Publications by authors named "Mark D Stegall"

153 Publications

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

Am J Transplant 2020 Dec 28. Epub 2020 Dec 28.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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 =  1.68 ). 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 =  2.09 ; PFNC =  2.40 ; PCC =  2.24 ). 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 =  1.62 ) than CLDKT (aHR =  2.29 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.
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http://dx.doi.org/10.1111/ajt.16471DOI Listing
December 2020

Chronic Histologic Changes Are Present Regardless of HLA Mismatches: Evidence from HLA Identical Living Donor Kidney Transplants.

Transplantation 2020 Dec 10. Epub 2020 Dec 10.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, The William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN Department of Transplant Surgery, Mayo Clinic, Rochester, MN, Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, Division of Transfusion Medicine, Mayo Clinic, Rochester, MN, Department of Immunology, Mayo Clinic, Rochester, MN.

Background: At 5 and 10 years after kidney transplantation, chronic histologic changes such as arteriolar hyalinosis and mesangial expansion are common, however, determining etiology is difficult. We compared surveillance biopsies in living donor kidney transplants (LDKTx) from HLA matched siblings (termed HLA-identical (HLA-ID)) to HLA non-ID to investigate which histologic changes were likely due to alloimmune injury and which were due to non-alloimmune injury.

Methods: We performed a retrospective, cohort study comparing HLA-ID sibling LDKTx (n=175) to HLA non-ID LDKTx (n=175; matched for age, sex and year of transplant +/- 2 years) performed at a single institution from 03/1999 to 11/2018.

Results: Baseline characteristics and maintenance immunosuppression were similar. Mortality rates were similar, but in the HLA-ID group, 10-year death-censored graft survival was higher (93.8% vs 80.9% HLA non-ID LDKTx, p<0.001), rejection rates were lower (after 1 year 9.6% vs 27.1%; p<0.001) and Banff inflammation scores including glomerulitis and peritubular capillaritis were lower on surveillance biopsies at 1, 5 and 10 years. In contrast, chronic Banff scores (interstitial fibrosis, arteriolar hyalinosis, mesangial expansion, etc.) were similar in prevalence and severity on surveillance biopsies at 1, 5 and 10 years.

Conclusions: HLA-ID LDKTx have less inflammation and less transplant glomerulopathy, but most chronic histologic changes were similar to less-well matched LDKTx. We conclude that these types of chronic changes are not associated with HLA mismatches and may be due to non-immunologic causes (hypertension, obesity, etc.) suggesting that new management approaches to prevent these lesions may be needed.
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http://dx.doi.org/10.1097/TP.0000000000003579DOI Listing
December 2020

Kidney Microstructural Features at the Time of Donation Predict Long-term Risk of Chronic Kidney Disease in Living Kidney Donors.

Mayo Clin Proc 2021 01 20;96(1):40-51. Epub 2020 Oct 20.

Divisions of Nephrology & Hypertension, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To determine whether microstructural features on a kidney biopsy specimen obtained during kidney transplant surgery predict long-term risk of chronic kidney disease in the donor.

Patients And Methods: We studied kidney donors from May 1, 1999, through December 31, 2018, with a follow-up survey for the results of recent blood pressure and kidney function tests (estimated glomerular filtration rate [eGFR] and proteinuria). If not recently available, blood pressure and eGFRs were requested from a local clinic. Microstructural features on kidney biopsy at the time of donation were assessed as predictors of hypertension and kidney function after adjusting for years of follow-up, baseline age, sex, and clinical predictors.

Results: There were 807 donors surveyed a mean 10.5 years after donation. An eGFR less than 45 mL/min/1.73 m in 6.4% (43/673) of donors was predicted by larger glomerular volume per standard deviation (odds ratio [OR], 1.48; 95% CI, 1.08 to 2.04) and nephron number below the age-specific 5th percentile (OR, 3.38; 95% CI, 1.31 to 8.72). An eGFR less than 60 mL/min/1.73 m in 42.5% (286/673) of donors was not predicted by any microstructural feature. Residual eGFR (postdonation/predonation eGFR) was predicted by nephron number below the age-specific 5th percentile (difference, -6.07%; 95% CI, -10.24% to -1.89%). Self-reported proteinuria in 5.1% (40/786) of donors was predicted by larger glomerular volume (OR, 1.42; 95% CI, 1.08 to 1.86). Incident hypertension in 18.8% (119/633) of donors was not predicted by any microstructural features.

Conclusion: Low nephron number for age and larger glomeruli are important microstructural predictors for long-term risk of chronic kidney disease after living kidney donation.
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http://dx.doi.org/10.1016/j.mayocp.2020.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796899PMC
January 2021

Long-term Outcomes of Sequential Hematopoietic Stem Cell Transplantation and Kidney Transplantation: Single-center Experience.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States.

Background: Experience with sequential hematopoietic stem cell transplant (HSCT) and kidney transplant (KT) is limited.

Methods: We conducted a retrospective observational study of adult patients who underwent both HSCT and KT at our center, with a median follow-up of 11 years.

Results: In our 54 patients cohort (94% autologous HSCT), 36 (67%) patients received HSCT first followed by KT, while 18 (33%) received KT prior to HSCT. In both groups, AL amyloidosis represented 50% of hematologic diagnosis. Only 4 patients expired due to hematologic disease relapse (2 patients in each group) and only 3 allografts were lost due to hematologic disease recurrence (HSCT first n=1 and KT first n=2). Overall 1-year, 5 years and 10 years death-censored graft survival rates were 94%, 94%, and 94%, respectively for HSCT first group and 89%, 89%, and 75%, respectively for KT first group. Overall 1-year, 5 years and 10 years patients survival rates were 100%, 97% and 90%, respectively for HSCT first group and 100%, 76% and 63%, respectively for KT first group.

Conclusions: Our study supports safety of sequential KT and HSCT, with improved overall patient survival compared to recipients of HSCT remaining on dialysis and good long-term kidney allograft outcome.
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http://dx.doi.org/10.1097/TP.0000000000003477DOI Listing
October 2020

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation.

Kidney Int 2021 01 8;99(1):186-197. Epub 2020 Aug 8.

Université de Paris, INSERM, PARCC, Paris Translational Research Centre for Organ Transplantation, Paris, France; Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address:

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.
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http://dx.doi.org/10.1016/j.kint.2020.07.025DOI Listing
January 2021

Global Glomerulosclerosis in Kidney Biopsies With Differing Amounts of Cortex: A Clinical-Pathologic Correlation Study.

Kidney Med 2019 Jul-Aug;1(4):153-161. Epub 2019 Jul 12.

Divisions of Nephrology and Hypertension (RSN, AD) and Biomedical Statistics and Informatics (CLL, WKK), and Departments of Laboratory Medicine and Pathology (SS) and Surgery (MDS), Mayo Clinic, Rochester, MN; Department of Nephrology, Cleveland Clinic, Cleveland, OH (JJA); and Division of Epidemiology, Mayo Clinic, Rochester, MN (ADR).

Rationale & Objective: The number of glomeruli is often used to determine the adequacy of a kidney biopsy (eg, at least 10 glomeruli). It is often assumed that biopsy specimens with limited amounts of cortex are too imprecise for detection of focal pathology.

Study Design: Clinical-pathologic correlation (cross-sectional).

Setting & Participants: Living kidney donors who underwent a needle core biopsy of their kidney at the time of donation.

Exposure: The amount of cortex biopsied as determined by either the number of glomeruli or area of cortex on histology.

Outcome: The percentage of globally sclerotic glomeruli, density of interstitial fibrosis foci, and severity of arteriosclerosis were determined.

Analytical Approach: A beta-binomial model assessed how the mean percentage of globally sclerotic glomeruli and patient variability in percentage of globally sclerotic glomeruli differed with the number of glomeruli on the biopsy specimen. Additional models assessed the association of interstitial fibrosis and arteriosclerosis with number of glomeruli.

Results: There were 2,915 kidney donors studied. Fewer glomeruli on the biopsy specimen associated with higher mean percentage of globally sclerotic glomeruli and higher patient variability in percentage of globally sclerotic glomeruli. Smaller cortical volume on imaging correlated with both less cortex on biopsy and higher percentage of globally sclerotic glomeruli. Based on a statistical simulation, the probability of patient percentage of globally sclerotic glomeruli ≥ 10% if the biopsy percentage of globally sclerotic glomeruli is ≥10% (positive predictive value) was 45% with 1 to 9 glomeruli versus 31% with 10 or more glomeruli; the negative predictive value was 91% versus 98%. Fewer glomeruli also associated with more interstitial fibrosis and arteriosclerosis.

Limitations: The study was limited to living kidney donors. Patient variability in percentage of globally sclerotic glomeruli was based on a statistical model because multiple biopsy specimens per patient were not available.

Conclusions: The amount of cortex on a needle core biopsy is not completely random. Chronic changes from loss of cortex contribute to low amounts of cortex on a kidney biopsy specimen.
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http://dx.doi.org/10.1016/j.xkme.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380371PMC
July 2019

A study from The Mayo Clinic evaluated long-term outcomes of kidney transplantation in patients with immunoglobulin light chain amyloidosis.

Kidney Int 2021 03 23;99(3):707-715. Epub 2020 Jul 23.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Longer survival using modern therapies has increased the number of patients with immunoglobulin light-chain amyloidosis receiving kidney transplantation. We evaluated 60 patients with immunoglobulin light chain amyloidosis who underwent kidney transplantation based on their hematologic response for outcomes of death, graft failure, and complications. Patient hematologic responses (light-chain in blood or urine) prior to kidney transplantation were three patients had no response, five had a partial response, six had a very good partial response, 37 had a complete response, and nine were treatment-naive patients (never treated for this disorder). After transplantation, seven of nine treatment-naive patients achieved a complete response. The median follow-up for the entire transplant cohort was 61 months. The estimated median overall survival from the time of kidney transplantation was 123 months for the entire group. Median overall survival was not reached for the very good partial response plus complete response groups, it was 47 months for no response plus partial response groups, and 117 months for the treatment-naive group (all significantly different). Median overall survival of very good partial response was 81 months, while the median was not reached in the complete response group (no significant difference). The time to amyloid recurrence was significantly longer in complete response compared to very good partial response (median 181 vs 81 months). Death-censored graft survival at one- and five-years was 98.3%, and 95.8%, respectively for all groups. Of the 60 patients, three had allograft failure, 19 died with a functioning graft, and 13 had an amyloid recurrence. Thus, outcomes after kidney transplant in patients with immunoglobulin light-chain amyloidosis seem acceptable if a very good partial response or complete response is achieved either before or after transplantation.
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http://dx.doi.org/10.1016/j.kint.2020.06.036DOI Listing
March 2021

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

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

Transplantation 2021 02;105(2):436-442

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.

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.
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http://dx.doi.org/10.1097/TP.0000000000003254DOI Listing
February 2021

The Use of GLP1R Agonists for the Treatment of Type 2 Diabetes in Kidney Transplant Recipients.

Transplant Direct 2020 Feb 13;6(2):e524. Epub 2020 Jan 13.

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic Rochester, MN.

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been shown to improve glucose control and diabetes-related comorbidities in patients without solid organ transplants. The effectiveness, safety, and tolerability of GLP1RA after kidney transplantation have not been adequately studied.

Methods: We retrospectively reviewed data on kidney transplant recipients performed in our institution, who were initiated on GLP1RA either for the treatment of type 2 diabetes diagnosed before transplantation or posttransplant diabetes. We analyzed efficacy, safety, and the effect on kidney allograft function.

Results: Seventeen kidney transplant recipients were initiated on GLP1RA therapy, 14 of which remained on the medication for at least 12 months. The use of GLP1RA had no significant impact on weight loss, but was associated with a significant reduction in the total daily insulin dose, from the median of 63 [interquartile range 43-113] IU to 44 [interquartile range 25-88] and reduction in the risk of hypoglycemia in patients who were on therapy for at least approximately 12 months. Kidney function remained stable and none of the recipients experienced acute rejection. Tacrolimus dose was not significantly changed. Five patients (29%) discontinued GLP1RA therapy-4 due to side effects and 1 due to uncontrolled hyperglycemia.

Conclusions: GLP1RA may be a relatively safe and effective treatment for kidney transplant recipients with type 2 diabetes that allows for a reduction in insulin requirements. More studies are needed to determine whether the use of these agents will translate into an improvement in allograft and patient survival.
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http://dx.doi.org/10.1097/TXD.0000000000000971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004635PMC
February 2020

Kidney Structural Features from Living Donors Predict Graft Failure in the Recipient.

J Am Soc Nephrol 2020 02 23;31(2):415-423. Epub 2020 Jan 23.

Division of Nephrology and Hypertension,

Background: Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear.

Methods: Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient.

Results: The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure.

Conclusions: Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft's "intrinsic quality" at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.
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http://dx.doi.org/10.1681/ASN.2019090964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003295PMC
February 2020

Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties.

Liver Transpl 2020 04 4;26(4):549-563. Epub 2020 Mar 4.

William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN.

The liver is an immunologically active organ with a tolerogenic microenvironment at a quiescent state. The immunoregulatory properties of the liver appear to be retained after transplantation because liver allografts can reduce alloresponses against other organs that are simultaneously transplanted. Mechanisms of this phenomenon remain unknown. Given the known immunomodulatory properties of mesenchymal stromal cells (MSCs), we hypothesized that liver mesenchymal stromal cells (L-MSCs) are superior immunomodulators and contribute to liver-mediated tolerance. L-MSCs, generated from human liver allograft biopsies, were compared with adipose mesenchymal stromal cells (A-MSCs) and bone marrow mesenchymal stromal cells (BM-MSCs). Trilineage differentiation of L-MSCs was confirmed by immunohistochemistry. Comparative phenotypic analyses were done by flow cytometry and transcriptome analyses by RNA sequencing in unaltered cell cultures. The in vitro functional analyses were performed using alloreactive T cell proliferation assays. The transcriptome analysis showed that the L-MSCs are different than the A-MSCs and BM-MSCs, with significant enrichment of genes and gene sets associated with immunoregulation. Compared with the others, L-MSCs were found to express higher cell surface levels of several select immunomodulatory molecules. L-MSCs (versus A-MSCs/BM-MSCs) inhibited alloreactive T cell proliferation (22.7% versus 56.4%/58.7%, respectively; P < 0.05) and reduced the frequency of interferon ɤ-producing T cells better than other MSCs (52.8% versus 94.4%/155.4%; P < 0.05). The antiproliferative impact of L-MSCs was not dependent on cell-to-cell contact, could be reversed incompletely by blocking programmed death ligand 1, and required a higher concentration of the competitive inhibitor of indoleamine 2,3-dioxygenase for complete reversal. In conclusion, L-MSCs appear to be uniquely well-equipped immunomodulatory cells, and they are more potent than A-MSCs and BM-MSCs in that capacity, which suggests that they may contribute to liver-induced systemic tolerance.
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http://dx.doi.org/10.1002/lt.25718DOI Listing
April 2020

The need for novel trial designs, master protocols, and research consortia in transplantation.

Clin Transplant 2020 01 31;34(1):e13759. Epub 2019 Dec 31.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.

Large multicenter, randomized controlled trials are the paradigm for determining the efficacy and safety of new therapies. However, applying this classical approach to many areas of transplantation is difficult. For most types of organ transplants, the number of transplants performed is too small for such a trial (lung, pancreas, or vascular composite transplantation are examples). In larger populations such as kidney transplantation, the major unmet needs commonly involve small subsets of patients (antibody-mediated rejection, recurrent renal disease, etc). This issue is not unique to transplantation and has been successfully overcome in other areas of medicine. In oncology, for example, novel trial designs such as adaptive trial design and master protocols are now relatively common. In addition, the existence of multicenter, ongoing clinical research consortia have greatly enhanced the successful implementation of these novel trial designs. In this manuscript, we examine how novel trial designs, master protocols, and research consortia might enhance studies in transplantation aimed at the regulatory approval of new agents. Our premise is that more efficient approaches to clinical trials already exist and, through a coordinated effort by researchers, the pharmaceutical industry, and regulatory bodies like the FDA, they can be implemented in transplantation.
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http://dx.doi.org/10.1111/ctr.13759DOI Listing
January 2020

Clinical outcomes after ABO-incompatible renal transplantation.

Lancet 2019 11;394(10213):1988-1989

New York University Langone Transplant Institute, New York, NY, USA.

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http://dx.doi.org/10.1016/S0140-6736(19)32490-0DOI Listing
November 2019

Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: Is there still a role for desensitization?

Clin Transplant 2019 12 26;33(12):e13751. Epub 2019 Nov 26.

The William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.

Kidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting-list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait-listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.
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http://dx.doi.org/10.1111/ctr.13751DOI Listing
December 2019

Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study.

BMJ 2019 09 17;366:l4923. Epub 2019 Sep 17.

Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, Paris, France.

Objective: To develop and validate an integrative system to predict long term kidney allograft failure.

Design: International cohort study.

Setting: Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States.

Participants: Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).

Main Outcome Measure: Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.

Results: Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.

Conclusion: An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.

Trial Registration: Clinicaltrials.gov NCT03474003.
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http://dx.doi.org/10.1136/bmj.l4923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746192PMC
September 2019

Ten Years of Kidney Paired Donation at Mayo Clinic: The Benefits of Incorporating ABO/HLA Compatible Pairs.

Transplantation 2020 06;104(6):1229-1238

Mayo Clinic William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.

Background: We examined the 10-year experience of Mayo Clinic's kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time.

Methods: We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from September 2007 to June 2018.

Results: The median (interquartile range) time from KPD entry to transplantation was 89 days (42-187 days). The factors independently associated with receiving a transplant >3 months after KPD entry included recipient blood type O and calculated panel reactive antibodies ≥98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: cytomegalovirus mismatch (18.5% [10/54]), Epstein-Barr virus (EBV) mismatch (EBV) (9.3% [5/54]), age/size mismatch (51.9% [28/54]), or altruistic reasons (20.3% [11/54]). Cytomegalovirus and EBV mismatch were avoided in 90% (9/10) and 100% (5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index scores than their actual donor (median [interquartile range] 31.5 [12.3-47]; P < 0.001 and 26 (-1 to 46); P = 0.01 points lower, respectively). Median time to transplant from KPD entry for compatible pair recipients was 70 days (41-163 days), and 44.4% (24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs.

Conclusions: KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs.
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http://dx.doi.org/10.1097/TP.0000000000002947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359217PMC
June 2020

Deep Learning-Based Histopathologic Assessment of Kidney Tissue.

J Am Soc Nephrol 2019 10 5;30(10):1968-1979. Epub 2019 Sep 5.

Departments of Pathology and

Background: The development of deep neural networks is facilitating more advanced digital analysis of histopathologic images. We trained a convolutional neural network for multiclass segmentation of digitized kidney tissue sections stained with periodic acid-Schiff (PAS).

Methods: We trained the network using multiclass annotations from 40 whole-slide images of stained kidney transplant biopsies and applied it to four independent data sets. We assessed multiclass segmentation performance by calculating Dice coefficients for ten tissue classes on ten transplant biopsies from the Radboud University Medical Center in Nijmegen, The Netherlands, and on ten transplant biopsies from an external center for validation. We also fully segmented 15 nephrectomy samples and calculated the network's glomerular detection rates and compared network-based measures with visually scored histologic components (Banff classification) in 82 kidney transplant biopsies.

Results: The weighted mean Dice coefficients of all classes were 0.80 and 0.84 in ten kidney transplant biopsies from the Radboud center and the external center, respectively. The best segmented class was "glomeruli" in both data sets (Dice coefficients, 0.95 and 0.94, respectively), followed by "tubuli combined" and "interstitium." The network detected 92.7% of all glomeruli in nephrectomy samples, with 10.4% false positives. In whole transplant biopsies, the mean intraclass correlation coefficient for glomerular counting performed by pathologists versus the network was 0.94. We found significant correlations between visually scored histologic components and network-based measures.

Conclusions: This study presents the first convolutional neural network for multiclass segmentation of PAS-stained nephrectomy samples and transplant biopsies. Our network may have utility for quantitative studies involving kidney histopathology across centers and provide opportunities for deep learning applications in routine diagnostics.
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http://dx.doi.org/10.1681/ASN.2019020144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779356PMC
October 2019

Preoperative Factors Predicting Admission to the Intensive Care Unit After Kidney Transplantation.

Mayo Clin Proc Innov Qual Outcomes 2019 Sep 23;3(3):285-293. Epub 2019 Aug 23.

William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.

Objective: To identify preoperative factors predicting early admission (within 30 days) of adult kidney transplant recipients to the intensive care unit (ICU).

Patients And Methods: This is a single-center retrospective study of consecutive kidney transplant recipients between January 1, 2007, and December 31, 2016. Children (aged <18 years) and patients who underwent simultaneous multiorgan transplantation were excluded from the analysis. Associations between demographic, transplant-related, and comorbidity variables with ICU admission within 30 days of transplantation were analyzed using univariate and multivariate logistic regression models.

Results: Of the 1527 eligible patients, 305 (20%) required early ICU admission. In univariate analysis, older age, higher body mass index (BMI), previous transplantation, myocardial infarction, congestive heart failure, obstructive pulmonary disease, longer ischemia time, pretransplant dialysis, and transplantation from a deceased donor were associated with increased odds of ICU admission. After multivariate adjustment, every 10-year increase in recipient age (odds ratio [OR], 1.26; 95% CI, 1.12-1.42; <.001), 5-unit increase in BMI (OR, 1.11; 95% CI, 1.00-1.22; =.049), pretransplant dialysis (OR, 1.57; 95% CI, 1.19-2.08; =.002), and deceased donor transplantation (OR, 1.82; 95% CI, 1.29-2.55; <.001) were associated with the increased risk of ICU admission. Preemptive transplantation (OR, 0.64; 95% CI, 0.48-0.84; =.002) and living donor kidney transplantation (OR, 0.55; 95% CI, 0.39-0.77; <.001) were associated with lower odds of ICU admission after transplantation.

Conclusion: Recipient age, BMI, and the need for pretransplant dialysis are associated with a higher risk of early ICU admission after kidney transplantation, whereas living donor kidney transplantation and preemptive transplantation decrease these odds. Early referral of patients with end-stage renal disease for preemptive transplantation and living donor kidney transplantation can significantly reduce transplant-related ICU admissions.
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http://dx.doi.org/10.1016/j.mayocpiqo.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713836PMC
September 2019

Using computer-assisted morphometrics of 5-year biopsies to identify biomarkers of late renal allograft loss.

Am J Transplant 2019 10 6;19(10):2846-2854. Epub 2019 May 6.

Department of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota.

The current Banff scoring system was not developed to predict graft loss and may not be ideal for use in clinical trials aimed at improving allograft survival. We hypothesized that scoring histologic features of digitized renal allograft biopsies using a continuous, more objective, computer-assisted morphometric (CAM) system might be more predictive of graft loss. We performed a nested case-control study in kidney transplant recipients with a surveillance biopsy obtained 5 years after transplantation. Patients that developed death-censored graft loss (n = 67) were 2:1 matched on age, gender, and follow-up time to controls with surviving grafts (n = 134). The risk of graft loss was compared between CAM-based models vs a model based on Banff scores. Both Banff and CAM identified chronic lesions associated with graft loss (chronic glomerulopathy, arteriolar hyalinosis, and mesangial expansion). However, the CAM-based models predicted graft loss better than the Banff-based model, both overall (c-statistic 0.754 vs 0.705, P < .001), and in biopsies without chronic glomerulopathy (c-statistic 0.738 vs 0.661, P < .001) where it identified more features predictive of graft loss (% luminal stenosis and % mesangial expansion). Using 5-year renal allograft surveillance biopsies, CAM-based models predict graft loss better than Banff models and might be developed into biomarkers for future clinical trials.
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http://dx.doi.org/10.1111/ajt.15380DOI Listing
October 2019

Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial.

Am J Transplant 2019 10 19;19(10):2876-2888. Epub 2019 Apr 19.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.

We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28).
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http://dx.doi.org/10.1111/ajt.15364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790671PMC
October 2019

The Relationship Between Frailty and Decreased Physical Performance With Death on the Kidney Transplant Waiting List.

Prog Transplant 2019 06 17;29(2):108-114. Epub 2019 Mar 17.

2 Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA.

Introduction: Frailty and decreased physical performance are associated with poor outcomes after kidney transplant. Less is known about their relationship with pretransplant outcomes. The aim of this study was to characterize associations between frailty and physical performance with death on the kidney transplant waiting list.

Design: Since December 2014, high-risk kidney transplant candidates at our center (age > 59, diabetic and/or history of >3 years dialysis) have undergone frailty and physical performance testing using Fried Criteria and the Short Physical Performance Battery.

Results: Between December 2014 and November 2016, 272 high-risk candidates underwent testing and were approved for transplant. Both frailty and physical performance score were significantly associated with death on the waiting list (hazard ratio [HR]: 6.7, confidence interval [CI]: 1.5-30.1; P = .01; HR: 0.8 per 1-point increase, CI: 0.7-1.0; P = .02, respectively). The relationship between frailty, physical performance score, and death on the waiting list appeared to be independent of age, diabetes, or duration of dialysis.

Discussion: Frailty and decreased physical performance appear to be independently associated with increased mortality on the kidney transplant waiting list. Further studies are needed to determine whether improving frailty and physical performance prior to transplant can decrease waiting list mortality.
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http://dx.doi.org/10.1177/1526924819835803DOI Listing
June 2019

Use of Eculizumab for Active Antibody-mediated Rejection That Occurs Early Post-kidney Transplantation: A Consecutive Series of 15 Cases.

Transplantation 2019 11;103(11):2397-2404

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

Background: Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month posttransplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of eculizumab as primary therapy for active AMR early posttransplant.

Methods: We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014, and January 31, 2018, and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis.

Results: Fifteen patients had early active AMR at a median (interquartile range [IQR]) of 10 (7-11) days posttransplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven, and 2 cases were presumed on the basis of donor-specific antibody trends and allograft function. Within 1 week of treatment, the median estimated glomerular filtration rate increased from 21 to 34 mL/min (P = 0.001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4-6 months. No graft losses occurred, and at last follow-up (median [IQR] of 13 [12-19] mo), the median IQR estimated glomerular filtration rate increased to 52 (46-60) mL/min.

Conclusions: Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.
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http://dx.doi.org/10.1097/TP.0000000000002639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699919PMC
November 2019

Modeling graft loss in patients with donor-specific antibody at baseline using the Birmingham-Mayo (BirMay) predictor: Implications for clinical trials.

Am J Transplant 2019 08 13;19(8):2274-2283. Epub 2019 Mar 13.

William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota.

Predicting which renal allografts will fail and the likely cause of failure is important in clinical trial design to either enrich patient populations to be or as surrogate efficacy endpoints for trials aimed at improving long-term graft survival. This study tests our previous Birmingham-Mayo model (termed the BirMay Predictor) developed in a low-risk kidney transplant population in order to predict the outcome of patients with donor specific alloantibody (DSA) at the time of transplantation and identify new factors to improve graft loss prediction in DSA+ patients. We wanted define ways to enrich the population for future therapeutic intervention trials. The discovery set included 147 patients from Mayo Cohort and the validation set included 111 patients from the Paris Cohort-all of whom had DSA at the time of transplantation. The BirMay predictor performed well predicting 5-year outcome well in DSA+ patients (Mayo C statistic = 0.784 and Paris C statistic = 0.860). Developing a new model did not improve on this performance. A high negative predictive value of greater than 90% in both cohorts excluded allografts not destined to fail within 5 years. We conclude that graft-survival models including histology predict graft loss well, both in DSA+ cohorts as well as DSA- patients.
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http://dx.doi.org/10.1111/ajt.15312DOI Listing
August 2019

Patient experience after kidney transplant: a conceptual framework of treatment burden.

J Patient Rep Outcomes 2019 Jan 30;3(1). Epub 2019 Jan 30.

Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, USA.

Background: Kidney transplant recipients face a lifelong regimen of medications, health monitoring and medical appointments. This work involved in managing one's health and its impact on well-being are referred to as treatment burden. Excessive treatment burden can adversely impact adherence and quality of life. The aim of this study was to develop a conceptual framework of treatment burden after kidney transplantation. Qualitative interviews were conducted with kidney transplant recipients (n = 27) from three Mayo Clinic transplant centers. A semi-structured interview guide originally developed in patients with chronic conditions and tailored to the context of kidney transplantation was utilized. Themes of treatment burden after kidney transplantation were confirmed in two focus groups (n = 16).

Results: Analyses confirmed three main themes of treatment burden after kidney transplantation: 1) work patients must do to care for their health (e.g., attending medical appointments, taking medications), 2) challenges/stressors that exacerbate felt burden (e.g., financial concerns, health system obstacles) 3) impacts of burden (e.g., role/social activity limitations).

Conclusions: Patients describe a significant amount of work involved in caring for their kidney transplants. This work is exacerbated by individual, interpersonal and system-related factors. The framework will be used as a foundation for a patient-reported measure of treatment burden to promote better care after kidney transplantation.
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http://dx.doi.org/10.1186/s41687-019-0095-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353980PMC
January 2019

Larger nephron size, low nephron number, and nephrosclerosis on biopsy as predictors of kidney function after donating a kidney.

Am J Transplant 2019 07 1;19(7):1989-1998. Epub 2019 Feb 1.

Division of Nephrology & Hypertension, Mayo Clinic, Rochester, Minnesota.

It is unclear whether structural findings in the kidneys of living kidney donors predict postdonation kidney function. We studied living kidney donors who had a kidney biopsy during donation. Nephron size was measured by glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area. Age-specific thresholds were defined for low nephron number (calculated from CT and biopsy measures) and nephrosclerosis (global glomerulosclerosis, interstitial fibrosis/tubular atrophy, and arteriosclerosis). These structural measures were assessed as predictors of postdonation measured GFR, 24-hour urine albumin, and hypertension. Analyses were adjusted for baseline age, gender, body mass index, systolic and diastolic blood pressure, hypertension, measured GFR, urine albumin, living related donor status, and time since donation. Of 2673 donors, 1334 returned for a follow-up visit at a median 4.4 months after donation, with measured GFR <60 mL/min/1.73 m in 34%, urine albumin >5 mg/24 h in 13%, and hypertension in 5.3%. Larger glomerular volume and interstitial fibrosis/tubular atrophy predicted follow-up measured GFR <60 mL/min/1.73 m . Larger cortex volume per glomerulus and low nephron number predicted follow-up urine albumin >5 mg/24 h. Arteriosclerosis predicted hypertension. Microstructural findings predict GFR <60 mL/min/1.73 m , modest increases in urine albumin, and hypertension shortly after kidney donation.
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http://dx.doi.org/10.1111/ajt.15259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591036PMC
July 2019

Factors at de novo donor-specific antibody initial detection associated with allograft loss: a multicenter study.

Transpl Int 2019 May 8;32(5):502-515. Epub 2019 Feb 8.

William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA.

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor-specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death-censored allograft loss were assessed by Cox proportional modeling. Death-censored allograft survival was 77.0% (87/113) during a median follow-up of 2.2 (IQR 1.2-3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6-15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1-13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post-transplant (years) until donor-specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody-mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.
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http://dx.doi.org/10.1111/tri.13395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483899PMC
May 2019

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

Am J Transplant 2019 03 23;19(3):625-632. Epub 2019 Jan 23.

Critical Path Institute, Tucson, Arizona.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.
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http://dx.doi.org/10.1111/ajt.15214DOI Listing
March 2019

Long-term Immunosuppression Adherence After Kidney Transplant and Relationship to Allograft Histology.

Transplant Direct 2018 Oct 7;4(10):e392. Epub 2018 Sep 7.

William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.

Background: Nonadherence to immunosuppression after kidney transplant is an important contributor to graft failure. Little is known about how nonadherence changes 3 years posttransplant when Medicare coverage of immunosuppression ends and how that nonadherence impacts allograft histology. The goal of this study was to compare rates of nonadherence during posttransplant years 1 to 3 to years 3 to 5 and examine the relationship between nonadherence during years 3 to 5 and 5-year allograft histology.

Methods: We retrospectively analyzed 552 conventional kidney allografts in patients transplanted at our center between January 1, 1999, and June 1, 2010, who used the Mayo Clinic Specialty Pharmacy for the first 5 years posttransplant. Nonadherence was defined as less than 80% proportion of days covered. Overall adherence to immunosuppression appeared to be higher during years 3 and 5 compared to between years 1 and 3 (89.4% vs 82.9%, respectively; < 0.0001 [paired test]).

Results: Overall nonadherence during posttransplant years 3 to 5 appeared to be associated with fibrosis and inflammation on 5-year allograft biopsy but not with transplant glomerulopathy (16.9% vs 5.9%, = 0.004; 10.4% vs 8.5%, = 0.61, respectively). After adjusting for nonadherence to calcineurin inhibitor and prednisone therapy, only nonadherence to antimetabolite therapy remained significantly associated with 5-year fibrosis and inflammation (odds ratio, 10.6; 95% confidence interval, 1.5-76.1; = 0.02).

Conclusions: Efforts to improve long-term adherence, possibly through the use of specialty pharmacies and increased adherence to antimetabolite therapy, may improve long-term allograft histology and survival, although further studies are needed to confirm these findings.
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http://dx.doi.org/10.1097/TXD.0000000000000824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233670PMC
October 2018

Long-term outcomes of eculizumab-treated positive crossmatch recipients: Allograft survival, histologic findings, and natural history of the donor-specific antibodies.

Am J Transplant 2019 06 15;19(6):1671-1683. Epub 2018 Dec 15.

William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.

We aimed to determine the long-term outcomes of eculizumab-treated, positive crossmatch (+XM) kidney transplant recipients compared with +XM and age-matched negative crossmatch (-XM) controls. We performed an observational retrospective study and examined allograft survival, histologic findings, long-term B-cell flow cytometric XM (BFXM), and allograft-loss-associated factors. The mean (SD) posttransplant follow-up was 6.3 (2.5) years in the eculizumab group; 7.6 (3.5), +XM control group; 7.9 (2.5), -XM control group. The overall and death-censored allograft survival rates were similar in +XM groups (P = .73, P = .48) but reduced compared with -XM control patients (P < .001, P < .001). In the eculizumab-treated group, 57.9% (11/19) of the allografts had chronic antibody-mediated rejection, but death-censored allograft survival was 76.6%, 5 years; 75.4%, 7 years. Baseline IgG3 positivity and BFXM ≥300 were associated with allograft loss. C1q positivity was also associated with allograft loss but did not reach statistical significance. Donor-specific antibodies appeared to decrease in eculizumab-treated patients. After excluding patients with posttransplant plasmapheresis, 42.3% (9/21) had negative BFXMs; 31.8% (7/22), completely negative single-antigen beads 1 year posttransplant. Eculizumab-treated +XM patients had reduced allograft survival compared with -XM controls but similar survival to +XM controls. BFXM and complement-activating donor-specific antibodies (by IgG3 and C1q testing) may be used for risk stratification in +XM transplantation.
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http://dx.doi.org/10.1111/ajt.15175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509017PMC
June 2019