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ABSTRACT: The identification of suitable donor kidneys for transplant candidates with high levels of circulating antibodies against human leukocyte antigen (HLA) is a major challenge and results in prolonged waiting times for transplantation. Technological advances in antibody characterization have permitted a more comprehensive assessment of anti-HLA antibody activity, as well as providing new insights into the clinical effect of HLA antibody class and specificity. Protocols have been developed that enable successful transplantation in patients with donor-specific antibodies (anti-HLA antibodies reactive against their donors). These protocols provide satisfactory early to intermediate-term allograft survival, and constitute an important advance in transplantation. Nevertheless, acute antibody-mediated rejection (AMR) remains a significant challenge, occurring in 20-50% of antibody-incompatible kidney transplantations. Although therapy directed toward lowering donor-specific antibody activity seems to be successful in reversing acute AMR, this condition still has an important negative impact on allograft survival. In addition, subclinical AMR seems to complicate a substantial proportion of positive-crossmatch transplantations even in the absence of allograft dysfunction, and may result in chronic histological abnormalities and shortened allograft function. New interventions for preventing acute AMR, such as anti-C5 antibody-mediated complement blockade and proteasome inhibitor-mediated plasma cell depletion, are promising therapeutic avenues currently under investigation.
Nature Reviews Nephrology 03/2010; 6(5):297-306. · 7.09 Impact Factor
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Transplantation 12/2009; 89(6):648-9. · 4.00 Impact Factor
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ABSTRACT: To outline recent studies describing the mechanisms of antibody-mediated rejection (AMR) and new clinical protocols aimed at prevention and/or treatment of this difficult clinical entity.
The natural history of acute AMR after positive cross-match kidney transplantation involves an acute rise in donor-specific alloantibody (DSA) in the first few weeks after transplantation. Whereas the exact cellular mechanisms responsible for AMR are not known, it seems likely that both pre-existing plasma cells and the conversion of memory B cells to new plasma cells play a role in the increased DSA production. One recent study suggested that combination therapy with plasmapheresis, high-dose IVIG and rituximab was more effective treatment for AMR than high-dose intravenous immunoglobulin (IVIG) alone, but the role of anti-CD20 antibody is still unclear. Two new promising approaches to AMR focus on depletion of plasma cells with the proteasome inhibitor, bortezomib, and the inhibition of terminal complement activation with a humanized, anti-C5 antibody, eculizumab.
The pathogenesis of AMR in several different clinical settings is becoming clearer and more effective treatments are being developed. Whether the prevention or successful treatment of AMR will decrease the prevalence of chronic injury and improved long-term graft survival will require longer-term studies.
Current opinion in organ transplantation 11/2009; 15(1):8-10. · 1.22 Impact Factor
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ABSTRACT: Transplant glomerulopathy (TG) is a histopathologic entity of kidney allografts related to anti-human leukocyte antigen (HLA) antibodies. The goal of this study was to determine the relationships among antibody characteristics (level and specificity), risk for TG, and graft survival.
The presence and characteristics of anti-HLA antibody were assessed by single antigen beads assays in stored pretransplant sera from 598 kidney recipients with negative T-cell crossmatch. Transplant glomerulopathy was diagnosed by surveillance and clinical biopsies.
Thirty-nine percent of patients presented with anti-HLA antibodies pretransplant. Transplant glomerulopathy was diagnosed in 73 patients (12%) during 54+/-19 months of follow-up. The risk of TG increased with higher anti-HLA-II antibody levels (HR=1.890, 95% CI 1.42-2.52; P<0.0001), donor specificity of the antibodies (3.524 [1.67-7.44]; P=0.001), and in patients with history of antibody-mediated rejection (4.985 [2.77-8.97]; P<0.0001, multivariate Cox). Graft survival during the follow-up period was 95% without TG and 62% with TG (P<0.0001). The presence of C4d in peritubular capillaries was an independent risk factor for graft failure after TG diagnosis. Thus, 25% of TG/C4d and 80% of TG/C4d+ grafts failed (P<0.0001). Of interest, higher anti-HLA-II levels were related to the presence of C4d (3.216 [1.376-7.517]; P=0.007).
In T-cell negative crossmatch patients, higher anti-HLA-II antibody levels are related to the increase in the risk of developing TG. Higher antibody levels are also related to the presence of C4d in peritubular capillaries in TG biopsies. Furthermore, the presence of C4d in TG is related to the reduced graft survival.
Transplantation 10/2008; 86(5):681-5. · 4.00 Impact Factor
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Transplantation 10/2006; 82(5):720. · 4.00 Impact Factor
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ABSTRACT: The transplantation of living donor renal allografts across blood group barriers requires protocols to reduce and maintain anti-blood group antibody at safe levels. These protocols lead to an increase in resource utilization and cost of transplantation and may result in increased complications.
In this retrospective study, we compared 40 ABO-incompatible to 77 matching ABO-compatible living donor renal allografts with respect to complications, resource utilization, and cost from day -14 to 90 days after transplantation.
Overall, surgery-related complications and resource utilization were increased in the ABO-incompatible group, primarily due to the desensitization protocol and antibody-mediated rejection. In the absence of rejection, the mean number of complications was similar for both groups. ABO-incompatible kidney transplantation was approximately 38,000 US dollars more expensive than ABO-compatible transplants, but was cost effective when compared to maintaining the patient on dialysis while waiting for a blood group compatible deceased donor kidney. Actuarial graft and patient survival was similar in the two groups.
We conclude that ABO-incompatible living donor kidney transplantation is a viable option for patients whose only donor is blood group incompatible despite the additional resource utilization and cost of therapy.
Transplantation 08/2006; 82(2):155-63. · 4.00 Impact Factor
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Stephen C. Textor,
Sandra J. Taler,
Nancy Driscoll,
Timothy S. Larson, James Gloor,
Matthew Griffin,
Fernando Cosio,
Thomas Schwab,
Mikel Prieto,
Scott Nyberg,
Michael Ishitani,
Mark Stegall
Transplantation 06/2005; 79(12):1769-1770. · 4.00 Impact Factor
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James Gloor
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ABSTRACT: Individuals who have developed anti-HLA class I and II antibodies are said to be immunized or sensitized. High levels of donor specific anti-HLA antibodies present at the time of transplantation frequently result in early allograft loss due to humoral rejection. Lower levels of donor specific anti-HLA antibodies (DSA) are also associated with poor outcome. Technological advances in tissue typing permit the detection of low levels of DSA not seen with standard cytotoxicity cross-match tests. These tests which previously were used to screen patients to avoid transplantation of donor-immunized patients are now being used to stratify patients based on their degree of donor alloreactivity. New protocols have been developed which permit successful transplantation despite the presence of DSA. These protocols utilize intravenous immunoglobulin infusions prior to transplantation, either alone or in combination with plasmapheresis to block or remove DSA. Using these protocols many persons previously considered essentially nontransplantable are now able to successfully receive transplants. Improved recognition of the clinicopathological characteristics of humoral rejection have allowed earlier diagnosis and treatment of antibody-mediated allograft injury and improved the outcome. Although these advances have improved the outlook for highly immunized kidney transplant candidates, more study is needed to delineate the optimal approach to transplantation in this population.
Contributions to nephrology 02/2005; 146:11-21. · 1.49 Impact Factor
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Stephen C Textor,
Sandra J Taler,
Nancy Driscoll,
Timothy S Larson, James Gloor,
Matthew Griffin,
Fernando Cosio,
Thomas Schwab,
Mikel Prieto,
Scott Nyberg,
Michael Ishitani,
Mark Stegall
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ABSTRACT: Rising numbers of patients reaching end-stage kidney disease intensify the demand for expansion of the living-kidney-donor pool. On the basis of low risk in white donors with essential hypertension, our transplant center undertook a structured program of accepting hypertensive donors if kidney function and urine protein were normal. This study reports outcomes of hypertensive donors 1 year after kidney donation.
We studied detailed measurements of blood pressure (oscillometric, hypertensive therapy nurse [RN], and ambulatory blood pressure monitoring [ABPM]), clinical, and renal characteristics (iothalamate glomerular filtration rate [GFR], urine protein, and microalbumin) in 148 living kidney donors before and 6 to 12 months after nephrectomy. Twenty-four were hypertensive (awake ABPM>135/85 mm Hg and clinic/RN BP>140/90 mm Hg) before donation.
After 282 days, normotensive donors had no change in awake ABPM pressure (pre 121 +/- 1/75 +/- 2 vs. post 120 +/- 1/ 5 +/- 1 mm Hg), whereas BP in hypertensive donors fell with both nonpharmacologic and drug therapy (pre 142 +/- 3/85 +/- 2 to post 132 +/- 2/80 +/- 1 mm Hg, P<.01). Hypertensive donors were older (53.4 vs. 41.4 years, P<.001) and had lower GFR after kidney donation (61 +/- 2 vs. 68 +/- 1 mL/min/1.73m, P<.01). After correction for age, no independent BP effect was evident for predicting GFR either before or after nephrectomy. Urine protein and microalbumin did not change in either group after donor nephrectomy.
Our results indicate that white subjects with moderate, essential hypertension and normal kidney function have no adverse effects regarding blood pressure, GFR, or urinary protein excretion during the first year after living kidney donation. Although further studies are essential to confirm long-term safety, these data suggest that selected hypertensive patients may be accepted for living kidney donation.
Transplantation 07/2004; 78(2):276-82. · 4.00 Impact Factor
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ABSTRACT: With more patients reaching end-stage renal disease, the demand for living kidney donation is increasing rapidly. Many potential donors are now in older age groups. The effects of increasing BP with age and the measurement criteria for hypertension in this group are not well defined. A total of 238 potential donors between 18 and 72 yr of age were prospectively studied, with a comparison of "clinic" BP values measured in the outpatient clinic with an oscillometric recorder (Dinamap; Critikon), ambulatory BP monitoring (ABPM) findings, and standardized BP values determined by nurses using American Heart Association criteria. Renal function was evaluated on the basis of iothalamate clearance (GFR) and urinary protein and microalbumin excretion. Ninety-six percent of subjects were Caucasian. All subjects exhibited normal GFR and urinary protein excretion. Three age groups were defined (group I, </=35 yr, n = 64; group II, 36 to 49 yr, n = 109; group III, >/= 50 yr, n = 65). BP increased with age, as determined with all methods. Subjects >/= 50 yr of age exhibited the highest clinic readings (145 +/- 2/83 +/- 1 mmHg, compared with 129 +/- 2/76 +/- 1 mmHg for group I, P < 0.01). Awake ABPM and nurse-determined BP measurements were lower than clinic readings, including those for group III (131 +/- 2/80 +/- 1 mmHg, compared with 145 +/- 2/83 +/- 1 mmHg in the clinic, P < 0.001). With the use of systolic BP values of >140 mmHg and/or diastolic BP values of >90 mmHg, 36.7% of subjects were initially considered hypertensive; this proportion decreased to 11% overall with awake ABPM findings (>135/85 mmHg). Measurement variability (SD in ABPM) and the effects of misclassification were greatest for donors >/= 50 yr of age. Multivariate regression indicated that GFR of both donors and recipients decreased with age, but regression identified no independent effect of BP. Recipient outcomes for up to 2 yr were equally good for donor kidneys considered normotensive or hypertensive on the basis of clinic BP measurements. These data indicate that higher arterial BP with age can lead to misclassification of many older living kidney donors. Sixty-two subjects with excellent kidney function were misclassified as hypertensive with clinic oscillometric measurements alone. Detailed evaluations of ABPM findings, GFR, and urinary protein levels are warranted for Caucasian subjects with high clinic BP readings who are otherwise suitable potential donors.
Journal of the American Society of Nephrology 08/2003; 14(8):2159-67. · 9.66 Impact Factor
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Mark D Stegall,
Timothy S Larson,
Mikel Prieto, James Gloor,
Stephen Textor,
Scott Nyberg,
Sylvester Sterioff,
Michael Ishitani,
Matthew Griffin,
Thomas Schwab, [......],
Fernando Cosio,
Yogish Kudva,
Deborah Dicke-Henslin,
Michelle Kreps,
Lynette Fix,
Cherise Bauer,
Mary Murphy,
Kay Kosberg,
Deborah Tarara,
Jorge Velosa
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ABSTRACT: With the established benefits of living-donor kidney transplantation, our primary emphasis at Mayo Clinic, Rochester has been to develop protocols that allow living donation to occur even in the presence of relatively unusual or generally contraindicated situations. This approach has significantly increased the number of patients receiving kidney transplants in the past few years. Our protocols for extended criteria donors and recipients along with the exclusive use of laparoscopic donor nephrectomy have been major contributors to the increase in volume. ABO-incompatible and positive-crossmatch living-donor kidney transplant protocols also have increased the availability of transplants for our patients. Protocol biopsies have aided in the diagnosis of subclinical rejection, polyoma virus and chronic allograft nephropathy. Innovative immunosuppressive protocols such as calcineurin inhibitor-free immunosuppression have decreased rejection and improved both short and long-term renal allograft survival.
Clinical transplants 02/2002;
