Twelve-month kidney and liver outcomes of kidney transplantation from Hepatitis C Viremic deceased donors to aviremic recipients.

INTRODUCTION: Utilization of hepatitis C viremic (HCV+) deceased donor kidneys (DDKT) for aviremic recipients increases opportunities for transplantation with excellent short-term outcomes. Our primary aim was to understand longer-term outcomes, specifically assessing kidney and liver function in the first year posttransplant. METHODS: This was a retrospective single-center study of adult DDKT recipients of HCV+ kidneys (cases) matched 1:1 to recipients of HCV- kidneys (comparators). Between-group outcomes were analyzed using comparisons of means and proportions, survival analysis methods, and multivariable mixed effects models. RESULTS: Sixty-five cases and 65 comparators had statistically comparable demographic and clinical characteristics. There were no between-group differences in serum creatinine or estimated glomerular filtration rate at month 12 (p = .662) or in their trajectories over months 1-12 (p > .292). Within the first 60 days, rates of liver function values >3 times upper limit of normal among cases were comparable to comparators for aspartate aminotransferase (AST) (14% vs. 6%, p = .242) and higher for alanine transaminase (ALT) (23% vs. 6%, p = .011). AST declined during the first 8 weeks (p = .005) and stabilized for both groups (p = .406) during the following 10 months. ALT declined during the first 8 weeks (p < .001), continued to decline over months 3-12 (p = .016), and the trajectory was unrelated to antiviral therapy initiation among cases. CONCLUSIONS: Aviremic recipients of HCV+ kidneys had comparable kidney outcomes to matched recipients of HCV- kidneys. Despite more HCV+ recipients having an elevation in ALT within the first 60 days, ALT values normalized with no identified liver complications attributed to HCV.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Kidney Transplantation From Hepatitis C Viremic Deceased Donors to Aviremic Recipients in a Real-world Setting.

Transplantation of hepatitis C viremic (HCV+) deceased donor kidney transplants (DDKT) into aviremic (HCV-) recipients is a strategy to increase organ utilization. However, there are concerns around inferior recipient outcomes due to delayed initiation of direct-acting antiviral (DAA) therapy and sustained HCV replication when implemented outside of a research setting. METHODS: This was a retrospective single-center matched cohort study of DDKT recipients of HCV+ donors (cases) who were matched 1:1 to recipients of HCV- donors (comparators) by age, gender, race, presence of diabetes, kidney donor profile index, and calculated panel-reactive antibody. Data were analyzed using summary statistics, t-tests, and chi-square tests for between-group comparisons, and linear mixed-effects models for longitudinal data. RESULTS: Each group consisted of 50 recipients with no significant differences in baseline characteristics. The 6-mo longitudinal trajectory of serum creatinine and estimated glomerular filtration rate did not differ between groups. All recipients had similar rates of acute rejection and readmissions (all P > 0.05). One case lost the allograft 151 d posttransplant because of acute rejection, and 1 comparator died on postoperative day 7 from cardiac arrest. HCV+ recipients initiated DAA on average 29 ± 11 d posttransplant. Ninety-eight percent achieved sustained virologic response at 4 and 12 wks with the first course of therapy; 1 patient had persistent HCV infection and was cured with a second course of DAA. CONCLUSIONS: Aviremic recipients of HCV+ DDKT with delayed DAA initiation posttransplant had similar short-term outcomes compared with matched recipient comparators of HCV- donors.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Center-level Variation in HLA-incompatible Living Donor Kidney Transplantation Outcomes.

BACKGROUND: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Association of medication non-adherence with short-term allograft loss after the treatment of severe acute kidney transplant rejection.

BACKGROUND: Medication non-adherence is a risk factor for acute kidney transplant rejection. The association of non-adherence with short-term allograft loss in patients who develop acute rejection and are subsequently treated with maximal therapy is unknown. METHODS: We conducted a retrospective single center cohort study of adult patients who developed acute rejection from January 2003 to December 2017 and were treated with lymphocyte depletion. Clinicopathologic characteristics including adherence status were collected and descriptive statistics utilized to compare groups. The primary outcome was all-cause graft loss at 6 months after acute rejection treatment. A multivariable logistic regression quantified the association of non-adherence with the outcome. RESULTS: A total of 182 patients were included in the cohort, of whom 71 (39%) were non-adherent. Compared to adherent patients, non-adherent patients were younger (mean age 37y vs 42y), more likely to be female (51% vs 35%) and developed acute rejection later (median 2.3y vs 0.5y from transplant). There were no differences in estimated glomerular filtration rate or need for dialysis on presentation, Banff grade, or presence of antibody mediated rejection between the 2 groups. Overall, 48 (26%) patients lost their grafts at 6 months after acute rejection treatment. In adjusted analysis, non-adherence was associated with all-cause graft loss at 6 months after acute rejection treatment [OR 2.64 (95% CI 1.23-5.65, p = 0.012]. CONCLUSIONS: After adjusting for common confounders, non-adherent patients were at increased risk for short-term allograft loss after a severe acute rejection despite lymphocyte depletion. This finding may aid clinicians in risk stratifying patients for poor short-term outcomes and treatment futility.

Non-immunoglobulin A mesangial immune complex glomerulonephritis in kidney transplants.

We have observed a predominantly mesangial non-immunoglobulin A immune complex mesangial glomerulopathy (MG) in renal transplants with mesangial deposits by immunofluorescence and electron microscopy. Clinicopathological features of 28 patients with MG were analyzed and compared with 28 transplant controls, matched for age, sex, ethnicity, donor type, estimated glomerular filtration rate, and interval from transplant to biopsy. Indications for biopsy in the MG group were allograft dysfunction in 64%, allograft dysfunction/proteinuria in 29%, and proteinuria in 7%. Biopsy indications in controls were allograft dysfunction (61%), allograft dysfunction/proteinuria (18%), proteinuria (14%), and delayed graft function (7%). Most MG cases had mild mesangial hypercellularity with endocapillary proliferation in 2 and crescents in 2 without fibrinoid necrosis. Immunoglobulin M-dominant deposits were present in 83%, and immunoglobulin G was dominant in 17% with mesangial deposits in 93% of cases by electron microscopy. Compared with controls, MG had higher Banff interstitial inflammation score (i) (P = .036) and was associated with concurrent acute T-cell-mediated rejection (P = .023), but not with acute or chronic antibody-mediated rejection. MG patients and controls had similar prevalence of polyomavirus nephropathy and Epstein-Barr virus infection. At follow-up, most MG patients had stable estimated glomerular filtration rate with no or stable proteinuria. Disease-specific graft survival was not different in MG versus controls. We conclude that, in view of the apparent self-limited nature of this lesion, additional treatment may not be required in these patients. Awareness of this lesion may thus spare patients unwarranted further intervention.

Brain wave maturation and neurodevelopmental outcome in extremely low gestational age neonates.

OBJECTIVE: Infants born at extremely low gestational ages are at high risk for developmental impairments. Early predictors of these impairments are useful for both clinicians and researchers. Our objective was to assess the correlation between the rate of brain wave maturation as measured by serial amplitude-integrated electroencephalograms (aEEGs) and scores on standardized measures of infant development in extremely low gestational age neonates. STUDY DESIGN: This was a prospective observational study of 65 infants born before 28 weeks' gestational age who were assessed with an aEEG monthly between 28 and 36 weeks' postmenstrual age and with the Bayley Scales of Infant and Toddler Development-III at 18 to 22 months adjusted age. We analyzed the correlation between the rate of brain wave maturation on aEEG and Bayley Scales of Infant and Toddler Development-III Cognitive and Motor Scales. RESULT: The mean rate of brain wave maturation was 0.83 (±0.36) points per week. Brain wave maturation was not correlated with either the Cognitive or Motor Scale (adjusted regression coefficients for Cognitive and Motor Scales were 1.61 (s.e.: 4.20; P=0.70) and 2.39 (s.e.: 4.62; P=0.61), respectively. CONCLUSION: Among extremely preterm infants, the rate of maturational changes in brain wave characteristics between 28 and 36 weeks' postmenstrual age is not predictive of developmental abilities at 18 to 22 months adjusted age.

Mammalian target of rapamycin inhibitors in organ transplantation: an unkept promise.

The initial enthusiasm for the advent of a potentially nonnephrotoxic immunosuppressant has been muted by data unmasking nephrotoxicity of mammalian target of rapamycin inhibitors, including renal podocyte injury resulting in proteinuria. Adverse reactions, including anemia, thrombocytopenia, hyperlipidemia, and especially diabetogenesis, have limited its use to niche indications such as prevention or amelioration of malignancy in organ transplant. The class seems to be best used to address malignancy in organ allograft recipients and as a first-line therapy in lymphangioleiomyomatosis.

Healthcare costs in renal transplant recipients using branded versus generic ciclosporin.

BACKGROUND: Generic ciclosporin A modified (CsA) does not have an equivalent pharmacokinetic profile to branded CsA in some transplant populations, potentially leading to negative clinical consequences and increased long-term costs. OBJECTIVE: To assess direct healthcare costs for de novo renal transplant recipients in the US receiving branded versus generic CsA in the first month after transplantation. METHODS: Administrative claims data from eight private US health plans were linked to the Organ Procurement and Transplantation Network data. A total of 227 renal transplant cases between 1996 and 2004 were included: 183 were dispensed branded CsA and 44 received generic CsA. Log transformed multiple linear regression was used to model total first-year healthcare costs after the initial CsA claim, controlling for both patient demographics and clinical characteristics and clustering at the transplant centre level. RESULTS: After controlling for patient factors and pre-CsA costs, total healthcare costs were significantly higher (p = 0.04) for patients receiving generic CsA versus branded CsA. The main driver for the difference was the cost associated with immunosuppressants other than CsA (p = 0.01). CONCLUSION: Despite initial perceived cost savings associated with generic CsA, de novo renal transplant recipients incurred greater total healthcare costs than those treated with branded CsA. Patients receiving generic CsA may need higher doses or other immunosuppressants to maintain the transplanted kidney than patients receiving branded CsA. Providers and payers need to be aware of potential differences in total healthcare costs between formulations of bioequivalent critical-dose drugs to make the best choice for patient care.

Linking the US transplant registry to administrative claims data: expanding the potential of transplant research.

OBJECTIVE: In the United States, data on transplanted and waitlisted patients collected by the Organ Procurement and Transplantation Network (OPTN) have been widely used in transplantation research. Administrative claims data, collected by health plans for reimbursement purposes, are also commonly used in health-services research. This study linked OPTN and private payer claims data to assess the relationship between data elements common to both sources. METHODS: All transplanted or waitlisted patients in the registry were considered for inclusion. A multistep match algorithm was employed to link OPTN and payer data from years 1995 to 2004. Variables common to both datasets that contained relevant information for similar time periods were compared. RESULTS: A total of 21,419 solid organ transplant recipients and 8808 waitlist patients were included in the final linked database. Organ type and demographic variable distributions in the linked dataset were similar to the overall OPTN database. Using claims as the reference group, sensitivity and specificity values were on average 0.72 and 0.69, respectively, and were highest for the indicators of immunosuppression use at discharge and follow-up. CONCLUSION: This comparison of payer data with information reported by transplant centers to the OPTN provides important insight into the value of both data sources. Using administrative claims to augment the registry data with utilization and cost information will be useful for evaluation of both economic and clinical endpoints in solid organ transplantation.

Calcineurin inhibitor avoidance versus steroid avoidance following kidney transplantation: Postoperative complications.

This study compared early postoperative complications in kidney transplant recipients treated with either a sirolimus-based calcineurin inhibitor (CNI)-free regimen or a tacrolimus-based steroid-free regimen. We used a single-center, prospective, sequential but nonrandomized study design. Consecutive recipients of primary cadaveric or non-HLA identical kidney transplant recipients received either a CNI-free regimen, consisting of sirolimus 5 mg daily beginning postoperative day 3, mycophenolate mofetil 1 gm twice a day, and methylprednisolone 500 mg intraoperatively, then prednisone 30 mg daily tapered to 10 mg daily at 3 months, or a prednisone-free regimen, consisting of methylprednisolone 500 mg, 250 mg, and 125 mg from days 0 to 2, then no further steroids, tacrolimus 0.075 mg/kg twice a day, and mycophenolate mofetil 1 g twice a day. All patients received thymoglobulin induction 6 mg/kg total dose. Outcome measures were patient and graft survival, BPAR, surgical and wound complications, viral infections and posttransplant diabetes mellitus (PTDM). Both groups had excellent early outcomes with no significant difference in patient or graft survival, early renal function, BPAR, surgical or wound complications, or viral infections between the two groups. Patients in the sirolimus-based CNI-free group had a significantly higher incidence of PTDM and a trend toward more discontinuation due to drug toxicity. Whether either regimen improves long-term outcomes awaits longer follow-up.

Short-term results under three different immunosuppressive regimens at one center.

We examined short-term outcomes and posttransplant medical complications under three different immunosuppressive regimens at a single center. The study design was a randomized, prospective, open-label trial comparing a calcineurin inhibitor-free (CNI) protocol to standard triple therapy with tacrolimus, prednisone, and mycophenolate mofetil. They were also compared to a concurrent but nonrandomized third cohort treated with a prednisone-free protocol. All three groups had excellent early outcomes with no significant difference in patient or graft survival or biopsy-proven acute rejection. Serum creatinine was significantly lower in the CNI-free recipients. Lipid panels and posttransplant diabetes mellitus were significantly lower in the prednisone-free patients. Prednisone-free kidney transplant recipients have improved early glucose metabolism and hyperlipidemia compared to CNI-free or standard triple therapy recipients with comparable rejection and graft survival rates.