Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes

The effect of low titers of donor-specific antibodies (DSAs) detected only by sensitive solid-phase assays (SPAs) on renal transplant outcomes is unclear. We report the results of a systematic review and meta-analysis of rejection rates and graft outcomes for renal transplant recipients with such preformed DSAs, defined by positive results on SPA but negative complement-dependent cytotoxicity and flow cytometry crossmatch results. Our search identified seven retrospective cohort studies comprising a total of 1119 patients, including 145 with isolated DSA-SPA. Together, these studies suggest that the presence of DSA-SPA, despite a negative flow cytometry crossmatch result, nearly doubles the risk for antibody-mediated rejection (relative risk [RR], 1.98; 95% confidence interval [CI], 1.36–2.89; P<0.001) and increases the risk for graft failure by 76% (RR, 1.76; 95% CI, 1.13–2.74; P=0.01). These results suggest that donor selection should consider the presence of antibodies in the recipient, identified by the SPA, even in the presence of a negative flow cytometry crossmatch result.

---

Página original: http://jasn.asnjournals.org/cgi/content/short/23/12/2061?rss=1

Association of HLA Mismatch With Death With a Functioning Graft A...

Association of HLA Mismatch With Death With a Functioning Graft After Kidney Transplantation: A Collaborative Transplant Study Report

Authors: Opelz, G.; Döhler, B.

Source: American Journal of Transplantation, Volume 12, Number 11, 1 November 2012 , pp. 3031-3038(8)

Abstract:

HLA mismatches may correlate with risk of death with a functioning graft (DWFG) because of requirement for higher immunosuppression doses and more antirejection therapy. Deceased-donor kidney transplants (n = 177 584) performed 1990-2009 and reported to the Collaborative Transplant Study were analyzed. The incidence of DWFG was found to be 4.8% during year 1 posttransplant and 7.7% during years 2-5 (Kaplan-Meier estimates). Most frequent causes of DWFG were infection, cardiovascular disease and malignancy (32.2%, 30.9% and 3.6% in year 1; 16.4%, 29.6% and 15.9% in years 2-5). HLA-A + B + DR mismatches were significantly associated with DWFG during year 1 (p < 0.001), a correlation that diminished but persisted during years 2-5 (p < 0.001). HLA mismatch was associated with DWFG because of infection (p < 0.001 during year 1, p = 0.043 during years 2-5) or cardiovascular disease (p < 0.001 during year 1, p = 0.030 during years 2-5) but not malignancy. There was also a significant association between HLA mismatch and hospitalization for viral (p < 0.001) or bacterial (p = 0.002) infection. Multivariable analysis showed that mismatches for HLA class II were more strongly associated with both hospitalization and DWFG than mismatches for HLA class I.

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1600-6143.2012.04226.x

Affiliations: 1: Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany

Página original: http://www.ingentaconnect.com/content/mksg/ajt/2012/00000012/00000011/art00021

Increased Urinary CCL2: Cr Ratio at 6 Months is Associated With Late Renal Allograft Loss

Background: Early noninvasive markers that identify patients at risk of renal allograft loss may stratify patients for more intensive monitoring or therapy. CCL2 is a CCR2 receptor chemokine that is a chemoattractant protein for monocytes/macrophages, T cells, and natural killer cells. We have previously demonstrated in a multicenter cohort that urinary CCL2 at 6 months is an independent predictor for the development of IFTA at 24 months. The goal of this study was to determine if early urinary CCL2 is a predictor of graft loss in an independent patient cohort. Methods: A prospective, observational cohort study was conducted in the Transplant Manitoba Adult Kidney Program (n=231 patients) from 1997 to 2008. Six-month urinary CCL2 was measured by ELISA, corrected for urinary creatinine, and correlated with long-term graft outcomes. Results: Urine CCL2: Cr at 6 months was significantly associated with death-censored graft loss (HR, 2.42; 95% CI, 1.54-3.82, P<0.0001). On multivariate analysis, urinary CCL2: Cr at 6 months remained an independent predictor of death-censored graft loss (HR, 2.20; 95% CI, 1.18-4.10, P=0.01) after adjustment for pretransplant/de novo donor-specific antibody and delayed graft function. An early posttransplant (<=6 months) multivariate model of CCL2, recipient age, and delayed graft function yielded an AUC 0.87 for prediction of death-censored graft loss. A cutoff value of urinary CCL2: Cr 34.8 ng/mmol yielded a strong positive predictive value of 0.96. Conclusions: This study confirms in an independent prospective cohort that early urinary CCL2 at 6 months is a noninvasive, independent predictor for late renal allograft loss. (C) 2012 Lippincott Williams & Wilkins, Inc.

---

Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Increased_Urinary_CCL2___Cr_Ratio_at_6_Months_is.98797.pdf

Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD , SD ) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, ) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; ); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

---

Página original: http://www.hindawi.com/journals/jtran/2012/941640/

Cinacalcet for the Treatment of Hyperparathyroidism in Kidney Transplant Recipients: A Systematic Review and Meta-analysis

Background: Hyperparathyroidism is present in up to 50% of transplant recipients 1 year after transplant, often despite good graft function. Posttransplant patients frequently have hypercalcemia-associated hyperparathyroidism, limiting the role of vitamin D analogues and sometimes requiring parathyroidectomy. Multiple observational studies have investigated treatment of posttransplant hyperparathyroidism with the calcimimetic agent cinacalcet. Methods: We performed a systematic review and meta-analysis of prospective and retrospective studies from 2004 through January 26, 2012, using MEDLINE. We identified studies evaluating treatment with cinacalcet in renal transplant recipients with hyperparathyroidism. We performed random effects meta-analysis to determine changes in calcium, phosphorus, parathyroid hormone, and serum creatinine. Results: Twenty-one studies with 411 kidney transplant recipients treated with cinacalcet for hyperparathyroidism met inclusion criteria. Patients were treated for 3 to 24 months. By meta-analysis, calcium decreased by 1.14 mg/dL (95% confidence interval, −1.00 to −1.28), phosphorus increased by 0.46 mg/dL (95% confidence interval, 0.28–0.64), parathyroid hormone decreased by 102 pg/mL (95% confidence interval, −69 to −134), and there was no significant change in creatinine (0.02 mg/dL decrease; 95% confidence interval, −0.09 to 0.06). Cinacalcet resulted in hypocalcemia in seven patients. The most common side effect was gastrointestinal intolerance. Conclusions: From nonrandomized studies, cinacalcet appears to be safe and effective for the treatment of posttransplant hyperparathyroidism. Larger observational studies and randomized controlled trials, performed over longer follow-up times and looking at clinical outcomes, are needed to corroborate these findings.

---

Página original: http://journals.lww.com/transplantjournal/Fulltext/2012/11270/Cinacalcet_for_the_Treatment_of.10.aspx

Posttransplant Malignancies in Solid Organ Adult Recipients: An Analysis of the U.S. National Transplant Database

Background: De novo posttransplant malignancy (PTM) is a serious complication of transplantation. Incidences may vary among solid organ transplantations (SOTs) and may take to particular screening recommendations and posttransplantation care. Methods: Adult recipients, from the U.S. Organ Procurement Transplant Network/United Network for Organ Sharing database (data as of September 3, 2010), of a primary kidney transplantation (KT), liver transplantation (LT), heart transplantation (HT) or lung transplantation (LuT) performed in the United States between 1999 and 2008 were selected. Multiple-organ recipients and those whose grafts failed within 2 weeks after transplantation were excluded. The incidence of PTM (in 1000 person-years) was estimated using the Kaplan-Meier product-limit method and compared with SOT and the general population. Results: The cohort included 193,905 recipients (123,380 KT; 43,106 LT; 16511 HT; and 10,908 LuT). PTM incidence was 8.03, 11.0, 14.3, and 19.8 in KT, LT, HT, and LuT, respectively. In general, PTM recipients were 3 to 5 years older, mostly whites, and are males in all SOTs. In KT, the type of cancer with the highest incidence was posttransplant lymphoproliferative disorder (PTLD, 1.58%), followed by lung (1.12%), prostate (0.82%), and kidney (0.79%) cancers; in LT, PTLD (2.44%), lung and bronchial (2.18%), primary hepatic (0.91%), and prostate (0.88%) cancers; in HT, lung and bronchial (3.24%) and prostate (3.07%) cancers, and PTLD (2.24%); and in LuT, lung and bronchial cancers (5.94%), PTLD (5.72%), and colorectal cancer (1.38%). PTLD, Kaposi sarcoma, and lung and bronchial cancers were increased in all SOTs, when compared with an older (55- to 59-year-old) population. Conclusions: Cancer incidence is different among solid organ transplantations, and ratios may be higher than those in the 55- to 59-year-old population.

---

Página original: http://journals.lww.com/transplantjournal/Fulltext/2012/11270/Posttransplant_Malignancies_in_Solid_Organ_Adult.3.aspx