with long-term follow up. Cysteamine therapy has greatly improved the prognosis of cystinosis, and delayed the onset of end-stage renal disease, but is not sufficient to avoid dialysis [8, 15, 20]. Renal transplantation is the best therapeutic option for ESRD and improves both survival rates and quality of life. However, few studies have examined the outcome of renal transplantation in cystinosis patients, and there is no data about long-term outcomes of renal transplantation at the era of cysteamine therapy. We demonstrate here a better graft survival compared to matched controls and show that cystinosis is an independent protective factor for graft survival. We also describe some late complications of the disease.

In pediatric cohorts, the outcome of kidney transplantation in patients with cystinosisis generally better than that for other patients undergoing transplantation [15, 21]. Indeed, results from the database of the North American Pediatric Renal Transplant Cooperative Study suggest that the outcome of renal transplantation is favorable in patients with a primary diagnosis of cystinosis, whereas a diagnosis of congenital nephrotic syndrome or focal segmental glomerulosclerosis associated with a high risk of graft failure, as expected [21]. More recently, data collected between 1979 and 2008 by the European Society for Paediatric Nephrology (ESPN)/European Renal Association and European Dialysis and Transplant Association (ERA/EDTA) registry showed that 5-year graft survival was better in 245 cystinosis patients compared to 490 control children undergoing kidney transplantation for another cause (94.0 % versus 84.0 %, respectively) [15]. Similarly, the Australian and New Zealand (ANZDATA) registry showed encouraging results: the 10-year death-censored survival of first transplant recipients with cystinosis (n = 44) was 86% at the era of cysteamine therapy [22]. Here, we report similar rate of graft survival at 5 and 10 years among both patients with cystinosis and control patients (92 % and 86 % at 5 years, 86.5 and 72 % at 10 years, respectively). Furthermore, we show that graft survival is better in patients with cystinosis compared to controls with respectively 180 months graft survival of 81 % and 39 % (p = 0.01) and 53 % of patients with cystinosis have a functional graft at 340 months of follow up. We confirmed, by multivariate analysis, that cystinosis is an independent protective factor for graft survival.

Interestingly, preliminary unpublished data suggest that the mTORC1 pathway is down-regulated in cystinosis patients, which may explain the very good long-term outcome of renal transplantation in these individuals, and the previously suggested better immune tolerance of patient with cystinosis [23]. In our cohort, deceased donors were older in the control than in the cystinosis group (37 vs. 30 years, respectively, p < 0.05), but this small difference is unlikely to explain the large difference in long-term graft survival. Actually, the proportion of well-defined standard criteria donor was strictly similar in both groups. We compared patients with cystinosis with age-matched control patients, including the usual renal diseases observed at this age: 9 control patients (9.7 %) had a renal disease with potential recurrence in the transplant: 7 had primary focal and segmental glomeruslosclerosis and 2 had hemolytic and uremic syndrome. These diseases are known to have bad prognosis after kidney transplantation, and could participate in the long-term difference in graft survival we observed. But, after exclusion of these 9 patients, we confirmed that graft survival was better in patients with cystinosis than in control patients. Furthermore, multivariate analysis including recurring disease in the analysis, confirmed that cystinosis was an independent protective factor for graft survival.

We confirmed that ABMR is a pejorative factor. However, surprisingly, immunization tended to be a protective factor, but statistical significance was not reached. These data are probably not clinically relevant, since our cohort is too small.

We also found that the rate of patient survival was excellent (97.0 % at 10 years), whereas prognosis in the ANZDATA study was poorer, with 88 % survival at 10 years in patients treated with cysteamine [22]. However, in these two cohorts, at the era of cysteamine, none of the deaths was related to cystinosis or chronic kidney disease. Thus we can suppose that this difference is not relevant regarding to the specific outcome of cystinosis after transplantation. In the opposite, in the early group (no cysteamine) of the ANZDATA study, the majority of deaths were cystinosis or chronic kidney disease related.

One of the limits of our study is that patients with cystinosis have been followed longer than controls (144 and 72 months, respectively). Indeed, because cystinosis is a rare disease, patients may be followed longer in tertiary centers, introducing bias into the very long-term data. However, a longer follow-up, as well as a more important proportion of adolescent patients in cystinosis group, should drag survival data down. Indeed, it has been shown that adolescent patients have lower rate of graft survival compared to other age groups [24]. Furthermore, a longer follow up in the cystinosis group may have overestimated the rate of long term post transplantation complication compared to control patients. Interestingly, in our study, median age at the time of renal replacement therapy was higher than that reported in previous studies, with values ranging between 10.1 and 12.8 years [15, 22]. Van Stralen et al. .refer to their findings as ‘disappointing’, because the expected age at ESRD onset is above 18 years among patients treated with cysteamine. Nevertheless, a recent analysis of the ERA/EDTA registry showed that 17/26 incident patients with cystinosis-related ESRD were older than 20 years [25].

Proximal tubular disease does not occur in the transplanted kidney because cystine lysosomal efflux transport system is functional in the engrafted kidney. However, retention of a native kidney can result in the persistence of renal tubular Fanconi syndrome. Interestingly, one year after transplantation, one patient developed cystine crystals in the transplanted kidney, which were diagnosed on protocol biopsy. Nonetheless, the outcome of renal transplantation in this patient was excellent, and serum creatinine was 186 μM more than 20 years after transplantation. Indeed, protocol biopsies have shown that cystine crystals may be deposited within the interstitial tissue and less frequently within glomeruli without any clinical or biological manifestations. These crystals are present in the host’s own mononuclear cells which have subsequently infiltrated the transplant [26, 27].

Renal transplantation does not correct the systemic metabolic defect of cystinosis and cystine continues to accumulate in most organs and will lead to late systemic complications. In particular, the cystinotic process is known to gradually alter beta-cell function over the years [28]. Because pancreatic insufficiency may trigger post-transplant diabetes mellitus during glucocorticoid-based immunosuppression [29], the use of steroid-free immunosuppressive regimens has also been proposed [30]. In our cohort, patients with cystinosis received the same immunosuppressive regimens than other patients, particularly the proportion of patients treated with tacrolimus, which is involved in the development of post-transplant diabetes mellitus, was similar in both groups. Numerically more cystinosis patients developed diabetes compared to controls but it was not statistically significant. The median time to diabetes onset post transplantation was 78 months, confirming that, in patients with cystinosis, diabetes can develop a long time after transplantation, and doesn’t seem to be related to immunosuppressive regimen. The use of a cystine-depleting agent (cysteamine) by all patients during follow-up may explain this favorable outcome, because this agent probably limits the risk of cystinosis-related diabetes. Thus, immunosuppressive maintenance treatment regimens should be equivalent between patients with or without cystinosis, because the potential risk of diabetes after transplantation is not sufficient to necessitate specific treatment in patients with cystinosis.

Two patients developed neurological complications of cystinosis during follow up, with myopathy leading in one patient to a restrictive pattern of chronic respiratory failure. These neurological complications were first described many years ago, but their incidence after transplantation and the effectiveness of cysteamine therapy in preventing them are poorly documented [9, 30].

All cystinosis-related complications during follow up occurred in patients with high cystine leukocyte content, showing that maintaining cysteamine treatment is critical for the management of these patients. We recommend regular monitoring of cysteine leukocyte content and treatment with cysteamine must be continued to maintain cystine levels below 1 nmol hemicystin/mg of protein.