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Kidney tx cystinosis webinar

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Cystinosis is a rare autosomal recessive lysosomal disorder with an estimated incidence of 1 per 100 000 to 200 000 live births

The gene responsible for the disease, CTNS, was identified in 1998

Kidney involvement is the most serious clinical event, because it leads to end stage renal disease (ESRD) before the age of 20 in more than 90 % of patients

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Kidney tx cystinosis webinar

  1. 1. Kidney Transplantation in Cystinosis Mitra Basiratnia Ped nephrologist SUMS
  2. 2. Introduction  Cystinosis is a rare autosomal recessive lysosomal disorder with an estimated incidence of 1 per 100 000 to 200 000 live births  The gene responsible for the disease, CTNS, was identified in 1998  Kidney involvement is the most serious clinical event, because it leads to end stage renal disease (ESRD) before the age of 20 in more than 90 % of patients 2
  3. 3. Introduction  Systemic treatment with cysteamine, delays the time between diagnosis and the onset of ESRD, but is not sufficient to prevent it.  Renal transplantation is the best therapeutic option for ESRD in young patients  Few studies have investigated the safety and efficacy of kidney transplantation in cystinosis patients 3
  4. 4.  Between 1976 and 1989, 22 children (11 females, 11 males) with nephropathic cystinosis received 28 renal allografts  None of the patients had ever been treated with cystine- depleting agents before and after TX  Patient and graft survival did not differ from non-cystinotic children.  There is a need for a specific metabolic treatment for cystinosis starting at early age and possibly persisting after transplantation. 4
  5. 5. 5
  6. 6. ⦁ They assessed 15 cystinotic patients with renal TX (1375-1385) ⦁ Mean F.up was 43mo /mean age at TX was 8 years (2-13) ⦁ Four years patient and graft survival was 100% and 86.7%, respectively. ⦁ The cause of graft loss was vascular insult in 2 patients. ⦁ Mean age at TX was lower in comparison to other studies ( 8 years VS 9 years) 6
  7. 7.  441 kidney transplants performed in 362 cystinotic patients younger than 31 years between 1987 and 2017  three equal eras (1987‐1997, 1998‐2007, and 2008‐2017) to assess changes in outcomes  Eras 2 and 3 had lower risk of acute rejection 7
  8. 8. Eras 2 and 3 had higher 5‐year mean GFR 8
  9. 9.  Five‐year graft survival was similar across eras, but 5‐year patient survival was higher for era 2  Age at ESRD, acute rejection, GFR at 5 years, and patient survival improved over time. 9
  10. 10.  Data of renal transplantation (n = 31) in 30 adult patients with cystinosis in 5 French university transplant centers between 1980 and 2013  A control cohort of 93 patients was matched for age, graft date, living/deceased donor status and transplant center  Median age at transplantation was 20.4 years (7–36.5).  At transplantation, all patients with cystinosis had corneal cystine deposits, 3 had diabetes and 7 had hypothyroidism. 10
  11. 11.  Graft survival was better in patients with cystinosis than in control patients (p = 0.013).  Graft survival at 5 and 10 years was 92.0 and 86.5 % in cystinosis group, respectively, and 86.0 % and 72.0 % in control group.  Multivariate analysis confirmed that cystinosis was an independent protective factor for graft survival 11
  12. 12.  Specific complications of cystinosis occurred during follow up: diabetes mellitus (n = 4), hypothyroidism (n = 1), liver involvement (n = 1), neurologic involvement (n = 2).  Proportion of post-transplant diabetes mellitus (PTDM) was not statistically different in cystinosis group compared to control group  They concluded that Renal transplantation appears to be safe with excellent long-term outcomes in patients with cystinosis. 12
  13. 13. Kaplan-Meier analysis of graft survival during follow up. 13
  14. 14. Protective and pejorative factors for graft survival 14
  15. 15. Graft outcome  In pediatric cohorts, the outcome of kidney transplantation in patients with cystinosisis generally better than that for other patients undergoing transplantation  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)  Australian and New Zealand (ANZDATA) registry showed the 10-year survival of first transplant recipients with cystinosis (n = 44) was 86% at the era of cysteamine therapy 15
  16. 16.  the rate of patient survival was excellent (97.0 % at 10 years)  One patient died after 51 months of follow-up, because of a car accident  at the era of cysteamine, none of the deaths was related to cystinosis or chronic kidney disease  In the opposite, in the early group (no cysteamine) of the ANZDATA study, the majority of deaths were cystinosis or chronic kidney disease related 16
  17. 17. 17 preliminary unpublished data suggest that the mTORC1 pathway is down-regulated in cystinosis patients, which may explain the very good longer outcome of renal transplantation in these individuals and the previously suggested better immune tolerance of patient with cystinosis
  18. 18. protocol biopsy  A protocol biopsy was performed one year after transplantation in 13 patients with cystinosis  Cystine crystals were observed in the renal biopsy from only one patient  the patient had a functional graft 22 years after transplantation (serum creatinine level 182 μM). 18
  19. 19. Kidney transplant biopsy showing cystine crystal into recipient mononuclear cells 19
  20. 20.  Proximal tubular disease does not occur in the transplanted kidney because cystine lysosomal efflux transport system is functional in the engrafted kidney  retention of a native kidney can result in the persistence of renal tubular Fanconi syndrome  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 20
  21. 21. Complications of cystinosis after renal transplantation  Renal transplantation does not correct the systemic metabolic defect of cystinosis  Cystine accumulate in most organs and will lead to late systemic complications.  Those over the age of 30 were usually doing poorly, although many were still working  Lack of prolonged compliance with cysteamine therapy may have been a major cause of these problems 21
  22. 22.  Diabetes can develop a long time after transplantation, and doesn’t seem to be related t immunosuppressive regimen.  The use of a cystine-depleting cysteamine by all patients probably limits the risk of cystinosis-related diabetes  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 22
  23. 23.  Neurological complications consisted in progressive distal myopathy in two patients, leading to interdigital amyotrophy  It is estimated that depletion of excess cystine from muscle requires 4 to 11 years of therapy.  One patient presented 3 years after transplantation with behavioral disorder without any motor or sensitive deficiency. 23
  24. 24.  Another patient with hepatic involvement presented with cholestasis  Corneal transplantation was performed in two patients during follow up  One patient developed PTLD, successfully treated with chemotherapy. 24
  25. 25. “ 25 All patients who developed cystinosis complications had cystine leukocyte content above 2 at the time of the complication
  26. 26. CONCLUSION  Long-term outcome of cystinosis patients undergoing renal transplantation is excellent.  Renal transplant recipients with cystinosis have a better long-term outcome than other renal transplant recipients  Kidney transplant outcomes for children and young adults with cystinosis have improved over the last three decades. 26