Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression.

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.

The negative impact of T cell-mediated rejection on renal allograft survival in the modern era.

The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell-mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA-DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor-specific antibodies (P = .002). HLA-DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA-DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA-DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA-DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA-DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report.

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m2). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.

HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity.

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch, HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell-mediated rejection (P = .0006), HLA-DR/DQ de novo donor-specific antibody development (P < .0001), antibody-mediated rejection (P < .0001), as well as all-cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation.

The current immunosuppressive pipeline in kidney transplantation is limited. In part, this is due to excellent one-year allograft outcomes with the current standard of care (ie, calcineurin inhibitor in combination with anti-proliferative agents). Despite this success, a recent Federal government-sponsored systematic review has identified gaps/limits in the evidence of what constitutes optimal calcineurin inhibitor use in the short- and long-term. Moreover, recent empiric approaches to minimize/withdraw/convert from calcineurin inhibitors have come with the price of increased alloreactivity. As the time horizon to replace calcineurin inhibitors on a global scale may be distant, the transplant community should seize the opportunity to develop ways to personalize calcineurin inhibitor immunosuppression to the individual-transitioning from empiricism to precision. The authors argue in this viewpoint that the path to precision will require measures capable of detecting subclinical alloreactivity to define adequacy of immunosuppression, as well as novel genetic analytics to accurately define alloimmune risk at the individual level-both approaches will require validation in clinical trials.

Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development.

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.