Maha Mohamed

Tacrolimus pharmacogenetics: The CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and south asians

Previously, we demonstrated that the dose-normalized tacrolimus blood concentration after renal transplantation was associated with a single nucleotide polymorphism (SNP) in the CYP3AP1 gene, probably through linkage with an SNP in the CYP3A5 gene. Individuals with at least one CYP3A5*1 allele synthesize CYP3A5 and CYP3A5*3/*3 homozygotes do not. We now present results with direct typing of the CYP3A5 genotype for this group of 180 kidney-only transplant recipients from a single center. South Asian and white patients with at least one CYP3A5*1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with CYP3A5*3/*3 homozygotes, confirming our previous findings for the CYP3AP1 SNP. There was a significant delay in achieving target blood concentrations in those with at least one CYP3A5*1 allele. Determination of the CYP3A5*1/*3 genotype could be used to predict the tacrolimus dose requirement and, given incomplete linkage, would be better than determination of the CYP3AP1 genotype.

Antithymocyte Globulin is Associated with a Lower Incidence of De Novo Donor-Specific Antibodies in Moderately Sensitized Renal Transplant Recipients

Background Recent evidence suggests that de novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and graft failure after kidney transplantation. The effects of induction immunosuppression on dnDSA are unknown. Methods The study population comprised 114 consecutive moderately sensitized (positive DSA and negative flow crossmatch) recipients who received deceased donor renal transplants between December 2009 and November 2011. Patients were divided into two groups based on induction immunosuppression: antithymocyte globulin (ATG) (n=85) or basiliximab (n=29) and were followed up for 36 months. Results Patients in the ATG group received a mean dose of 4.98 mg/kg±7.9 mg/kg, had a significantly higher PRA, and received more plasmapheresis and IVIG at the time of transplant. The incidence of dnDSA (P=0.02, HR=0.33, 95% CI 0.09–1.24) and ABMR (P=0.001, HR=0.9, 95% CI 0.04–0.87) was significantly lower in the ATG group. In multivariate regression analyses, ATG induction was the single most important variable associated with both ABMR and dnDSA. Conclusions In moderately sensitized deceased donor renal transplant recipients, induction with ATG is associated with a reduction in the occurrence of dnDSA and ABMR when compared with basiliximab.

Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean calculated panel reactive antibody and MFImax ranged from 10.3% to 57.2%, and 262 to 1691, respectively, between low and high-risk protocols. Mean MFImax increased significantly from transplant to one-week and one-year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32% including 14% cellular, 12% antibody-mediated and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71 to 6.45) and increased donor specific antibodies at 1 week post-transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

In kidney transplant recipients with BK polyomavirus infection, early BK nephropathy, microvascular inflammation, and serum creatinine are risk factors for graft loss.

Little information is available on the risk factors for graft loss in kidney transplant recipients with BK polyomavirus (BKPyV) nephropathy (BKVN) in the presence or absence of antibody‐mediated rejection (AMR).

Outpatient Management of Delayed Graft Function is Associated with Reduced Length of Stay without an Increase in Adverse Events

Delayed graft function (DGF) is a common and costly complication of kidney transplantation. In July 2011, we established a multidisciplinary DGF clinic managed by nurse practitioners to facilitate early discharge and intensive management of DGF in the outpatient setting. We compared length of stay, 30‐day readmission, acute rejection, and patient/graft survival in 697 consecutive deceased donor kidney transplantations performed between July 2009 and July 2014. Patients were divided into three groups: no DGF (n = 487), DGF before implementation of the DGF clinic (n = 118), and DGF clinic (n = 92). Baseline characteristics including age, gender, panel reactive antibody, retransplantation rates, HLA mismatches, induction, and maintenance immunosuppression were not significantly different between pre‐ and post‐DGF clinic groups. Length of stay was significantly longer in pre‐DGF clinic (10.9 ± 6.2 vs. 6.1 ± 2.1 days, p < 0.001). Thirty‐day readmission (21% vs. 16%), graft loss (7% vs. 20%), and patient death (2% vs. 11%) did not differ significantly between pre‐ and post‐DGF clinic. Patients in the DGF clinic were less likely to develop acute rejection (21% vs. 40%, p = 0.006). Outpatient management of DGF in a specialized clinic is associated with substantially shorter hospitalization and lower incidence of acute rejection without significant difference in 30‐day readmission or patient and graft survival.

Which is more nephrotoxic for kidney transplants: BK nephropathy or rejection?

Little data exist comparing outcomes following BK nephropathy (BKN) vs acute rejection. We reviewed outcomes among recipients who had a primary diagnosis of biopsy‐proven BKN or rejection between 1 and 18 months post‐transplant. There were 96 cases of BKN and 256 cases of rejections. We compared outcomes of BKN with all rejection combined and also with cellular rejection. Seven of 256 (2.7%) patients developed BKN after treatment of rejection. Conversely, 8 of 96 (8.3%) developed rejection after BKN. The eGFR at time of diagnosis in the BKN group (33.7 ± 12.6) was lower than the rejection group (44.8 ± 23.3, P < .001). The eGFR at 6 months after diagnosis of BKN was 32.7 ± 14.9 and for rejection was 48.8 ± 20.7 (P ≤ .001). The mean eGFR at 3 years postdiagnosis was 41.6 ± 18.5 in BKN and 53 ± 21.3 for rejection (P = .001). The graft failure incidence rates were similar between 2 groups. A similar pattern was observed comparing BKN with cellular rejection. While the difference in rate of graft loss between BKN and rejection did not reach statistical significance, kidney function up to 3 years after diagnosis was worse for BKN than for rejection, suggesting that BKN is at least as damaging to kidneys as rejection.

Older kidney transplant patients experience less antibody-mediated rejection: a retrospective study of patients with mild to moderate sensitization.

There is a paucity of data stratifying by age the incidence of antibody‐mediated rejection (AMR) in kidney transplant patients.

Characteristics and Outcomes of Kidney Transplant Recipients with a Functioning Graft for More than 25 Years

Background: Information regarding the clinical characteristics and outcomes of kidney transplant recipients (KTRs) with > 25 years of graft survival is limited. Methods: In this single-center observational study, we characterized KTRs transplanted between 1973 and 1992 with active follow-up as of July 31, 2017. Results: We identified 112 patients with > 25 years of allograft function. The mean posttransplantation follow-up was 29.8 ± 4.0 years. Glomerulonephritis was the most common cause of end-stage renal disease (ESRD) (52%). The majority received live donor transplants (66%), including 25 patients (22%) with human leukocyte antigen-matched kidneys. The incidence of biopsy-confirmed acute rejection was 21%, ranging from 0 to 26 years post transplantation. Donor-specific antibodies (DSA) were checked in 80% of patients at a mean of 28.4 ± 0.11 years post transplantation. Of these, only 15% were positive. The incidence of malignancy was 44%, with nonmelanoma skin cancers being most common. The incidence of infectious complications was 77%, mostly represented by urinary tract infections. At the time of last follow-up, 63% were on a calcineurin inhibitor (CNI)-free regimen, mean serum creatinine was 1.4 ± 0.6 mg/dL, and the prevalence of hypertension and dyslipidemia was 89 and 88%, respectively. Conclusion: The majority of patients with a long-term functioning graft had glomerulonephritis as cause of ESRD, had received a live donor kidney, were on a CNI-free regimen, and had a low incidence of DSA and opportunistic infections. These characteristics define a unique group of patients requiring specific posttransplantation monitoring and management.

BK viremia is not associated with adverse outcomes in the absence of BK nephropathy

There are limited data regarding the association of different levels of BK viremia and BK nephropathy (BKN), and graft outcomes. We studied the BK plasma PCR levels of all kidney transplant recipients (KTR) transplanted at our institution between 01/01/2006 and 06/30/2014. Patients were divided into groups based on their highest BK plasma PCR level within the first year following transplantation: undetectable, low (<1000 copies/mL), moderate (1000‐10 000 copies/mL), high (>10 000‐100 000 copies/mL), very high (>100 000 copies/mL), and those that had biopsy‐proven BKN. There were a total of 1146 KTR during the study period: 813 with undetectable BK levels and 333 with any detectable BK level (87 with low, 79 with moderate, 88 with high, 34 with very high level BK, and 45 that had BKN). Compared to KTR with an undetectable BK level, incidence of mortality, graft failure, rejections,and infections were not significantly different for those with low, moderate, high, or very high BK level. Patients with BKN had a higher rate of infection and higher rates of total graft failure or death‐censored graft failure compared to those with undetectable BK levels. BK viremia in the absence of BKN does not significantly increase the risk of rejection, infections, or graft failure compared to an undetectable BK level.

Rituximab and Monitoring Strategies for Late Antibody-Mediated Rejection After Kidney Transplantation

Background There is limited information on treatment strategies and monitoring strategies for late antibody-mediated rejection (ABMR) after kidney transplantation. Methods In this observational and nonrandomized study, we compared 78 patients diagnosed with late ABMR (>3 months after transplant) who were treated with standard of care steroids/IVIG (n = 38) ± rituximab (n = 40) at our center between March 1, 2013 and December 31, 2016. All patients had follow-up biopsy and donor-specific antibodies (DSA) monitoring within 3 to 12 weeks. Results Patients had biopsy 7.3 ± 7 years after transplant and were followed for 15.9 ± 9.6 months after ABMR was diagnosed. Both treatment strategies were associated with a significant decline in DSA, microvascular inflammation (peritubular capillaritis + glomerulitis), and C4d Banff scores. In univariate regression analyses, rituximab, estimated glomerular filtration rate (eGFR), Banff i, t, v, chronicity (interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy) scores on the first biopsy, and eGFR and Banff v score on follow-up biopsy were associated with graft loss. Multivariate analyses retained only rituximab (hazard ratio, 0.23; 95% confidence interval, 0.06-0.84; P = 0.03) and eGFR at follow-up biopsy (0.84; 95% confidence interval, 0.76-0.92; P < 0.001) as significant predictors of graft loss. Kaplan-Meier analyses demonstrated that the benefit associated with rituximab was apparent after 1 year (15% vs 32% graft loss, P = 0.02). Conclusion Treatment of late ABMR with steroids/IVIG ± rituximab was effective in reducing DSA and microcirculation inflammation. The addition of rituximab was associated with better graft survival. Follow-up biopsies could be considered in the management of acute rejection to monitor the effect of therapy. Randomized studies on the best therapeutic options for ABMR are needed.