Publications by authors named "Carrie A Schinstock"

27 Publications

  • Page 1 of 1

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 Mar;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 2021

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

Imlifidase Shows Promise for the Most Disadvantaged Sensitized Transplant Candidates.

Transplantation 2020 Oct 21. Epub 2020 Oct 21.

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

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http://dx.doi.org/10.1097/TP.0000000000003497DOI Listing
October 2020

Measuring human leukocyte antigen alloantibodies: beyond a binary decision.

Curr Opin Organ Transplant 2020 Dec;25(6):529-535

Comprehensive Transplant Center, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Purpose Of Review: Accurate measurement of human leukocyte antigen antibodies is critical for making clinical decisions treating patients awaiting transplantation or monitoring them post transplantation. Single antigen bead assay results are given as Mean Fluorescence Intensity, falling short of providing the required quantitative measure.

Recent Findings: Titration studies were shown to circumvent the limitation of target-saturation that affect interpretation of single antigen bead assays especially in highly sensitized patients with strong antibodies. In fact, titration information can serve to measure efficacy of antibody removal during pretransplant desensitization using plasmapheresis/intravenous immunoglobulin (PP/IVIg) approaches. Moreover, recent studies indicate that knowing the donor-specific antibody titer has prognostic value that can guide PP/IVIg desensitization treatments. Newer data demonstrates an additional layer of information obtained by titration studies allowing to stratify patients with very high cPRA (>99%) based on the strength of the antibodies present, rather than the breadth. This data can thereby identify patients that are more likely to benefit from desensitization approaches on the transplant wait-list.

Summary: Titration studies have a prognostic value with regards to quantifying antibody strength. Obtaining this information does not require performing the complete set of dilutions. In fact, performing two to three specific dilutions can provide relevant information while maintaining practical cost.
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http://dx.doi.org/10.1097/MOT.0000000000000822DOI Listing
December 2020

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

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.

Transplantation 2020 05;104(5):911-922

Centre for Transplant and Renal Research, Westmead Institute of Medical Research, University of Sydney and Renal Unit, Westmead Hospital, NSW, Australia.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
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http://dx.doi.org/10.1097/TP.0000000000003095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176344PMC
May 2020

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

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

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

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

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

Maintaining the Health of the Renal Allograft: Laboratory and Histologic Monitoring After Kidney Transplantation.

Clin Lab Med 2018 12 5;38(4):607-621. Epub 2018 Oct 5.

Division of Transfusion Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA.

Advances in posttransplant care, including new immunosuppressive medications have led to excellent short-term renal allograft survival. However, there is a small therapeutic window within which the patient and the clinician must balance the risk of rejection, with side effects such as infection, malignancy, and toxicity. Laboratory testing plays a key role in this ongoing monitoring, which includes relatively simple tests, such as serum creatinine, to complex tests, such as solid-phase assays, used to monitor for donor-specific antibody and surveillance allograft biopsies. This article reviews the role of the laboratory tests and surveillance biopsies in posttransplant monitoring.
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http://dx.doi.org/10.1016/j.cll.2018.07.003DOI Listing
December 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

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

Am J Transplant 2019 01 19;19(1):123-131. Epub 2018 Jul 19.

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.
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http://dx.doi.org/10.1111/ajt.14979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309659PMC
January 2019

De novo donor-specific antibody following BK nephropathy: The incidence and association with antibody-mediated rejection.

Clin Transplant 2018 03 11;32(3):e13194. Epub 2018 Feb 11.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Background And Objectives: The risk of de novo donor-specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR > 15 000 copies), BKN, antibody-mediated rejection (AMR), and allograft loss.

Patients And Methods: We performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014. Cox proportional hazards regression with time-dependent covariates were used to assess the relationships among BKN, isolated BKV, dnDSA, and the subsequent risk of AMR and allograft loss.

Results: In multivariate analysis, we observed that BKN, but not BKV was a risk factor for dnDSA (HR, 3.18, P = .008). Of the patients with BK nephropathy, 14.0% (6/43) developed dnDSA, which occurred within 14 months of BK diagnosis. DnDSA in this setting remains a risk factor for subsequent AMR (HR 4.75, P = .0001) and allograft loss (HR 2.63, P = .018).

Conclusions: BKN is an independent risk factor for development of dnDSA. Improved understanding of the characteristics of patients with BKN who are at highest risk for development of dnDSA would be valuable to customize immunosuppression reduction in this population.
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http://dx.doi.org/10.1111/ctr.13194DOI Listing
March 2018

Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates.

Transplantation 2017 10;101(10):2429-2439

1 William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN. 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Background: Avoiding donor-specific antibody (DSA) is difficult for sensitized patients. Improved understanding of the risk of low level DSA is needed.

Methods: We retrospectively compared the outcomes of 954 patients transplanted with varied levels of baseline DSA detected by single antigen beads and B flow cytometric crossmatch (XM). Patients were grouped as follows: -DSA/-XM, +DSA/-XM, +DSA/low +XM, +DSA/high +XM, and -DSA/+XM and followed up for a mean of 4.1 ± 1.9 years (similar among groups, P = 0.49).

Results: Death-censored allograft survival was similar in all groups except the +DSA/high +XM group, which was lower at 79.1% versus 96.2% in the -DSA/-XM group (P < 0.01). The incidence of chronic antibody-mediated rejection (CAMR) based on surveillance biopsy was higher with increasing DSA (8.2% -DSA/-XM, 17.0% +DSA/-XM, 30.6% +DSA/low +XM, and 51.2% +DSA/high +XM, P < 0.01), but similar in groups without baseline DSA (8.1% -DSA/-XM vs 15.4% -DSA/+XM, P = 0.19). Having a calculated panel-reactive antibody (cPRA) of 80% or greater was independently associated with CAMR (hazard ratio, 5.2; P = 0.03) even when DSA was undetected at baseline. By 2 years posttransplant, the incidence of CAMR was 19.4% in patients with cPRA of 80% or greater and undetected DSA and negative XM at baseline.

Conclusions: Kidney transplantation with low-level DSA with or without a low positive XM is a reasonable option for highly sensitized patients and may be advantageous compared with waiting for a negative XM deceased donor. The risk for CAMR is low in patients with no DSA even if the XM is positive. Patients with cPRA of 80% or greater are at risk for CAMR even if no DSA is detected.
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http://dx.doi.org/10.1097/TP.0000000000001619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481511PMC
October 2017

32 Doses of Bortezomib for Desensitization Is Not Well Tolerated and Is Associated With Only Modest Reductions in Anti-HLA Antibody.

Transplantation 2017 06;101(6):1222-1227

1 Division of Transplantation Surgery, Mayo Clinic, Rochester, MN. 2 Division of Transfusion Medicine, Mayo Clinic, Rochester, MN. 3 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. 4 Division of Health Sciences Research, Mayo Clinic, Rochester, MN. 5 Division of Transplantation Surgery and von Liebig Transplant Center, Mayo Clinic, Rochester, MN.

Background: We previously showed that bortezomib (BTZ) partially depletes plasma cells, yet has limited efficacy for desensitization in kidney transplant candidates when up to 16 doses is given.

Methods: This study aimed to determine the safety and efficacy of 32 doses of BTZ (1.3 mg/m of body surface area) in 10 highly sensitized kidney transplant candidates with alloantibodies against their intended living donor.

Results: Dose reduction was needed in 2 patients and 2 others completely discontinued therapy for adverse events. Anti-HLA antibodies mean fluorescence intensity (MFI) values were stable prior to BTZ (P = 0.96) but decreased after therapy (mean decrease of 1916 [SE, 425] MFI, P < 0.01). No patient developed a negative crossmatch against their original intended donor, and the calculated panel-reactive antibodies based on MFI of 2000, 4000, and 8000 was unchanged in all patients.

Conclusions: These data suggest that 32 doses of BTZ monotherapy was not well tolerated and resulted in only a modest reduction in anti-HLA antibodies.
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http://dx.doi.org/10.1097/TP.0000000000001330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935916PMC
June 2017

Early subclinical inflammation correlates with outcomes in positive crossmatch kidney allografts.

Clin Transplant 2016 08 22;30(8):925-33. Epub 2016 Jun 22.

Division of Transplantation Surgery, Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.

The aim of this study was to investigate correlations between early subclinical findings (10- and 90-day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). We compared 34 +XMKTx (19 receiving eculizumab and 15 receiving standard of care without eculizumab) to 13 -XMKTx (between August 2001 and August 2011). At 10 days, light microscopy identified subclinical inflammation in only 18% of +XMKTx, while intragraft gene expression identified inflammation in 79% (gene sets for activated macrophages, dendritic cells, NK cells or T cells). Inflammation persisted at 90 days and was associated with the development of transplant glomerulopathy by 2 years and graft loss. In contrast, endothelial cell (EC) changes present at 90 days by either electron microscopy or gene expression were not associated with transplant glomerulopathy or graft loss in this cohort. Eculizumab treatment did not appear to alter inflammation or EC changes. Therefore, intragraft inflammation might be an appropriate surrogate marker of progression and also a target of therapy to prevent chronic antibody-mediated rejection.
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http://dx.doi.org/10.1111/ctr.12766DOI Listing
August 2016

Interpreting Anti-HLA Antibody Testing Data: A Practical Guide for Physicians.

Transplantation 2016 Aug;100(8):1619-28

1 William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN.2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

The development of sensitive methods for alloantibody detection has been a significant advance in clinical transplantation. However, the complexity of the data from solid phase and crossmatch assays has led to potential confusion about how to use the results for clinical decision making. The goal of this review is to provide a practical guide for transplant physicians for the interpretation of antibody data to supplement consultation with local tissue typing experts. Sources of variability in both the solid phase and crossmatch assay are discussed as are recent data regarding C1q binding antibodies and IgG subclass testing. Although definitive approaches to alloantibody testing are not possible with our current knowledge, we outline a pragmatic approach that we hope will enhance clinical management in this area.
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http://dx.doi.org/10.1097/TP.0000000000001203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961613PMC
August 2016

Discordance Between Iothalamate and Iohexol Urinary Clearances.

Am J Kidney Dis 2016 Jan 9;67(1):49-55. Epub 2015 Oct 9.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN. Electronic address:

Background: Iothalamate and iohexol are contrast agents that have supplanted inulin for the measurement of glomerular filtration rate (GFR) in clinical practice. Previous studies have noted possible differences in renal handling of these 2 agents, but clarity about the differences has been lacking.

Study Design: Study of diagnostic test accuracy.

Setting & Participants: 150 participants with a wide range of GFRs were studied in an outpatient clinical laboratory facility.

Index Tests: Simultaneous urinary clearances of iothalamate, iohexol, and creatinine.

Reference Test: None.

Outcome: Relative differences between the urinary clearances. Iohexol and iothalamate in plasma and urine were assayed concurrently by a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.

Results: Mean iohexol, iothalamate, and creatinine clearances were 52±28 (SD), 60±34, and 74±40 mL/min/1.73 m(2), respectively. The proportional bias of iohexol to iothalamate urinary clearance was 0.85 (95% CI, 0.83-0.88) and was proportional across the GFR range. The mean proportional bias of iohexol clearance compared with creatinine clearance is 1.27 (95% CI, 1.20-1.34), whereas that of iothalamate clearance compared with creatinine clearance is 1.09 (95% CI, 1.03-1.15).

Limitations: Lack of reference standard.

Conclusions: This study reveals a significant and consistent difference between urinary clearances of iothalamate and iohexol. Comparison of studies reporting renal clearance measurements using iohexol versus iothalamate must account for this observed bias.
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http://dx.doi.org/10.1053/j.ajkd.2015.08.020DOI Listing
January 2016

Intravitreal Antivascular Endothelial Growth Factor Therapy May Induce Proteinuria and Antibody Mediated Injury in Renal Allografts.

Transplantation 2015 Nov;99(11):2382-6

1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. 2 Department of Laboratory Medicine and Anatomic Pathology, Mayo Clinic, Rochester, MN. 3 The William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.

Introduction: Systemic adverse effects of intravenous antivascular endothelial growth factor (VEGF) therapy include: hypertension, proteinuria, renal failure, and thrombotic microangiopathy. Intravitreal therapy with these agents is generally believed to be safe.

Methods: We report 2 cases of renal transplant recipients who developed significant allograft dysfunction after the initiation of intravitreal anti-VEGF therapy.

Results: The first case is a 67-year-old man with polycystic kidney disease and recipient of a zero-antigen mismatch kidney allograft which developed worsening proteinuria over the first year after transplantation. At 4 months, a biopsy showed only minimal fibrosis and atrophy. At 1 year, an allograft biopsy showed phospholipase A 2 receptor-negative membranous nephropathy. The second patient was a 52-year-old man with tuberous sclerosis who was a recipient of a living related kidney allograft with diminished but stable graft function 16 years from transplantation. After the initiation of intravitreal anti-VEGF therapy, there was an escalating degree of proteinuria. Renal biopsy revealed acute and chronic antibody-mediated rejection with glomerular thrombi and transplant glomerulopathy.

Conclusions: These cases, although do not prove causality, point to the need for careful follow-up of renal transplant recipients undergoing intravitreal therapy with anti-VEGF agents. These locally administered agents may play a role in the development of proteinuria and modulate antibody-mediated phenomena. We recommend that in renal transplant recipients undergoing therapy with intravitreal anti-VEGF agents, proteinuria be checked monthly, and there should be a low threshold for performing a biopsy to evaluate for allograft injury.
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http://dx.doi.org/10.1097/TP.0000000000000750DOI Listing
November 2015

Thinking beyond new clinical guidelines: update in hypertension.

Mayo Clin Proc 2015 Feb;90(2):273-9

Department of Internal Medicine, Mayo Clinic, Rochester, MN; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Electronic address:

Hypertension is one of the most common conditions managed by generalists and is a major risk factor for multiple conditions. Surrounded by great debate, the committee appointed to the Eighth Joint National Committee published their suggestions for new hypertension treatment guidelines in early 2014. We suggest a new target blood pressure (BP) for the general population older than 60 years of less than 150/90 mm Hg, up from less than 140/90 mm Hg as recommended by the Seventh Joint National Committee, and in diabetic patients, a goal of less than 140/90 mm Hg, up from the Seventh Joint National Committee recommendation of less than 130/80 mm Hg. Regardless of the BP target recommendations suggested by the Eighth Joint National Committee and other organizations, obtaining accurate BP readings and recognizing white-coat and masked hypertension is imperative. Home and ambulatory BP monitoring are useful tools in addition to proper in-office BP readings. The optimal care of the hypertensive patient involves accurate BP characterization, careful use of guidelines, and good clinical judgment.
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http://dx.doi.org/10.1016/j.mayocp.2014.07.016DOI Listing
February 2015

New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy.

Curr Opin Nephrol Hypertens 2014 Nov;23(6):611-8

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

Purpose Of This Review: To discuss new insights regarding chronic antibody-mediated rejection (CAMR) and its progression to transplant glomerulopathy. We will describe the progression to transplant glomerulopathy from a histologic perspective and provide updates on what is known about its pathophysiology, prognosis, and potential therapy.

Recent Findings: Transplant glomerulopathy is a major contributor to long-term renal allograft loss and is most often associated with CAMR. On the basis of protocol biopsies, we have found that 3.5% of conventional transplants and 27.5% of positive crossmatch kidney transplants have transplant glomerulopathy at 1 year. The pathophysiology of the process is largely unknown, but complement activation was previously thought to be essential. However, CAMR appears to develop despite terminal complement blockade and many C4d negative cases of CAMR have been identified. Thus, complement independent mechanisms, such as direct endothelial cell activation and the infiltration of natural killer cells and monocytes, are likely key to the development of transplant glomerulopathy.

Summary: Transplant glomerulopathy is often the result of CAMR and leads to allograft loss. It is characterized by distinctive histologic changes, and its pathophysiology is a multifaceted process involving both innate and adaptive immunity. Despite advances in the understanding of this condition, no effective therapy exists.
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http://dx.doi.org/10.1097/MNH.0000000000000070DOI Listing
November 2014

Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive for early detection of acute kidney injury.

Nephrol Dial Transplant 2013 May 23;28(5):1175-85. Epub 2012 Apr 23.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN, USA.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) protein is a promising biomarker to detect acute kidney injury (AKI). Earlier detection of AKI could facilitate evaluation of novel therapeutic strategies.

Methods: Random and 24-h urine samples were prospectively obtained from 125 normal volunteers for analytic validation of a urinary enzyme-linked immunosorbent assay for NGAL. For clinical validation of the test, urine from 363 emergency department patients admitted to the hospital was obtained for NGAL enzyme-linked immunosorbent assay and urinalysis and AKI was determined by the use of Acute Kidney Injury Network (AKIN) criteria.

Results: NGAL was stable in urine for 7 days when ambient, 4 °C or frozen (-20 or -70 °C). The assay was linear between 0.24 and 10,000 ng/mL with a limit of quantitation of 0.24 ng/mL. Intra- and inter-assay precision were excellent (coefficient of variation <5%); however, urinary white blood cells were associated with increased NGAL levels. The 95th percentile reference value for NGAL in females is ≤ 65.0 and ≤ 23.4 ng/mL in males. Urinary NGAL levels increased with AKI stage but had only fair sensitivity (65%) and specificity (65%) to differentiate no AKI versus Stages 1, 2 or 3 (area under the curve 0.70). Urinalysis with microscopy was very specific (91%) but not very sensitive (22%) with an area under the curve of 0.57.

Conclusions: NGAL can be reliably measured in clinical urine samples, although pyuria is an important potential confounder. In our cohort, increased urinary NGAL was associated with AKI by the AKIN criteria; however, the sensitivity and specificity were only fair, in part because patients with pre-renal causes are not excluded by AKIN criteria. Conversely, findings on microscopic urinalysis are very specific for AKI.
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http://dx.doi.org/10.1093/ndt/gfs127DOI Listing
May 2013

Outcomes of arteriovenous fistula creation after the Fistula First Initiative.

Clin J Am Soc Nephrol 2011 Aug 7;6(8):1996-2002. Epub 2011 Jul 7.

Mayo Clinic, Guggenheim 542, 200 1st Street SW, Rochester, MN 55905, USA.

Background And Objectives: The arteriovenous fistula (AVF) is the preferred hemodialysis access, but AVF-failure rate is high, and complications from AVF placement are rarely reported. There is no clear consensus on predictors of AVF patency. This study determined AVF outcomes and patency predictors at Mayo Clinic Rochester following the Fistula First Initiative.

Design, Setting, Participants, & Measurements: A retrospective cohort study of AVFs placed at Mayo Clinic from January 2006 through December 2008 was performed. The AVF placement-associated primary and secondary failure rates, complications, interventions, and hospitalizations were examined. Kaplan-Meier survival curves and Cox proportional hazard models were used to determine primary and secondary patency and associated predictors.

Results: During this time frame, 317 AVFs were placed in 293 individual patients. The primary failure rate was 37.1% after excluding patients not initiated on hemodialysis during follow-up (n = 38) or those with indeterminate outcome (37 lost to follow-up; six died; two transplanted). Of usable AVFs, 11.4% later failed. AVF creation incurred complications and hospitalization in 21.2% and 12.3% of patients, respectively. The risk for reduced primary patency was increased by diabetes (HR, 1.54; 95% CI, 1.14 to 2.07); the risk for reduced primary and secondary patency was decreased with larger arteries (HR, 0.83; 95% CI, 0.73 to 0.94; and HR, 0.69; 95% CI, 0.56 to 0.84, respectively).

Conclusions: Primary failure remains a major issue in the post-Fistula First era. Complications from AVF placement must be considered when planning AVF placement. Our data demonstrate that artery size is the main predictor of AVF patency.
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http://dx.doi.org/10.2215/CJN.11251210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156429PMC
August 2011