Ten years of Israel’s organ transplant law: is it on the right track?

Abstract The Israeli organ donor law was established in 2008. In the ensuing 10 years there have been some improvements in deceased donation and living donor rates and a reduction in the unethical practice of transplant tourism. There is, however, controversy regarding increased access to transplant for those who have been living donors, who are family members of deceased donors, or who have registered their intent to donate. The issue of routine retrieval versus obtaining consent for organ donation has also been raised. This commentary will address these issue, and propose some steps for improvement of the current Israeli organ donation system

The role of CYP3A5 polymorphism and dose adjustments following conversion of twice-daily to once-daily tacrolimus in renal transplant recipients

Abstract Background Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD. Methods A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA. Results Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort. Conclusions The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements. Trial registration Clinical trials.gov identifier: NCT0188448

A Clinical and Pathological Variant of Acute Transplant Glomerulopathy

Acute transplant glomerulopathy transplant glomerulopathy (TG) is a common cause of late renal allograft loss. We describe a unique case of a renal transplant recipient who developed rapid-onset nephrotic-range proteinuria and acute kidney injury secondary to C4d negative acute TG. Two courses of intravenous Rituximab resulted in significant improvement in proteinuria and allograft function. In the setting of acute nephrotic-range proteinuria postrenal allograft, both renal biopsy with electron microscopy and screening for de novo donor-specific antibody should be performed to distinguish atypical presentations of TG from other diagnoses.Peer Reviewe

A prospective cohort conversion study of twice-daily to once-daily extended-release tacrolimus: role of ethnicity

Abstract Background Tacrolimus is a widely used calcineurin inhibitor in kidney transplantation. It is available as twice-daily Prograf® (Tac-BID) and once-daily Advagraf® (Tac-OD). Although therapeutically equivalent, some patients require dose adjustments to achieve similar trough concentrations [C0] after conversion. Tacrolimus exposure is affected by ethnicity in the de novo setting but the role of ethnicity in determining dose requirements and adjustments after conversion is unknown. Methods In this study, 496 renal transplant recipients (RTRs) were prospectively converted from Tac-BID to Tac-OD, with dose adjustments targeted to achieve similar [C0] at 12 months post-conversion. Renal function, acute rejection and Tac dose adjustments by ethnicity were analyzed. Results There were similar numbers of recipients from living and deceased donors. The mean transplant duration was 7 years. Of the RTRs, 60% were Caucasian and 40% were identified as belonging to an ethnic minority. There was no change in estimated renal function (eGFR) post-conversion to Tac-OD. At 12 months, 35/488 (7%) RTRs were receiving a reduced dose, 101/488 (21%) required a dose increase of which 77 (16%) were receiving at least a 30% increase in dose over baseline. The percentage of those in ethnic groups requiring a dose increase of >30% varied from 8.0% for South Asians to 27.5% for East Asians (P = 0.03), despite East Asians having a similar baseline dose of Tac-BID (3.59 mg/day) compared to the entire cohort (3.53 mg/day). Conclusions Ethnicity may play an important role in dosing requirements when converting from Tac-BID to Tac-OD, unrelated to baseline dose. Further investigation is required to determine the reasons for ethnic variability when patients are converted between tacrolimus preparations

Post-transplant outcomes in recipients of living donor kidneys and intended recipients of living donor kidneys

Abstract Background Long-term kidney transplant survival at the population level is consistently favorable, but this survival varies widely at an individual level due to both recipient and donor factors. The distinct contribution of recipient and donor factors to individual post kidney transplant outcome remains unclear. Comparing outcomes in deceased donor (DD) recipients with potential but non-actualized living donors (DD1) to those recipients with actualized living donors (LD), and to DD recipients without potential living donors (DD0) may provide transplant candidates with more information about their own post-transplant prognosis. Methods We conducted an observational retrospective cohort study of kidney transplant candidates presenting to our centre for evaluation between 01/01/06 and 31/12/18, and who also received a transplant during that time. Patients were followed to 31/08/2019. Candidates were classified as DD0, DD1, or LD based on whether they had an identified living donor at the time of initial pre-transplant assessment, and if the donor actualized or not. Primary outcome was 5-year death-censored graft survival, adjusted for common pre- and post-transplant donor and recipient risk factors. Secondary outcomes analyzed included patient survival and graft function. Results There were 453 kidney transplant recipients (LD = 136, DD1 = 83, DD0 = 234) who received a transplant during the study period. DD0 and DD1 did not differ in key donor organ characteristics. The 5-year death censored graft survival of DD1 was similar to LD (p = 0.19). DD0 graft survival was inferior to LD (p = 0.005), but also trended inferior to DD1 (p = 0.052). By multivariate Cox regression analysis, LD demonstrated similar 5-year graft survival to DD1 (HR for graft loss 0.8 [95% CI 0.25–2.6], p = 0.72) but LD graft survival was superior to DD0 (HR 0.34 [0.16–0.72], p = 0.005). The 5-year patient survival in DD1 was similar to LD (p = 0.26) but was superior to DD0 (p = 0.01). Conclusions DD recipients with potential but non-actualized living donors exhibit similar mid-term graft and patient survival compared to LD recipients. Having an identified living donor at the time of pre-transplant assessment portends a favorable prognosis for the recipient

Reduction in New-Onset Diabetes Mellitus after Renal Transplant with Erythropoietin-Stimulating Agents: A Retrospective Cohort Study

Background: Studies have shown that erythropoietin-stimulating agents (ESAs) protect mice against the development of diabetes through direct effects on pancreatic ß cells. However, the effect of ESAs on the incidence of diabetes in humans has not been well studied. It is unknown whether exposure to ESAs is associated with a reduced incidence of new-onset diabetes after transplant (NODAT). Objective: The objective of this study is to examine the relationship between ESA exposure post-renal transplant and the development of NODAT. Design: We performed a single center, retrospective cohort analysis. Patients: We compared patients who received a first live or deceased donor renal allograft, with any exposure to an ESA vs. those without such exposure and who developed NODAT and who did not. Patients with a prior history of diabetes mellitus or multi-organ transplant, including a second renal transplant were excluded. Measurements and methods: NODAT was defined based on the 2008 Canadian Diabetes Association criteria. Multivariate logistic regression analysis was performed to determine factors independently associated with NODAT. Results: One hundred thirty-two (29 %) patients were exposed to an ESA, four of which developed NODAT compared to 128 who did not develop NODAT ( p < 0.0001). Of those not exposed to an ESA, 15 % (48/319) developed NODAT. By Fisher's exact test, exposure to an ESA at any time post-transplant reduced the risk of developing NODAT; odds ratio (OR) = 0.08, 95 % confidence interval (CI) (0.018–0.352), p = 0.0008. Older age; OR = 1.41, 95 % CI (1.036–1.933), p < 0.02, higher random blood sugar at discharge; OR = 1.30, 95 % CI (1.077–1.57), p < 0.006 and deceased donor; OR 2.18 CI (1.009–4.729), p = 0.04 were associated with an increased risk of NODAT. Limitations: The limitations of this study include its retrospective nature, single center, and homogenous population; thus, generalizability of the results must be approached with caution. Conclusion: ESA exposure may be associated with a reduced incidence of NODAT in the post-renal transplant population. The role of ESA in preventing NODAT requires further investigation

Reduction in new-onset diabetes mellitus after renal transplant with erythropoietin-stimulating agents: a retrospective cohort study

Abstract Background Studies have shown that erythropoietin-stimulating agents (ESAs) protect mice against the development of diabetes through direct effects on pancreatic ß cells. However, the effect of ESAs on the incidence of diabetes in humans has not been well studied. It is unknown whether exposure to ESAs is associated with a reduced incidence of new-onset diabetes after transplant (NODAT). Objective The objective of this study is to examine the relationship between ESA exposure post-renal transplant and the development of NODAT. Design We performed a single center, retrospective cohort analysis. Patients We compared patients who received a first live or deceased donor renal allograft, with any exposure to an ESA vs. those without such exposure and who developed NODAT and who did not. Patients with a prior history of diabetes mellitus or multi-organ transplant, including a second renal transplant were excluded. Measurements and methods NODAT was defined based on the 2008 Canadian Diabetes Association criteria. Multivariate logistic regression analysis was performed to determine factors independently associated with NODAT. Results One hundred thirty-two (29 %) patients were exposed to an ESA, four of which developed NODAT compared to 128 who did not develop NODAT (p < 0.0001). Of those not exposed to an ESA, 15 % (48/319) developed NODAT. By Fisher’s exact test, exposure to an ESA at any time post-transplant reduced the risk of developing NODAT; odds ratio (OR) = 0.08, 95 % confidence interval (CI) (0.018–0.352), p = 0.0008. Older age; OR = 1.41, 95 % CI (1.036–1.933), p < 0.02, higher random blood sugar at discharge; OR = 1.30, 95 % CI (1.077–1.57), p < 0.006 and deceased donor; OR 2.18 CI (1.009–4.729), p = 0.04 were associated with an increased risk of NODAT. Limitations The limitations of this study include its retrospective nature, single center, and homogenous population; thus, generalizability of the results must be approached with caution. Conclusion ESA exposure may be associated with a reduced incidence of NODAT in the post-renal transplant population. The role of ESA in preventing NODAT requires further investigation